Compositions and methods for preventing stress-induced fear, depression-like and anxiety-like behaviors

Abstract

The present disclosure relates to methods and compositions that can prevent and protect against all three types of stress-induced maladaptive behaviors: fear, depression-like behavior, and anxiety-like behavior, thereby preventing a wide variety of stress-induced fear, anxiety, and depressive disorders. In some embodiments, the compositions and methods use ketamine, a ketamine analog, or a pharmaceutically acceptable salt, derivative, or metabolite thereof, a glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist, or a α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) agonist in combination with a serotonin 4 receptor (5-hydroxytryptamine (serotonin) receptor 4 or 5-HT4R) agonist. In certain embodiments, one or more of the compositions can be administered before a stressor. In certain embodiments, one or more of the compositions can be administered after a stressor.

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims priority based on U.S. Provisional Patent Application No. 63 / 006,594, filed on April 7, 2020, the entire content of which is incorporated herein by reference.

[0002] Field The present disclosure relates to methods and compositions that can prevent and protect against all three types of stress - induced maladaptive behaviors of fear, depressive - like behaviors, and anxiety - like behaviors, and thus prevent a wide variety of stress - induced fear, anxiety disorders, and depressive disorders. In some aspects, the compositions and methods use a serotonin 4 receptor (5 - hydroxytryptamine (serotonin) receptor 4, or 5 - HT4R) agonist in combination with ketamine, a ketamine analog, or a pharmaceutically acceptable salt, derivative or metabolite thereof, an antagonist of the N - methyl - D - aspartic acid (NMDA) receptor (NMDAR), or an agonist of the α - amino - 3 - hydroxy - 5 - methyl - 4 - isoxazolepropionic acid (AMPA) receptor (AMPAR). In certain aspects, one or more of the present compositions can be administered before exposure to a stressor. In certain aspects, one or more of the present compositions can be administered after exposure to a stressor.

Background Art

[0003] Background Exposure to stress is a major risk factor for mood and anxiety disorders, including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Therapeutic interventions for stress can prevent the onset of mood and anxiety disorders, thereby reducing the associated healthcare burden. These mental illnesses represent a significant global health challenge, affecting 20-30% of adults in the United States alone (NIMH, 2019). The current paradigm for treating these disorders is to alleviate symptoms with medication or treatment after the disorder has already developed. However, this approach can be inefficient, costly, and ineffective in up to one-third of patients (Fava and Davidson, 1996). Therefore, enhancing resilience to stress to prevent these disorders before they develop is an innovative approach to significantly reduce the global burden of mood and anxiety disorders.

[0004] Previously, the inventors found that a single injection of (R,S)-ketamine prior to stress exposure could prevent stress-related depressive-like behavior and reduce learned fear in male mice, but not anxiety-like behavior (Brachman et al., 2016, and McGowan et al., 2017). These results have been replicated in both sexes and in rats (Mastrodonato et al., 2018, Amat et al., 2016, and Dolzani et al., 2018).

[0005] Furthermore, the inventors previously demonstrated that three different serotonin receptor type 4 (5-HT4R) agonists exhibit preventive efficacy (Chen et al., 2020). RS-67,333 reduces learned fear and prevents anxiety-like behavior in male mice, but does not protect against depressive-like behavior. Purcalopride and PF-04995274 reduce learned fear and prevent depressive-like behavior in male mice, but do not alter stress-induced anxiety-like behavior. In addition, RS-67,333 can protect against anxiety-like behavior in female mice, but does not reduce learned fear and does not affect depressive-like behavior. Currently, there are no established medications administered to patients before stress exposure to prevent stress-related emotional deficits. Previous disclosures have shown that ((R,S)-ketamine, (2R,6R)-HNK, and 5-HT4R agonists protect against various combinations of fear, depressive-like behaviors, and anxiety-like behaviors, but that single doses are not preventive against all three types of behaviors. Therefore, an improved protocol is needed to prevent all three types of stress-related behaviors in both sexes. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Fava and Davidson. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996; 19(2):179-200. [Non-Patent Document 2] Brachman et al. Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior. Biological psychiatry 2016; 79(9):776-786. [Non-Patent Document 3] McGowan et al. Prophylactic ketamine attenuates learned fear. Neuropsychopharmacology. 2017; 42(8):1577-89. [Non-Patent Document 4] Mastrodonato et al. Ventral CA3 activation mediates prophylactic ketamine efficacy against stress-induced depressive-like behavior. Biol. Psychiatry 2018; 84:846-56. [Non-Patent Document 5] Amat et al. Previous ketamine produces an enduring blockade of neurochemical and behavioral effects of uncontrollable stress. J Neurosci. 2016;36:153-61. [Non-Patent Document 6] Dolzani et al. Inhibition of a descending prefrontal circuit prevents ketamine-induced stress resilience in females. eNeuro. 2018;5:pii: ENEURO.0025-18.2018. [Non-Patent Document 7] Chen et al. Prophylactic efficacy of 5-HT4R agonists against stress. Neuropsychopharmacology 2020; 45:542-52. [Overview of the Initiative] [Means for solving the problem]

[0007] Abstract This specification discloses compositions and methods that prevent and protect against all three types of stress-induced maladaptive behaviors—fear, depressive-like behaviors, and anxiety-like behaviors—and differ from previous compositions and methods that did not protect against all three with a single dose. These compositions and methods can be used, but are not limited to, to prevent a wide variety of stress-induced fear, anxiety, and depressive disorders, including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD).

[0008] In addition to reducing the burden of the disease, the disclosed compositions and methods can significantly reduce the financial costs associated with treating and managing the symptoms of stress-related mental disorders. Using these compositions and methods, novel compounds with stronger and longer-lasting efficacy against stress can be developed.

[0009] In one embodiment, the Disclosure provides a method for preventing or delaying stress-induced emotional disorder or stress-induced psychopathology in subjects where prevention or delay of stress-induced emotional disorder or stress-induced psychopathology is required. The method involves administering to a subject in an effective amount of one or more of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist), or a pharmaceutically acceptable salt, analogue, derivative or metabolite thereof, and ketamine, a ketamine analog, or a pharmaceutically acceptable salt, derivative or metabolite thereof, prior to exposure to a stressor.

[0010] This disclosure also provides a method for inducing and / or enhancing stress resilience in subjects for whom it is necessary to induce and / or enhance stress resilience. The method involves administering to a subject in an effective amount of one or more compositions comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist), or a pharmaceutically acceptable salt, analogue, derivative or metabolite thereof, and ketamine, a ketamine analog, or a pharmaceutically acceptable salt, derivative or metabolite thereof, prior to exposure to a stressor.

[0011] The disclosure further provides a method for preventing or delaying stress-induced emotional disorder or stress-induced psychopathology in subjects where prevention or delay of stress-induced emotional disorder or stress-induced psychopathology is required, by administering to the subject in an effective amount of one or more of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist) or a pharmaceutically acceptable salt, analogue, derivative or metabolite thereof and a glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist, prior to a stressor.

[0012] This disclosure also provides a method for inducing and / or enhancing stress resilience in subjects for whom it is necessary to induce and / or enhance stress resilience. This method may involve administering to a subject in an effective amount of one or more of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist) or a pharmaceutically acceptable salt, analogue, derivative or metabolite thereof and a glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist prior to a stressor.

[0013] Furthermore, the present disclosure provides a method for preventing or delaying stress-induced emotional disorder or stress-induced psychopathology in subjects where prevention or delay of stress-induced emotional disorder or stress-induced psychopathology is required, by administering to the subject in an effective amount of one or more of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist) or a pharmaceutically acceptable salt, analog, derivative or metabolite thereof, and an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) agonist, prior to a stressor.

[0014] This disclosure also provides a method for inducing and / or enhancing stress resilience in subjects for whom it is necessary to induce and / or enhance stress resilience. The method may include administering to a subject in an effective amount of one or more of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist), or a pharmaceutically acceptable salt, analogue, derivative or metabolite thereof, and an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) agonist, prior to the stressor.

[0015] In the above embodiment, administration of a 5-HT4R activator or agonist in combination with ketamine, a ketamine analog or a pharmaceutically acceptable salt, derivative or metabolite thereof, or either an NMDAR antagonist or an AMPAR agonist prevents all three types of stress-induced maladaptive behaviors: fear, depressive behavior, and anxiety-like behavior.

[0016] Therefore, the present disclosure also provides a method for preventing, delaying or reducing three types of stress-induced maladaptive behaviors: fear, depressive-like behavior, and anxiety-like behavior. The method includes administering to a subject, prior to a stressor, an effective amount of 1 or more compositions comprising an activator of serotonin 4 receptor (5-HT4R) (e.g., an agonist of serotonin 4 receptor (5-HT4R)), or a pharmaceutically acceptable salt, analog, derivative or metabolite thereof, and ketamine, a ketamine analog, or a pharmaceutically acceptable salt, derivative or metabolite thereof.

[0017] The present disclosure further provides a method for preventing, delaying or reducing three types of stress-induced maladaptive behaviors, fear, depressive-like behavior, and anxiety-like behavior, which includes administering to a subject, prior to a stressor, an effective amount of 1 or more compositions comprising an activator of serotonin 4 receptor (5-HT4R) (e.g., an agonist of serotonin 4 receptor (5-HT4R)), or a pharmaceutically acceptable salt, analog, derivative or metabolite thereof, and an antagonist of N-methyl-D-aspartic acid (NMDA) receptor (NMDAR).

[0018] The present disclosure also provides a method for preventing, delaying or reducing three types of stress-induced maladaptive behaviors, fear, depressive-like behavior, and anxiety-like behavior, which includes administering to a subject, prior to a stressor, an effective amount of 1 or more compositions comprising an activator of serotonin 4 receptor (5-HT4R) (e.g., an agonist of serotonin 4 receptor (5-HT4R)), or a pharmaceutically acceptable salt, analog, derivative or metabolite thereof, and an agonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR).

[0019] In a further aspect, the present disclosure provides a method of preventing or delaying stress-induced mood disorder or stress-induced psychopathology in a subject in which prevention or delay of stress-induced mood disorder or stress-induced psychopathology is needed. The method comprises administering to the subject, after exposure to a stressor, an effective amount of one or more compositions comprising an activator of serotonin 4 receptor (5-HT4R) (e.g., an agonist of serotonin 4 receptor (5-HT4R)), or a pharmaceutically acceptable salt, analog, derivative or metabolite thereof, and ketamine, a ketamine analog, or a pharmaceutically acceptable salt, derivative or metabolite thereof.

[0020] The present disclosure also provides a method for inducing and / or enhancing stress resilience in a subject in which induction and / or enhancement of stress resilience is needed. The method comprises administering to the subject, after exposure to a stressor, an effective amount of one or more compositions comprising an activator of serotonin 4 receptor (5-HT4R) (e.g., an agonist of serotonin 4 receptor (5-HT4R)), or a pharmaceutically acceptable salt, analog, derivative or metabolite thereof, and ketamine, a ketamine analog, or a pharmaceutically acceptable salt, derivative or metabolite thereof.

[0021] The present disclosure further provides a method for preventing or delaying stress-induced mood disorder or stress-induced psychopathology in a subject in which prevention or delay of stress-induced mood disorder or stress-induced psychopathology is needed, by administering to the subject, after exposure to a stressor, an effective amount of one or more compositions comprising an activator of serotonin 4 receptor (5-HT4R) (e.g., an agonist of serotonin 4 receptor (5-HT4R)), or a pharmaceutically acceptable salt, analog, derivative or metabolite thereof, and an antagonist of N-methyl-D-aspartic acid (NMDA) receptor (NMDAR).

[0022] This disclosure also provides a method for inducing and / or enhancing stress resilience in subjects for whom it is necessary to induce and / or enhance stress resilience. This method may include administering to a subject, after exposure to a stressor, one or more effective amounts of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist) or a pharmaceutically acceptable salt, analogue, derivative or metabolite thereof, and a glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist.

[0023] Furthermore, the present disclosure provides a method for preventing or delaying stress-induced emotional disorder or stress-induced psychopathology in subjects where prevention or delay of stress-induced emotional disorder or stress-induced psychopathology is required, by administering to the subject in an effective amount of one or more of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist) or a pharmaceutically acceptable salt, analog, derivative or metabolite thereof, and an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) agonist, after exposure to a stressor.

[0024] This disclosure also provides a method for inducing and / or enhancing stress resilience in subjects for whom it is necessary to induce and / or enhance stress resilience. The method may include administering to a subject, after exposure to a stressor, one or more effective amounts of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist), or a pharmaceutically acceptable salt, analogue, derivative or metabolite thereof, and an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) agonist.

[0025] In a further embodiment, the Disclosure provides a method for preventing, delaying, or reducing three types of stress-induced maladaptive behaviors, namely fear, depressive behavior, and anxiety-like behavior, comprising administering to a subject, after exposure to a stressor, one or more effective amounts of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist) or a pharmaceutically acceptable salt, analogue, derivative, or metabolite thereof, and ketamine, a ketamine analog, or a pharmaceutically acceptable salt, analogue, or metabolite thereof.

[0026] The disclosure further provides a method for preventing, delaying, or reducing three types of stress-induced maladaptive behaviors: fear, depressive-like behaviors, and anxiety-like behaviors, comprising administering to a subject after exposure to a stressor one or more effective amounts of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist) or a pharmaceutically acceptable salt, analogue, derivative or metabolite thereof, and a glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist.

[0027] The disclosure also provides a method for preventing, delaying, or reducing three types of stress-induced maladaptive behaviors, namely fear, depressive-like behavior, and anxiety-like behavior, comprising administering to a subject after exposure to a stressor one or more effective amounts of a composition comprising a serotonin 4 receptor (5-HT4R) activator (e.g., a serotonin 4 receptor (5-HT4R) agonist) or a pharmaceutically acceptable salt, analogue, derivative, or metabolite thereof, and an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) agonist.

[0028] In some embodiments, the HT4R activator or agonist and ketamine, ketamine analogs, or pharmaceutically acceptable salts, derivatives, or metabolites thereof, NMDAR antagonists, or AMPAR agonists are in the same composition. In some embodiments, the HT4R agonist or activator and ketamine, ketamine analogs, or pharmaceutically acceptable salts, derivatives, or metabolites thereof, NMDAR antagonists, or AMPAR agonists are in different compositions. In these embodiments, the compositions can be administered simultaneously or sequentially.

[0029] Examples of activators or agonists for 5-HT4R include, but are not limited to, 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1(n-butyl)-4-piperidinyl]-1-propanone HCl (RS-67,333 or RS67333), 4-amino-5-chloro-2,3-dihydro-N-[1-3-methoxypropyl)-4-piperidinyl]-7-benzofrancarboxamide monohydrochloride (Purcalopride), 4-[4-[4-tetrahydrofuran-3-yloxy)-benzo[d]isoxazole-3-yloxymethyl]-piperidine-1-ylmethyl]-tetrahydropyran-4-ol (PF-04995274), or combinations thereof.

[0030] In some embodiments, the Disclosure provides a method for preventing or delaying stress-induced emotional disorder or stress-induced psychopathology in subjects where prevention or delay of stress-induced emotional disorder or stress-induced psychopathology is required, by administering to a subject an effective amount of one or more of a composition comprising precalopride or a pharmaceutically acceptable salt, analogue, derivative or metabolite thereof and ketamine, a ketamine analogue, or a pharmaceutically acceptable salt, derivative or metabolite thereof, either before or after exposure to a stressor.

[0031] The disclosure also provides a method for inducing and / or enhancing stress resilience in subjects where it is necessary to induce and / or enhance stress resilience, by administering to the subject in an effective amount of one or more compositions comprising precalopride or a pharmaceutically acceptable salt, analogue, derivative or metabolite thereof, and ketamine, a ketamine analogue, or a pharmaceutically acceptable salt, derivative or metabolite thereof, either before or after exposure to a stressor.

[0032] This disclosure also provides a method for preventing, delaying, or reducing three types of stress-induced maladaptive behaviors: fear, depressive behavior, and anxiety-like behavior. The method involves administering to a subject an effective amount of one or more of a composition comprising precalopride or a pharmaceutically acceptable salt, analogue, derivative, or metabolite thereof and ketamine, a ketamine analog, or a pharmaceutically acceptable salt, derivative, or metabolite thereof, before or after exposure to a stressor.

[0033] In some embodiments, prucalopride and ketamine, ketamine analogs, or pharmaceutically acceptable salts, derivatives, or metabolites thereof are in the same composition. In some embodiments, prucalopride and ketamine, ketamine analogs, or pharmaceutically acceptable salts, derivatives, or metabolites thereof are in different compositions. In these embodiments, the compositions can be administered simultaneously or sequentially.

[0034] One or more of the compositions are administered to the subject approximately 48 hours to approximately 3 weeks before the stressor. In certain embodiments, one or more of the compositions are administered to the subject approximately 72 hours to approximately 2 weeks before the stressor. In certain embodiments, one or more of the compositions are administered to the subject approximately 1 week before the stressor.

[0035] In certain embodiments, one or more of the compositions are administered to the subject once prior to the stressor.

[0036] One or more of the compositions are administered to the subject approximately 1 hour to 1 week after exposure to the stressor. In certain embodiments, one or more of the compositions are administered to the subject approximately 12 hours to 2 weeks after exposure to the stressor. In certain embodiments, one or more of the compositions are administered to the subject approximately 1 day after exposure to the stressor.

[0037] In certain embodiments, one or more of the compositions are administered to a subject once after exposure to a stressor.

[0038] In certain embodiments, one or more of the compositions are administered in a series of boosters.

[0039] In certain embodiments, one or more of the compositions are administered at least once before the stressor and at least once after the stressor.

[0040] In certain embodiments, one or more of the compositions are administered to a subject orally, intravenously, intranasally, or by injection.

[0041] Stress-induced affective disorders that can be prevented or delayed by the compositions and methods of this disclosure include, but are not limited to, major depressive disorder (MDD) and / or post-traumatic stress disorder (PTSD). In certain embodiments, stress-induced affective disorders are selected from the group consisting of depressive behaviors and associated affective disorders, anhedonic behaviors and associated affective disorders, anxiety and associated affective disorders, cognitive impairments and deficits and associated disorders, stress-induced phobias, and combinations thereof.

[0042] In further embodiments, stress-induced affective disorder includes stress-induced psychopathology. In specific embodiments, stress-induced psychopathology includes depression and / or anxiety behavior.

[0043] This method may further include administering an effective dose of an antidepressant, anxiolytic, or a combination thereof to the target.

[0044] This method may further include administering an effective dose of a selective serotonin reuptake inhibitor (SSRI) or a pharmaceutically acceptable salt or derivative thereof.

[0045] This method may further include administering an effective amount of fluoxetine, paroxetine, sertraline, lithium, riluzole, prazosin, lamotrigine, ifenprodil, or a combination thereof.

[0046] The subject may be a mammal. In some embodiments, the subject is a human. The subject may be female or male. [Brief explanation of the drawing]

[0047] For the purpose of illustrating the present invention, specific embodiments of the present invention are shown in the drawings. However, the present invention is not limited to the detailed arrangement and means of the embodiments shown in the drawings.

[0048] [Figure 1A]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1B]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1C]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1D]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1E]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1F]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1G]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1H]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1I]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1J]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1K]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1L]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram). [Figure 1M]The combination of (R,S)-ketamine and prcalopride protects male 129S6 / SvEv mice from stress. Figure 1A shows the experimental design. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and persistence. Figure 1B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 1C shows mean freezing at re-exposure in all groups of mice. Mice administered (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg) showed reduced freezing compared to the control group administered with physiological saline. Figure 1D shows the immobility time on day 1 of the fast-paced training (FST), indicating that all groups showed similar immobility times. Figure 1E shows the immobility time on day 2 of the FST, showing that (R,S)-ketamine (30 mg / kg), prcalopride (1.5 and 3 mg / kg), and (R,S)-ketamine + prcalopride (10 + 3 mg / kg, 10 + 10 mg / kg, and 30 + 10 mg / kg) reduced immobility times compared to mice administered with physiological saline. Figure 1F is a graph of the distance traveled during the open field (OF). Mice in all groups traveled similar distances. Figure 1G is a graph showing the time spent in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 1H is a graph showing the time spent in the open arm of the EPM. Mice in all groups spent a similar amount of time in the open arm of the EPM. Figure 1I is a graph showing the number of times mice entered the open arm of the EPM. (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) increased the number of times mice entered the open arm of the EPM compared to saline. Figure 1J is a graph showing the percentage of non-feeding mice versus feeding latency (in seconds) in OF. Figure 1K is a graph showing the feeding latency (in seconds) in OF for all mouse groups.Figures 1J and 1K show that (R,S)-ketamine + prukalopride (10+3 mg / kg) protected against stress-induced appetite loss in the NSF paradigm. Figure 1L is a graph showing feeding latency in seconds in the home cage for all mouse groups. Figure 1M is a graph showing weight loss in each mouse group. Figures 1L and 1M show that none of the administered drugs altered feeding latency in the home cage or weight loss in the NSF (n=5-15 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeter), no (number), sec (second), mg (milligram), kg (kilogram), g (gram).

[0049] [Figure 2A]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2B]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2C]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2D]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2E]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2F]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2G]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2H]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2I]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2J]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2K]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2L]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams). [Figure 2M]The combination of (R,S)-ketamine and prcalopride protects female 129S6 / SvEv mice from stress. Figure 2A shows the experimental design. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine, prcalopride, or a combination of prcalopride and (R,S)-ketamine in different dose combinations one week prior to CFC stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, behavioral despair, and fixation behavior. Figure 2B is a graph showing that mean freezing was similar across all groups during CFC training. Figure 2C shows that mean freezing was similar at re-exposure in all groups of mice. Figure 2D shows the immobility time on day 1 of FST. Figure 2E shows the immobility time on day 2 of FST. Figures 2D and 2E show that on days 1 and 2 of the FST, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time compared to the saline control. Figure 2F is a graph of movement distance in the OF. No drugs were assayed for altered behavior in the OF. Figure 2G is a graph showing time in the center of the EPM. Mice in all groups spent a similar amount of time in the center of the EPM. Figure 2H is a graph showing time in the open arm of the EPM. Figure 2I is a graph of entry into the open arm of the EPM. Figures 2H and 2I show that prcalopride (3 mg / kg) increased time in the open arm and entry into the open arm of the EPM compared to the saline control. Figure 2J is a graph of feeding latency (in seconds) in the proportion of non-feeding mice versus OF. Figure 2K is a graph of feeding latency (in seconds) in OF for all mouse groups. Figures 2J and 2K show that (R,S)-ketamine + prukalopride (10 + 1.5 mg / kg) prevented stress-induced appetite loss in the NSF paradigm (n=4-10 female mice / group). Figure 2L is a graph showing feeding latency (in seconds) in HC for all mouse groups. Figure 2M is a graph of weight loss for each mouse group.Figures 2L and 2M show that none of the administered drugs altered feeding latency in the home cage or weight loss in NSF (n=6-12 male mice / group). Error bars represent ±SEM. *p<0.05, **p<0.01, ***p<0.0001. Sal (saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), HC (home cage), cm (centimeters), no (numbers), sec (seconds), mg (milligrams), kg (kilograms), g (grams).

[0050] [Figure 3A]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3B]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3C]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3D]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3E]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3F]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3G]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3H]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3I]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3J]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3K]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3L]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3M]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3N]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3O]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram). [Figure 3P]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in male 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 3A shows the behavioral paradigm. Male 129S6 / SvEv mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 3 mg / kg) 5 minutes after CFC stress. Figure 3B is a graph showing that freezing was similar in all mice during CFC training. Figure 3C is a bar graph showing freezing during CFC re-exposure. Figure 3C shows that the combination of (R,S)-ketamine + prcalopride (10 + 3 mg / kg) significantly reduced freezing during CFC re-exposure. Figure 3D is a graph of immobility on day 1 of FST. On day 1 of the FST, behavior was similar across all groups. Figure 3E is a graph of immobility on day 2 of the FST. Figure 3E shows that the combination of (R,S)-ketamine (30 mg / kg) and (R,S)-ketamine + prukalopride (10 + 3 mg / kg) significantly reduced behavioral despair compared to the saline control. Figure 3F is a graph of total distance traveled in the OF. Figure 3G is a graph showing time spent in the center of the EPM. Figure 3H is a graph showing distance traveled in the center of the EPM. Figure 3I is a graph showing time spent in the open arm and center of the EPM. Figure 3J is a graph showing the number of times entering the open arm and center of the EPM. Figure 3K is a graph showing time spent in the closed arm of the EPM. Figure 3L is a graph showing the number of times entering the closed arm of the EPM. Figure 3M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF. Figure 3N is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 3O is a graph of feeding latency (in seconds) in HC for all mouse groups. Figure 3P is a graph of weight loss in each mouse group. Figures 3F to 3P show that behavior was similar across all OF, EPM, and NSF groups. Error bars represent ±SEM. *p<0.05, **p<0.01.CFC (contextual fear conditioning), Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), min (minute), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding suppression), mg (milligram), kg (kilogram), sec (second), cm (centimeter), m (meter), no (number), HC (home cage), g (gram).

[0051] [Figure 4A]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4B]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4C]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4D]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4E]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4F]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4G]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4H]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4I]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4J]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4K]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4L]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4M]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4N]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4O]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams). [Figure 4P]The combination of (R,S)-ketamine and prcalopride, when administered immediately after stress in female 129S6 / SvEv mice, reduced learned fear and behavioral despair. Figure 4A shows the behavioral paradigm. Female 129S6 / SvEv mice were administered saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or a combined dose of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) 5 minutes after CFC stress. Figure 4B is a graph showing that freezing was similar in all mice during CFC training. Figure 4C is a graph showing freezing during CFC re-exposure, which was similar in all mice during CFC re-exposure. Figure 4D is a graph of immobility on day 1 of FST. Figure 4D shows that the combination of (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg) significantly reduced immobility time on day 1 of the FST. Figure 4E is a graph of immobility on day 2 of the FST. Figure 4E shows that the combination of (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced behavioral despair compared to a saline control. Figure 4F is a graph of the distance traveled in the OF. Figure 4G is a graph showing the time spent in the center of the EPM. Figure 4H is a graph showing the distance traveled in the center of the EPM. Figure 4I is a graph showing the time spent in the open arm and center of the EPM. Figure 4J is a graph showing the number of entries into the open arm and center of the EPM. Figure 4K is a graph showing the time spent in the closed arm of the EPM. Figure 4L is a graph showing the number of times mice entered the closed arm in the EPM group. Figures 4F to 4L show that the behavior was similar across all groups in the OF and EPM groups. Figure 4M is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in the OF group. Figure 4N is a graph of feeding latency (in seconds) in the OF group for all mouse groups. Figures 4M and 4N show that the combination of (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite suppression in the NSF group. Figure 4O is a graph showing feeding latency (in seconds) in the HC group for all mouse groups.Figure 4P shows graphs of weight loss in each mouse group. Error bars represent ±SEM. *p<0.05, **p<0.01. CFC (Contextual Fear Conditioning), Sal (Saline), K ((R,S)-Ketamine), P (Pulcalopride), min (minute), FST (Forced Swim Test), OF (Open Field), EPM (Elevated Cross Maze), NSF (Novel Environment Feeding Suppression), mg (Milligrams), kg (Kilograms), sec (Seconds), cm (Centimeters), m (Meters), no (Numbers), HC (Home Cage), g (Grams).

[0052] [Figure 5A]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5B]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5C]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5D]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5E]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5F]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5G]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5H]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5I]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5J]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5K]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5L]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram). [Figure 5M]Prophylactic administration of (R,S)-ketamine and prcalopride suppresses appetite loss in female C57BL / 6 mice. Figure 5A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one week prior to CFC stress. Figure 5B is a graph showing that freezing was similar in all mice during CFC training. Figure 5C is a graph showing freezing during CFC re-exposure. Figure 5C shows that compared to mice administered saline, the level of freezing was significantly increased in mice administered (R,S)-ketamine (10 mg / kg) or (R,S)-ketamine and prcalopride (10 + 1.5 mg / kg). Figure 5D is a graph of immobility on day 1 of FST. Figure 5E is a graph of immobility on day 2 of the FST. None of the tested drugs altered the immobility time during the FST. Figure 5F is a line graph of the distance traveled in the OF. Figure 5G is a graph showing the time spent in the center of the EPM. Figure 5H is a graph showing the time spent in the open arm and center of the EPM. Figure 5I is a graph showing the number of times entered into the open arm and center of the EPM. Figures 5F to 5I were similar across all groups in the OF and EPM. Figure 5J is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the OF. Figure 5K is a graph of feeding latency (in seconds) in the OF for all mouse groups. Figure 5L is a graph of the percentage of unfeeding mice versus feeding latency (in seconds) in the HC. Figure 5M is a graph of uneaten feed. Figures 5J to 5M show that (R,S)-ketamine (10 mg / kg) and (R,S)-ketamine and prukalopride (10 + 1.5 mg / kg) suppressed appetite loss in NSF, but did not alter feeding latency or weight loss in the home cage. Error bars represent +SEM. *p<0.05, **p<0.01.Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), CFC (contextual fear conditioning), FST (forced swim test), OF (open field), EPM (elevated cross maze), NSF (novel environment feeding inhibition), min (minute), sec (second), mg (milligram), kg (kilogram), cm (centimeter), no (number), HC (home cage), g (gram).

[0053] [Figure 6A] The combination of (R,S)-ketamine and prcalopride did not alter behavioral despair in stress-free male 129S6 / SvEv mice. Figure 6A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before day 1 of the fasting regimen (FST). Figure 6B is a graph of immobility on day 1 of the FST. Figure 6C is a graph of immobility on day 2 of the FST. Immobility time was similar in all groups on days 1 and 2 of the FST. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), hr (hour), FST (forced swimming test), sec (second), min (minute), mg (milligram), kg (kilogram). [Figure 6B] The combination of (R,S)-ketamine and prcalopride did not alter behavioral despair in stress-free male 129S6 / SvEv mice. Figure 6A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before day 1 of the fasting regimen (FST). Figure 6B is a graph of immobility on day 1 of the FST. Figure 6C is a graph of immobility on day 2 of the FST. Immobility time was similar in all groups on days 1 and 2 of the FST. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), hr (hour), FST (forced swimming test), sec (second), min (minute), mg (milligram), kg (kilogram). [Figure 6C] The combination of (R,S)-ketamine and prcalopride did not alter behavioral despair in stress-free male 129S6 / SvEv mice. Figure 6A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before day 1 of the fasting regimen (FST). Figure 6B is a graph of immobility on day 1 of the FST. Figure 6C is a graph of immobility on day 2 of the FST. Immobility time was similar in all groups on days 1 and 2 of the FST. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), hr (hour), FST (forced swimming test), sec (second), min (minute), mg (milligram), kg (kilogram).

[0054] [Figure 7A] The combination of (R,S)-ketamine and prcalopride did not alter behavioral despair in stress-free female 129S6 / SvEv mice. Figure 7A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before day 1 of the fasting regimen (FST). Figure 7B is a graph of immobility on day 1 of the FST. Figure 7C is a graph of immobility on day 2 of the FST. Immobility time was similar in all groups on days 1 and 2 of the FST. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), hr (hour), FST (forced swimming test), sec (second), min (minute), mg (milligram), kg (kilogram). [Figure 7B]The combination of (R,S)-ketamine and prcalopride did not alter behavioral despair in stress-free female 129S6 / SvEv mice. Figure 7A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before day 1 of the fasting regimen (FST). Figure 7B is a graph of immobility on day 1 of the FST. Figure 7C is a graph of immobility on day 2 of the FST. Immobility time was similar in all groups on days 1 and 2 of the FST. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), hr (hour), FST (forced swimming test), sec (second), min (minute), mg (milligram), kg (kilogram). [Figure 7C] The combination of (R,S)-ketamine and prcalopride did not alter behavioral despair in stress-free female 129S6 / SvEv mice. Figure 7A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before day 1 of the fasting regimen (FST). Figure 7B is a graph of immobility on day 1 of the FST. Figure 7C is a graph of immobility on day 2 of the FST. Immobility time was similar in all groups on days 1 and 2 of the FST. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), hr (hour), FST (forced swimming test), sec (second), min (minute), mg (milligram), kg (kilogram).

[0055] [Figure 8A]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8B]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8C]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8D]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8E]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8F]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8G]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8H]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8I]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8J]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8K]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8L]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 8M]The combination of (R,S)-ketamine and prcalopride does not alter the fixation behavior of stress-free male 129S6 / SvEv mice. Figure 8A shows the behavioral paradigm. Mice were administered saline, (R,S)-ketamine (30 mg / kg), prcalopride (3 mg / kg), or (R,S)-ketamine + prcalopride (10 + 3 mg / kg) one hour before the OF. Figure 8B is a graph showing the distance traveled per minute in the OF. Figure 8C is a graph showing the total distance traveled in the OF. Figure 8D is a graph showing the time in the center of the EPM. Figure 8E is a graph showing the time in the open arm of the EPM. Figure 8F is a graph showing the number of times entering the open arm of the EPM. Figure 8G is a graph showing the number of times the glass bead was covered. Figures 8B to 8G show that the behavior was similar across all groups in the OF, EPM, and MB assays. Figure 8H is a graph of feeding latency in OF compared to the percentage of non-feeding mice. Figure 8I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 8J is a graph of weight loss. Figure 8K is a graph of feeding latency in HC compared to the percentage of non-feeding mice. Figure 8L is a graph of feeding latency (in seconds) in HC compared to the percentage of non-feeding mice for all mouse groups. Figure 8M is a graph of uneaten feed. Figures 8H to 8M show that behavior in NSF was not significantly altered by any of the drugs assayed. Error bars represent ±SEM. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), EPM (elevated cross maze), MB (glass bead hiding), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage).

[0056] [Figure 9A]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9B]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9C]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9D]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9E]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9F]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9G]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9H]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9I]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9J]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9K]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9L]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Figure 9M]The combination of (R,S)-ketamine and prcalopride reduces fixation motility in stress-free female 129S6 / SvEv mice. Figure 9A shows the behavioral paradigm. Mice were administered either saline, (R,S)-ketamine (10 mg / kg), prcalopride (1.5 mg / kg), or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) one hour before OF. Figure 9B is a graph showing the distance traveled per minute during OF. Figure 9C is a graph showing the total distance traveled during OF. Figures 9B and 9C show that prcalopride (1.5 mg / kg) significantly increased the distance traveled during OF compared to the saline control. Figure 9D is a graph showing the time spent in the center of the EPM. The time spent in the center of OF was similar in all groups. Figure 9E is a graph showing the time spent in the open arms of the EPM. Figure 9F is a graph showing the number of times mice entered the open arm in the EPM. Figures 9E and 9F show that the tested drugs did not alter behavior in the EPM. Figure 9G is a graph showing the number of glass bead cover-ups. Mice given prcalopride (1.5 mg / kg) or (R,S)-ketamine + prcalopride (10 + 1.5 mg / kg) significantly reduced the number of glass bead cover-ups in the MB assay. Figure 9H is a graph of the percentage of non-feeding mice versus feeding latency in OF. Figure 9I is a graph of feeding latency (in seconds) in OF for all mouse groups. Figure 9J is a graph of weight loss. Figure 9K is a graph of the percentage of non-feeding mice versus feeding latency in HC. Figure 9L is a graph of the percentage of non-feeding mice versus feeding latency (in seconds) in HC for all mouse groups. Figure 9M is a graph of uneaten food. Figures 9H to 9M show that behavior was similar across all groups. Error bars represent ±SEM. *p<0.05. Sal (physiological saline), K ((R,S)-ketamine), P (prucalopride), h (hour), OF (open field), MB (glass bead hiding), EPM (elevated cross maze), NSF (novel environment feeding suppression), cm (centimeters), min (minutes), mg (milligrams), kg (kilograms), sec (seconds), no (numbers), g (grams), HC (home cage). [Modes for carrying out the invention]

[0057] Detailed explanation definition The terms used herein generally have their common meanings in the art within the context of the present invention and in the specific context in which each term is used. Certain terms are described below or elsewhere in this specification to provide additional guidance to practitioners when describing the methods of the present invention and their uses. Furthermore, it will be understood that the same thing may be stated in multiple ways. Accordingly, other terms and synonyms may be used for any one or more terms discussed herein, and there is no special significance in whether a term is described or explained in detail herein. Synonyms are provided for certain terms. The listing of one or more synonyms does not preclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any terms discussed herein, is illustrative only and does not limit in any way the scope and meaning of the present invention or any exemplified terms. Similarly, the present invention is not limited to its preferred embodiments.

[0058] As used in this application, the term “subject” means mammals. Mammals include dogs, cats, rodents, cattle, horses, pigs, sheep, and primates. Accordingly, the compositions and methods disclosed herein can be used in veterinary medicines, for example, to treat companion animals, livestock, zoo laboratory animals, and wild animals. This disclosure is particularly desirable for human medical applications.

[0059] As used in this application, the term “patient” means a human subject. In some embodiments of this disclosure, the patient has been, will be, is expected to be, or is at risk of being exposed to stress. In some embodiments, the patient has, or is at risk of having, stress-induced phobia, anxiety, and / or depressive disorder.

[0060] The terms “therapeutic effective dose,” “effective dose,” “therapeutic effective size,” or “effective size” are used herein to mean an amount sufficient to cause a clinically significant improvement in a subject, or sufficient to delay, minimize, or alleviate one or more symptoms associated with a disease or disorder, or sufficient to produce a desired beneficial physiological change in a subject.

[0061] Terms such as "to treat" or "treatment" refer to means of slowing, mitigating, improving or alleviating at least one symptom of a disease or disorder, or improving the condition after the onset of the disease or disorder.

[0062] Terms such as "prevent" and "prevention" refer to acting before the onset of an obvious disease or disability to prevent the onset of the disease or disability, minimize its severity, or delay its progression.

[0063] The term “needs it” refers to an individual who has been exposed to stress, will be exposed to stress, is expected to be exposed to stress, or is at risk of being exposed to stress. In some embodiments, an individual “needs it” because they have or are at risk of having stress-induced fear, anxiety, and / or depressive disorder.

[0064] As used herein, the term “agent” means a substance that has an effect or can have an effect, and includes, but is not limited to, chemical substances, pharmaceuticals, biologics, small organic molecules, antibodies, nucleic acids, peptides, and proteins.

[0065] As used herein, “adverse effect” refers to an undesirable reaction caused by the administration of a drug.

[0066] The term “pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt, solvate, prodrug, e.g., ester or other precursor of a compound that, when administered to a recipient, can yield (directly or indirectly) an active compound or its active metabolite or residue. Such salts include pharmaceutically acceptable basic or acid addition salts, as well as pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. Such derivatives can be known without excessive experimentation by those skilled in the art. Derivatives are described, for example, in Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Vol. 1: Principles and Practice, which is incorporated herein by reference. In certain embodiments, pharmaceutically acceptable derivatives include salts, solvates, esters, carbamates, and phosphate esters.

[0067] Unless otherwise indicated, all numbers representing quantities of components, properties, etc., used in this disclosure and the associated claims should be understood in all cases to be modified by the term “about.” Therefore, unless otherwise indicated, the numerical parameters described in this disclosure and the associated claims are approximations that may vary depending on the desired properties to be obtained by the embodiments of the present invention. The terms “about” or “approximately” mean within an acceptable margin of error of a particular value as determined by those skilled in the art, which depends, in part, on how the value is measured or determined, i.e., on the limitations of the measurement system, i.e., the degree of precision required for a particular purpose, such as a pharmaceutical formulation. For example, “about” may mean within or above one standard deviation, according to convention in the art. Alternatively, “about” may mean within 20%, preferably 10%, more preferably 5%, and more preferably even further 1% of a given value. Or, particularly with respect to biological systems or processes, the term may mean within one order of magnitude of a given value, preferably within five times, and more preferably within two times. Where a specific value is stated in this application and claims, unless otherwise specified, the term “approximately” should be understood to mean within an acceptable margin of error for that specific value.

[0068] Abbreviation CFC (Contextual Fear Conditioning) FST Compulsory Swimming Test OF Open Field EPM Elevated Plus Maze NSF (Non-Science Physiology) - Novel Environment Feeding Restriction HC housing cage MB Glass Ball Concealer

[0069] Combination administration of two different activators or compounds as an intervention for stress-related phobias, depressive-like behaviors, and anxiety-like behaviors. This disclosure describes the use of combined administration of two different compounds or activators, a 5-HT4R agonist and ketamine, a ketamine analogue or a pharmaceutically acceptable salt, derivative, or metabolite thereof, an NMDAR antagonist, or an AMPAR agonist, as an intervention for stress-related behaviors. At various dosages, this combination effectively protects against stress-related fear, depressive-like behaviors, and anxiety-like behaviors, respectively. While behavioral interventions can be achieved by administering these compounds or activators in the form of one or more compositions, this disclosure also provides a basis for novel compounds that integrate the functional structures of both compounds or activators. Thus, this disclosure presents pharmacological interventions for stress-related mood and anxiety disorders.

[0070] Stress is a major risk factor for mood and anxiety disorders. However, currently there are no preventive medications that intervene in stress to prevent the development of mental health disorders such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). To address this problem, male 129S6 / SvEv mice were administered combination doses of prcalopride and (R,S)-ketamine in different dosage combinations one week prior to contextual fear conditioning (CFC) stress. Five days later, the mice were re-exposed to the training environment and then assayed for fear, depressive-like behaviors, and anxiety-like behaviors using forced swim tests (FST), open field (OF), elevated cross maze (EPM), and novelty environment feeding suppression (NSF). Prucalopride + (R,S)-ketamine reduced learned fear. Purcalopride plus (R,S)-ketamine protected against depressive behaviors in fast-tempered patients (FST) and novelty-induced hypovolemia, i.e., anxiety, in non-stimulant facilitative (NSF). In particular, the combination of purcalopride and (R,S)-ketamine reduced anxiety, as demonstrated by a reduction in hypovolemia, where neither drug alone was effective. Furthermore, it allowed for the administration of smaller doses of ketamine, achieving the same effect when used in combination with purcalopride, and in some cases, even reducing the amount of ketamine by a third.

[0071] The same protocol used in two separate female mouse strains showed the same results, including the reduction of anxiety, as indicated by a reduction in appetite, when neither drug alone was effective.

[0072] The effects of administering different combination doses of prcalopride and (R,S)-ketamine to male mice 5 minutes after CFC stress are also described herein. Five days later, the mice were re-exposed to the training environment and then assayed for fear, depressive behavior, and anxiety-like behavior using the Forced Swim Test (FST), Open Field (OF), Elevated Cross Maze (EPM), and Novel Environment Feeding Restriction (NSF). prcalopride + (R,S)-ketamine reduced learned fear. prcalopride + (R,S)-ketamine reduced behavioral despair. In particular, the combination of prcalopride and (R,S)-ketamine reduced fear where neither drug alone had an effect. Furthermore, smaller doses of ketamine could be administered, achieving the same effect when used in combination with prcalopride, and in some cases, one-third less ketamine could be administered.

[0073] The same protocol used in female 129S6 / SvEv mice showed the same results, including that the combination of prukalopride and (R,S)-ketamine reduced learned fear and behavioral despair. This combination also reduced anxiety, as indicated by a reduction in appetite, where neither drug alone was effective.

[0074] These results demonstrate that the combination of prcalopride, a 5-HT4R agonist, and (R,S)-ketamine is dose-specifically preventive against all three stress-induced behaviors, regardless of whether it is administered before or after stress exposure.

[0075] Finally, this specification shows that co-administration of prukalopride and (R,S)-ketamine to female mice not exposed to stressors reduced persistent behavior.

[0076] This compound, active substance, or composition can be administered via various routes, including oral, intravenous (iv or IV), intranasal (in or IN), intramuscular (im or IM), caudal, intrathecal, and subcutaneous (sc) routes.

[0077] 5-HT4R activator or agonist Serotonin 4 receptors (5-HT4Rs) are G protein-coupled receptors (GPCRs) that activate G protein G and stimulate the cAMP / PKA signaling pathway, leading to phosphorylation of cAMP response element-binding protein (CREB), and consequently, the expression of several genes involved in neuroplasticity (Vidal et al., 2014). The majority of 5-HT4Rs are expressed in the brains of primates and rodents, specifically in mesospinous neurons of the striatum, Ammon's horns of the hippocampus (Cornu Ammonis 1 (CA1) and CA3), granule cells of the dentate gyrus, and glutamatergic neurons of the cortex and amygdala (Rebholz et al., 2018). Furthermore, 5-HT4Rs are also found in the hypothalamus, ventral globus pallidus, olfactory bulb, septal area, and substantia nigra. Mice lacking 5-HT4R exhibit anhedonia and situation-dependent anxiety-like behavior (Amigo et al., 2016), and various 5-HT4R agonists can exert antidepressant and anxiolytic-like activity (Samuels et al., 2016).

[0078] In both humans and rodents, 5-HT4 expression is found in the limbic regions (mPFC, HPC, and NAc). The basal ganglia, i.e., the caudate nucleus and lentiform nuclei (putamen and globus pallidus), the substantia nigra, and the amygdala also express 5-HT4 receptors. 5-HT4 receptors are expressed at the somatic cell dendrite level, as well as at the axonal terminals of efferent spinal GABAergic neurons in the striatum, CA1 and CA3 in the hippocampus, granule cells in the dentate gyrus, and glutamatergic neurons in the cortex, hippocampus, and amygdala.

[0079] 5-HT4 receptors are also found at peripheral levels, particularly at the cardiac level where their activation exerts a positive inotropic effect, at the gastrointestinal level involved in bowel motility, at the adrenal gland level which plays a role in corticosterone secretion, and at the bladder level which triggers smooth muscle contraction.

[0080] The 5-HT4 receptor has seven transmembrane domains. The N-terminal region faces the extracellular environment, while the C-terminal domain binds to Gs proteins and faces the cytoplasm. For example, activation of the 5-HT4 receptor by an agonist can lead to the recruitment of Gs proteins that stimulate adenylyl cyclase (AC), which is responsible for cAMP production. Protein kinase A (PKA), which is activated by cAMP, modulates various ionic currents, particularly potassium currents, and its inhibition leads to neuronal hyperexcitability. PKA can also phosphorylate proteins that bind response elements to cAMP (CREB-cAMP response element-binding proteins), thereby increasing the transcription of brain-derived neurotrophic factors (BDNF), which are involved in cognition, mood, and cell survival.

[0081] The term "agonist" may refer to a substance, drug, or compound that can bind to and activate one or more receptors, such as 5-HT4R. The term "agonist" may refer to a compound that has the ability to initiate or enhance the biological function of a target protein (e.g., one or more receptors, such as 5-HT4R), whether by enhancing or initiating the activity or expression of the target protein. A 5-HT4R agonist may be a compound that activates the action of the 5-HT4 receptor. The term "agonist" may be defined in relation to the biological role of the target protein. In one embodiment, an agonist is a drug that binds to a receptor (e.g., 5-HT4R) and activates the receptor to produce a biological response. While agonists provided herein may specifically interact with (e.g., bind to) a target protein, compounds that initiate or enhance the biological activity of a target protein by interacting with other members of a signaling pathway to which the target protein is a member are also included, strictly speaking, in this definition. A 5-HT4R agonist may be a compound or drug that activates the action of 5-HT4R. A 5-HT4R agonist can be any agent that exerts a pharmacological effect by acting directly or indirectly on or via 5-HT4R. The terms “5-HT4R agonist,” “5-HT4 receptor agonist,” “5-HT4 receptor agonist,” and “5-HT4R agonist” are used interchangeably herein.

[0082] 5-HT4R agonists may be selective or non-selective for 5-HT4 receptors and may exhibit agonist or antagonist activity at other serotonin receptors. In one embodiment, 5-HT4R agonists are selective for 5-HT4 receptors.

[0083] 5-HT4R agonists may include complete agonists, partial agonists, or mixed 5-HT4R agonists / antagonists.

[0084] A "full agonist" may refer to a substance that binds to and activates a receptor in the maximum response that the agonist can induce at the receptor. Depending on the relative number of receptors and differences in receptor coupling, a drug may act as a full agonist in some tissues and as a partial agonist in others.

[0085] A "partial agonist" may refer to a compound that can bind to and activate a given receptor, but has only a partial effect on the receptor compared to a "full agonist" or a full agonist. A partial agonist may act as an antagonist if it competes with a full agonist for receptor occupancy and results in a net decrease in receptor activation compared to the effect or activation observed with a full agonist alone. A partial agonist may refer to a mixed agonist / antagonist that differentially affects receptor function within different dose ranges. For example, a partial agonist may function as an agonist at low doses and as an antagonist at high doses. A partial agonist may have a lower effect (typically 40-80%) on inducing changes in receptor conformation compared to a full agonist, and may induce an agonist effect at low doses but an antagonist effect at high doses.

[0086] The 5-HT4R agonist may be indole, benzamide, benzoate, arylketone, or benzamide.

[0087] Non-limiting examples of 5-HT4R agonists include 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1(n-butyl)-4-piperidinyl]-1-propanone HCl (RS-67,333 or RS67333), 4-amino-5-chloro-2,3-dihydro-N-[1-3-methoxypropyl)-4-piperidinyl]-7-benzofrancarboxamide monohydrochloride (Purcalopride), 4-[4-[4-tetrahydrofuran-3-yloxy)-benzo[d]isoxazole-3-yloxymethyl]-piperidine-1-ylmethyl]-tetrahydropyran-4-ol (PF-04995274), and combinations thereof.

[0088] Non-limiting examples of 5-HT4R agonists also include 2-[1-(4-piperonyl)piperazinyl]benzothiazole (PPB), 5-methoxytryptamine, PRX-03140, cisapride ((±)-cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate), BIMU-8 (2,3-dihydro-N-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octa-3-yl]-3-(1-methyleth (L)-2-oxo-1H-benzimidazole-1-carboxamide, RS67506 (methylsulfonylamino)ethyl-4-piperidinyl]-1-propanone hydrochloride), mosapride (4-amino-5-chloro-2-ethoxy-N-[[4-[(4-fluorophenyl)methyl]-2-morpholinyl]methyl]benzamide citrate), tegacerod (2-[(5-methoxy-1H-indole-3-yl)methylene]-N-pentyl-hydrazine carboxyimidoamide maleate), ML10302 (4-amino-5-chloro-2- 2-(1-piperidinyl)ethyl methoxybenzoate hydrochloride), Bercetrag (TD-5108) (N-[(1R,3R,5S)-8-[(2R)-2-hydroxy-3-(N-methylmethanesulfonamide)propyl]-8-azabicyclo[3.2.1]octane-3-yl]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-carboxamide), Nalopride (ATI-7505) ([(3R)-1-azabicyclo[2.2.2]octane-3-yl]6-[(3S,4R)-4-[(4-amino-5 -Chloro-2-methoxybenzoyl)amino]-3-methoxypiperidine-1-yl]hexanoate, sinitaprid (4-amino-N-[1-(cyclohexa-3-en-1-ylmethyl)piperidine-4-yl]-2-ethoxy-5-nitrobenzamide), metoclopramide (4-amino-5-chloro-N-(2-(2-(diethylamino)ethyl)-2-methoxybenzamide), lenzaprid (ATL-1251, BRL24924, (±)-endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]Nona-4-yl)benzamide), RQ-00000010(4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole-3-yl]oxy}methyl)piperidine-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid), SUVN-D4010(1-isopropyl-3-{5-[1,3,4]-oxadiazole-2-yl}-1H-indazole), TD-8954(4-{(4- [(2-isopropyl-1H-benzimidazole-4-carbonyl)amino]methyl}-piperidine-1-ylmethyl)piperidine-1-carboxylate methyl ester), SC53116(4-amino-5-chloro-N-[[(1S,7aS)-hexahydro-1H-pyrrolidine-1-yl]methyl]-2-methoxy-benzamide), BIMU-1(3-ethyl-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]octa) (-3-yl)-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride), donecoprid (MR31147, i.e., 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(cyclohexylmethyl)-4-piperidinyl]propan-1-one), LS650155 (Caeserod, i.e., 5-(8-amino-7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-3-(1-flu Examples include Enethylpiperidine-4-yl)-1,3,4-oxadiazole-2(3H)-one hydrochloride, PF-00885706, N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidine-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-11-yl]-2-oxoethyl]acetamide, and combinations thereof.

[0089] RS-67,333 is a high-affinity 5-HT4R partial agonist (Eglen et al., 1995). This drug is effective in improving behavioral disorders, reducing the number of amyloid plaques and the levels of amyloid-beta (Aβ) species, and reducing hippocampal astrogliosis and microgliosis in a 5xFAD mouse model of Alzheimer's disease (AD) (Giannoni et al., 2013). RS67333 is an aryl ketone. By incorporating an n-butyl group into piperidine, agonist activity was increased, resulting in high efficacy, optimal selectivity, and excellent bioavailability. Its increased hydrophobicity helps it cross the blood-brain barrier and allows for penetration into the brain (Eglen et al., 1995).

[0090] Purcalopride is a selective, high-affinity 5-HT4R agonist (Prins et al., 1999). Purcalopride is a derivative of the benzofuran family that exhibits increased selectivity for the 5-HT4 receptor but no affinity for hERG (human Ether-a-go-go related gene) channels. In 2018, it was approved by the FDA for chronic constipation and is currently being tested for chronic pseudo-obstruction. Purcalopride has also been tested in two separate clinical trials to investigate its effects on emotional processing in healthy volunteers after acute administration (e.g., single dose) or long-term administration (e.g., one week) (Morris et al., 2017; Zanos and Gould, 2018).

[0091] PF-04995274 is a potent partial 5-HT4R agonist (Grimwood et al., 2011). Clinical trials were conducted to evaluate PF-04995274 alone or in combination with donepezil for scopolamine-induced deficits in psychomotor and cognitive function in healthy adults. However, these trials were terminated, not due to safety concerns. Currently, a clinical trial is underway to investigate whether adjunctive administration of PF-04995247 has a positive effect on emotional processing and neuronal activity compared to placebo in patients with mediated treatment-resistant (TRD) depression (Morris et al., 2017).

[0092] The Tegase Rod is a partial agonist for the 5-HT4R, and also for the 5-HT1 (agonist) and 5-HT 2A-C It has moderate affinity for (antagonist) receptors.

[0093] Cisapride is a parasympathetic neurotransmitter that increases the release of acetylcholine into the enteric nervous system by activating 5-HT4R.

[0094] Sinitapride is 5-HT 1A and 5-HT4 receptor agonists, as well as 5-HT 2A It is a benzamide that acts as a receptor antagonist.

[0095] Mosapride is a selective 5-HT4R agonist, and its main active metabolite acts as a 5-HT3 receptor antagonist.

[0096] Metoclopramide is 5-HT4 and 5-HT 3A It is a receptor agonist. It is a D2 receptor antagonist. It is also an M1 muscarinic receptor agonist and an acetylcholinesterase inhibitor.

[0097] SUVN-D4010 is a potent, selective, and effective partial agonist of 5-HT4R with good bioavailability via the oral route.

[0098] Examples of mixed 5-HTR agonists / antagonists include, but are not limited to, buspirone, mianserin, trazodone, and mirtazapine.

[0099] The terms "serotonin," "5-hydroxytryptamine," and "5-HT" refer to phenolic amine neurotransmitters produced from tryptophan by hydroxylation and decarboxylation in serotonergic neurons of the central nervous system and enterochromaffin cells of the gastrointestinal tract. Serotonin is a precursor of melatonin.

[0100] Ketamine Ketamine ((RS)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone) is an antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR). Ketamine also acts on opioid receptors, sigma receptors, muscarinic receptors, and monoamine transporters.

[0101] Ketamine is a chiral compound. As used herein, the term “ketamine” may refer to (S)-ketamine (also called S(+)-ketamine or esketamine), (R)-ketamine (R(-)-ketamine), or a racemic mixture of (S)-ketamine and (R)-ketamine. In certain embodiments, the ketamine composition contains different proportions of S(+) and R(-) stereoisomers. In certain embodiments, the ketamine composition contains only (S)-ketamine or (R)-ketamine, or the ketamine enantiomer is enantiomerically concentrated. In certain embodiments, the ketamine composition is concentrated to contain, for example, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 99%, or more than 99.9% (S)-ketamine or (R)-ketamine. See Paul et al., 2009; Paskalis et al., 2010; Noppers et al., 2011; Matthewst et al., 2012; and International Publication No. 2013 / 138322.

[0102] Ketamine is a derivative of arylcyclohexylamine and contains a chiral center. Since 1950, numerous arylcyclohexylamines have been synthesized, and these compounds exhibit a wide range of possible pharmacological activities. When administered orally, it undergoes first-pass metabolism, where it is stereoselectively metabolized into a diverse range of metabolites, including norketamine, hydroxyketamine, dehydronorketamine, and hydroxynorketamine (HNK). After ketamine administration, (2S,6S)-HNK and (2R,6R)-HNK are the two major HNK metabolites found in plasma and the brain. Interestingly, studies have shown that the (2R,6R)-HNK metabolite is 1) essential for ketamine's antidepressant effect, 2) dependent on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation, and 3) non-hypnotic (Zanos et al., 2016). All of these compounds, including enantiomers and non-psychomimetic metabolites of ketamine, are expected to behave similarly in the manner currently described.

[0103] This disclosure also includes enantiomers and non-psychomimetic metabolites of ketamine. Such compounds include: (2R,6R)-HNK is a metabolite of ketamine that can mediate the antidepressant effect of ketamine and does not have ketamine-related side effects (Zanos et al., 2016). • (2S,6S)-HNK, a metabolite of ketamine (The synthesis of these compounds, (2R,6R)-HNK and (2S,6S)-HNK, is described in Zanos et al., 2016 and International Publication No. 2013 / 056229. Use of dehydrated and hydroxylated metabolites of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomers of (R,S)-ketamine in the treatment of depression and neuropathic pain) • (R)-Ketamine, the R-enantiomer of ketamine, has a rapid onset of action and a sustained antidepressant effect without psychomimetic side effects (Yang et al., 2015). (S)-Ketamine, the S-enantiomer of ketamine, is being developed as an intranasal spray and is currently in Phase III clinical trials for the treatment of treatment-resistant depression.

[0104] Finally, other ketamine analogs are also expected to be protective. Such compounds include the following: Fluorodeschloroketamine, an analogue of ketamine in which the chlorine (Cl) group is replaced with fluorine (F). • Tyretamine, an analogue of ketamine, commonly used as an anesthetic for animals.

[0105] NMDA receptor antagonists - ketamine and other compounds NMDA receptor antagonists are compounds that antagonize or inhibit the action of the NMDA receptor. NMDA receptor antagonists can be competitive antagonists, non-competitive antagonists, and / or glycine antagonists.

[0106] Non-specific examples of NMDA receptor antagonists include ketamine, dextromethorphan (DXM), histogranin, memantine, meperidine, methadone, methoxymethamine (MXE), phencyclidine (PCP), nitrous oxide (N2O), AP5 (APV, R-2-amino-5-phosphonopentanoate), AP7 (2-amino-7-phosphonoheptanoate), and CPPene ((3-[(R)-2-carboxypiper [Zin-4-yl]-propa-2-enyl-1-phosphonic acid, Selfotel, Amantadine, Atomoxetine, AZD6765, Agmatine, Chloroform, Dextralorphan, Dextromethorphan, Dextrolorphan, Diphenidine, Dizosylpine (MK-801), Ethanol, Ethiclidin, Gacyclidine, Ibogaine, Magnesium, Memantine, Nitromemantine, Lolicyclidine, Tenocyclidine Methoxyzine, Chiletamine, Neramexane, Eriprodil, Dexoxadrol, Ethoxadrol, Remasemide, Dersemin, WMS-2539, NEFA, 8A-PDHQ, HU-211, Aptiganel (Cerestat, CNS-1102), Lincophylline, Kynurenic acid, Lapatinel (GLYX-13), NRX-1074, 7-Chloroquinurenic acid, 4-Chloroquinurenin (AV-101), TK-40, 1-A Examples include minocyclopropanecarboxylic acid (ACPC), L-phenylalanine, xenone, or their analogs or derivatives. Ketamine derivatives such as lapastinel or Glyx-13 are also examples. Lapastinel is a partial agonist of the NMDA receptor glycine site. It is an amidated tetrapeptide (Thr-Pro-Pro-Thr-NH2) that rapidly crosses the blood-brain barrier but is not orally active.

[0107] Compounds that are mechanistically similar to ketamine are expected to be protective against stress-induced de novo psychopathology. Examples of such compounds include: Ro25-6981 is a GluN2B-selective antagonist that has been shown to have a rapid antidepressant effect in a rodent model of depression. • CP-101,606, a GluN2B-selective antagonist: A placebo-controlled trial of the NR2B-specific NMDA antagonist CP-101,606 plus paroxetine for treatment-resistant depression (TRD). GLYX-13 is a novel N-methyl-D-aspartate receptor (NMDAR) glycine site functional partial agonist and rapid-acting antidepressant. GLYX-13 received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) in January 2016 for the adjunctive treatment of MDD. • CX546 (Tocris), an ampaquine (AMPA receptor agonist) that reduces fentanyl-induced respiratory depression.

[0108] Non-specific examples of NMDA receptor antagonists include anti-receptor antibodies and anti-ligand antibodies.

[0109] Several synthetic opioids, such as pethidine, methadone, meperidine, dextropropoxifen, tramadol, levorphanol, and ketobemidone, function as NMDA receptor antagonists.

[0110] AMPA receptor agonist AMPA receptor agonists are compounds that activate the action of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Considering the finding that the antidepressant effect of ketamine metabolites in mice is due to sustained activation of AMPA receptors rather than inhibition of NMDARs, compounds that activate AMPA receptors (including metabolites) are expected to have a similar effect to that of ketamine (Zanos et al., 2016).

[0111] Therefore, in certain embodiments, AMPA receptor agonists can be used in the methods described herein. Non-limiting examples of AMPA receptor agonists include glutamate, AMPA, 5-fluorohydrazine, domoic acid, kiscalic acid, (2R,6R)-hydroxynorketamine, and CX546, as well as pharmaceutically acceptable salts, derivatives, or metabolites thereof.

[0112] Pharmaceutical compounds The 5-HT4R agonists, ketamines, NMDAR antagonists, and AMPAR agonists used in this method include all hydrates, solvates, and complexes of the compounds described herein. Where a chiral center or another form of isomeric center is present in the compound, all forms of such one or more isomers, such as enantiomers and diastereomers, are intended to be included herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically concentrated mixture, or the racemic mixture may be separated using known techniques to obtain individual enantiomers individually. The compounds described herein may be in racemic form or in the form of individual enantiomers. Enantiomers can be separated using known techniques, e.g., techniques described in IUPAC (1997) Pure and Applied Chemistry 69:1469-1474. Where the compound has an unsaturated carbon-carbon double bond, both cis (Z) and trans (E) isomers are within the scope of this disclosure. If a compound can exist in tautomeristic forms such as keto-enol tautomers, each tautomeristic form is considered to be included within this disclosure, regardless of whether it exists in equilibrium or primarily in one form.

[0113] Where the structure of a compound used in this disclosure contains a chiral carbon atom, such a compound may exist as a racemate, a racemic mixture, and an isolated single enantiomer. All such isomers of these compounds are expressly included in this disclosure. Each stereocarbon may be in an R or S configuration. It should be understood that isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this disclosure unless otherwise indicated. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, e.g., by the synthesis described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, published by John Wiley & Sons, NY, 1981. For example, resolution can be performed by preparative chromatography using a chiral column.

[0114] This disclosure is also intended to include the use of all isotopes of the atoms present on the compounds disclosed herein. Isotopes include atoms that have the same atomic number but different mass numbers. Isotope-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described herein, using appropriate isotope-labeling reagents instead of the unlabeled reagents used.

[0115] The compounds of this disclosure may be in salt form. As used herein, “salt” refers to a salt of a compound modified by preparing a salt of an acid or base of the compound. For compounds used in the treatment of mammals, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as phenols. Salts can be prepared using organic or inorganic acids. Such acid salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfons, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, and ascorbicates. Phenolates are alkaline earth metal salts, sodium, potassium, or lithium. In this regard, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic and organic acid or base addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or by separately treating the purified compounds of the present invention in the form of free bases or free acids with appropriate organic or inorganic acids or bases and isolating the salts thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate. (See, for example, Berge et al., (1977)''Pharmaceutical Salts'', J.Pharm.Sci.66:1-19).

[0116] This method also involves administering physiologically functional derivatives of the compound. As used herein, the term “physiologically functional derivative” refers to a compound (e.g., a drug precursor) that is converted in vivo to produce the compound or its active metabolites, or pharmaceutically acceptable salts, hydrates, or solvates of the compound. This conversion can occur through various mechanisms (e.g., metabolic or chemical processes), such as hydrolysis in the blood. Prodrugs are such derivatives, and a discussion of the use of prodrugs is presented in T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACS Symposium Series, and in “Bioreversible Carriers in Drug Design,” ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0117] Pharmaceutical composition 5-HT4R agonists, ketamine, ketamine analogs, or pharmaceutically acceptable salts, derivatives, or metabolites thereof, NMDAR antagonists and AMPAR agonists, as well as their salts, solvates, and physiologically functional derivatives, can be administered as raw chemical substances, but their active ingredients can also be presented as pharmaceutical compositions. Accordingly, this disclosure further provides pharmaceutical compositions comprising the agents or compounds of the present invention and / or their salts, solvates, and physiologically functional derivatives, as well as one or more pharmaceutically acceptable carriers, diluents, or excipients. The carriers, diluents, or excipients must be compatible with the other components of the formulation and acceptable in the sense that they are not harmful to the recipient. According to another aspect of this disclosure, a method for preparing a pharmaceutical composition is also provided, comprising mixing the compound or its salts, solvates, and physiologically functional derivatives with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0118] The term "composition" is intended to encompass, in the case of pharmaceutical compositions, any product comprising an active ingredient and an inactive ingredient (pharmaceutically acceptable excipient) constituting a carrier, as well as any product directly or indirectly arising from any combination, complexation, or aggregation of any two or more components, or from the dissociation of one or more components, or from any other type of reaction or interaction of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any composition prepared by mixing one or more compounds with a pharmaceutically acceptable excipient.

[0119] Acceptable excipients, diluents, and carriers for therapeutic use are well known in the pharmaceutical technology field and are described, for example, in Remington: The Science and Practice of Pharmacy. Lippincott Williams & Wilkins (ARGennaro edit. 2005). The selection of pharmaceutical excipients, diluents, and carriers can be made in relation to the intended route of administration and standard pharmacopoeia.

[0120] As used herein, the term “pharmaceutically acceptable” means “generally considered safe,” for example, physiologically tolerable, and typically does not cause allergic or similar adverse reactions, such as stomach upset or dizziness, when administered to humans. Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a federal or state regulatory agency, or described in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more specifically in humans.

[0121] The pharmaceutical compositions of this disclosure may be provided in unit dose forms containing a predetermined amount of the active ingredient per unit dose. Such units may contain, for example, 5 μg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of the compound, depending on the condition being treated, the route of administration, and the patient's age, weight, and symptoms. Thus, such unit doses may be administered more than twice a day. Preferred unit dose compositions contain a daily dose or a partial dose (for administration more than once a day) or an appropriate fraction of the active ingredient, as described above in this specification. Furthermore, such pharmaceutical compositions may be prepared by any method well known in the pharmaceutical field.

[0122] The pharmaceutical compositions of this disclosure can be adapted for administration by any suitable route, e.g., oral (including buccal or sublingual), inhalation, nasal, ocular, or parenteral (including intravenous and intramuscular) routes. The compositions can be injected. Such compositions can be prepared by any method known in the field of pharmacy, for example, by associating an active ingredient with a carrier or excipient.

[0123] In further embodiments, the disclosure provides pharmaceutical compositions suitable for administration via oral route.

[0124] Pharmaceutical compositions of this disclosure suitable for oral administration may be provided as individual units such as capsules or tablets, powders or granules, aqueous or non-aqueous liquid solutions or suspensions, food foams or whips, or oil-in-water or water-in-oil liquid emulsions.

[0125] For example, in the case of oral administration in the form of tablets or capsules, the active drug component can be combined with an orally non-toxic, pharmaceutically acceptable, inert carrier such as ethanol, glycerol, or water. Powders are prepared by grinding the compound to an appropriate fine size and mixing it with a similarly ground pharmaceutical carrier, such as an edible carbohydrate like starch or mannitol. Flavoring agents, preservatives, dispersants, and colorants may also be present.

[0126] Capsules are manufactured by preparing the powder mixture as described above and filling the formed gelatin sheaths with it. Before filling, glossing agents and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol may be added to the powder mixture. Disintegrants or solubilizers such as agar, calcium carbonate, or sodium carbonate may also be added to improve the feel of the medicine when taking the capsule.

[0127] Furthermore, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture as desired or as needed. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth, or sodium alginate), carboxymethylcellulose, polyethylene glycol, and waxes. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum. Tablets are formulated, for example, by preparing a powder mixture, granulating or slag it, adding lubricants and disintegrants, and pressing it into tablets. The powder mixture is prepared by mixing the properly ground compound with the above-mentioned diluent or base, and optionally with a binder such as carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone, a dissolution retarder such as paraffin, an absorption enhancer such as a quaternary salt, and / or an absorbent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as a syrup, starch paste, acacia mucilage, or a solution of cellulose or polymer material, and extruding it through a screen. As an alternative to granulation, the powder mixture can be passed through a tablet press, resulting in the incompletely formed slag being crushed into granules. The granules can be lubricated by adding stearic acid, stearate, talc, or mineral oil to prevent adhesion to the tablet mold. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a flow-inert carrier and compressed directly into tablets without going through a granulation or slag formation process. Transparent or opaque protective coatings can be formed, consisting of shellac sealing coats, sugar or polymer material coatings, and wax polishing coatings. Dyes can be added to these coatings to distinguish between diffe...

Claims

1. One or more compositions for use in the prevention or delay of stress-induced mood disorders or stress-induced psychopathology in a subject, comprising an effective amount of 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrochloride (purcaropride) and (R,S)-ketamine, wherein administration of said one or more compositions prevents or reduces three types of stress-induced maladaptive behaviors, namely, fear, depressive-like behavior, and anxiety-like behavior. One or more compositions characterized thereby.

2. One or more compositions for use in the induction and / or enhancement of stress resilience in a subject, comprising an effective amount of 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrochloride (purcaropride) and (R,S)-ketamine, wherein administration of said one or more compositions prevents or reduces three types of stress-induced maladaptive behaviors, namely, fear, depressive-like behavior, and anxiety-like behavior. One or more compositions characterized thereby.

3. One or more compositions for use in the prevention or delay of stress-induced mood disorders or stress-induced psychopathology in a subject, comprising an effective amount of 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrochloride (purcaropride) and any one of glutamate, AMPA, 5-fluorowillardine, domoic acid, quisqualic acid, (2R,6R)-hydroxynorketamine, and CX546, wherein administration of said one or more compositions prevents or reduces three types of stress-induced maladaptive behaviors, namely, fear, depressive-like behavior, and anxiety-like behavior. One or more compositions characterized thereby.

4. One or more compositions for use in inducing and / or enhancing stress resilience in a subject, comprising an effective amount of 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrochloride (prulcacridin) and any one of glutamate, AMPA, 5-fluorowillardine, domoic acid, quisqualic acid, (2R,6R)-hydroxynorketamine, and CX546, wherein administration of said one or more compositions prevents or reduces three types of stress-induced maladaptive behaviors, namely, fear, depressive-like behavior, and anxiety-like behavior. One or more compositions characterized thereby.

5. The one or more compositions according to any one of claims 1 to 4, wherein the one or more compositions are administered to the subject prior to a stressor.

6. The one or more compositions according to claim 5, wherein the one or more compositions are administered to the subject from 48 hours to 3 weeks prior to a stressor.

7. The one or more compositions according to claim 5, wherein the one or more compositions are administered to the subject from 72 hours to 2 weeks prior to a stressor.

8. The one or more compositions according to claim 5, wherein the one or more compositions are administered to the subject 1 week prior to a stressor.

9. The one or more compositions according to claim 5, wherein the one or more compositions are administered to the subject once prior to a stressor.

10. The one or more compositions according to any one of claims 1 to 9, wherein the one or more compositions are administered to the subject after a stressor.

11. The one or more compositions according to claim 10, wherein the one or more compositions are administered to the subject from 1 hour to 1 day after a stressor.

12. The one or more compositions according to claim 10, wherein the one or more compositions are administered to the subject once after a stressor.

13. The composition of 1 or more than 1 is administered to the subject at least once before a stress factor and then at least once after the stress factor, the composition of 1 or more than 1 according to any one of claims 1 to 4.

14. The composition of 1 or more than 1 is orally administered or intranasally administered to the subject, the composition of 1 or more than 1 according to any one of claims 1 to 13.

15. The stress-induced mood disorder is selected from the group consisting of major depressive disorder and post-traumatic stress disorder (PTSD), the composition of 1 or more than 1 according to any one of claims 1 and 3.

16. The stress-induced mood disorder is selected from the group consisting of stress-induced psychopathology, depressive-like behavior and related mood disorders, anhedonic behavior and related mood disorders, anxiety and related mood disorders, cognitive impairment and deficits and related disorders, stress-induced phobia, and combinations thereof. The composition of 1 or more than 1 according to any one of claims 1 and 3.

17. The stress-induced mood disorder includes stress-induced psychopathology, the composition of 1 or more than 1 according to any one of claims 1 and 3.

18. The subject is a human, the composition of 1 or more than 1 according to any one of claims 1 to 17.

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