Use of ritonavir or a derivative thereof for the manufacture of a medicament for the treatment of a psychotic disorder

Abstract

This application discloses the use of ritonavir or its derivatives in the preparation of medicaments for treating mental disorders. This application also discloses the discovery of mice (AtLAS) with difficulty in extinction of fear memories. ‑ / ‑ Intraperitoneal injection of ritonavir significantly restored the rigidity rate in model mice. Further immunoblotting and co-precipitation confirmed that ritonavir could significantly block the binding of Syn2a and Syngr-3, and promote the formation of VAMP2, Syntaxin, and SNAP25 trimers, thereby promoting the normal release of presynaptic membrane vesicles in neurons and restoring the rigidity rate in mice with refractory rigidity, thus achieving the treatment of mental disorders such as post-traumatic stress disorder.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and in particular to the use of ritonavir or its derivatives in the preparation of medicaments for the treatment of mental disorders. Background Technology

[0002] Post-traumatic stress disorder (PTSD) is a delayed-onset and persistent mental disorder that occurs after an individual experiences, witnesses, or is confronted with one or more events involving actual or threatened death, serious injury, or a threat to physical integrity, either themselves or others. It is a common mental disorder caused by exposure to extreme traumatic events and involves multiple brain circuits mediating stress and fear responses.

[0003] Pavlovian fear conditioning and extinction are widely accepted tools, known as "extinction" learning, that allow healthy individuals to recover to baseline emotional responses upon re-exposure to traumatic memory stimuli. Through numerous preclinical studies, researchers have found that impaired extinction mechanisms after traumatic stress play a crucial role in the development and maintenance of PTSD. Clinically, exposure therapy based on extinction learning mechanisms is widely used to treat PTSD. However, this treatment is only effective for some individuals, partially effective, ineffective, or unavailable for others. Combining medication with psychotherapy is gradually becoming a major research direction, with medication showing significant effects in alleviating symptoms and enhancing psychotherapy. Current techniques often use SSRIs such as sertraline, paroxetine, and fluoxetine; however, these drugs have significant side effects, such as severe gastrointestinal reactions (nausea, vomiting, diarrhea), neurological side effects (drowsiness, dizziness, nightmares), and in some cases, sexual dysfunction.

[0004] Therefore, there is an urgent need in this field to find new methods for treating post-traumatic stress disorder. Summary of the Invention

[0005] The purpose of this invention is to provide a pharmaceutical use for ritonavir or its derivatives.

[0006] Another object of the present invention is to provide a method for treating mental illness.

[0007] To address the aforementioned technical problems, the first aspect of this invention provides the use of ritonavir or its derivatives for:

[0008] (i) Treatment of mental disorders;

[0009] (ii) To prepare drugs for treating mental disorders;

[0010] (iii) Promotes the release of presynaptic vesicles from neurons;

[0011] (iv) Inhibit the formation of the Syn2a-Syngr-3 complex; and / or

[0012] (v) Promotes the formation of the vesicle-associated membrane protein 2 (VAMP2)-syntaxin-25kD synaptosome-associated protein (SNAP25) trimer complex.

[0013] In some preferred embodiments, the mental disorder includes: schizophrenia, affective disorders, stress-related disorders, psychogenic physiological disorders, personality disorders, habit and impulse control disorders, psychosexual disorders, intellectual disability, and behavioral, conduct, or emotional disorders of childhood and adolescence.

[0014] In some preferred embodiments, the schizophrenia includes: paranoid schizophrenia, simple schizophrenia, post-schizophrenic depression, travel-related psychosis, and peripheral psychosis.

[0015] In some preferred embodiments, the affective mental disorders include: mania, dysthymia, bipolar disorder, type I bipolar disorder, type II bipolar disorder, cyclical disorder, and depression.

[0016] In some preferred embodiments, the stress-related disorders include hysterical amnesia, hysterical fugue, hysterical psychosis, hysterical somatic disorders, acute stress disorder, post-traumatic stress disorder, adjustment disorder, phobia, anxiety disorder, and obsessive-compulsive disorder.

[0017] In some preferred embodiments, the psychogenic physiological disorders include anorexia nervosa, bulimia nervosa, insomnia, hypersomnia, sleep-wake rhythm disorder, decreased libido, and vaginismus.

[0018] In some preferred embodiments, the personality disorder includes paranoid personality disorder, schizoid personality disorder, and obsessive-compulsive personality disorder.

[0019] In some preferred embodiments, the habit and impulse control disorder includes pathological gambling, trichotillomania, fetishism, and transvestism.

[0020] In some preferred embodiments, the sexual psychological disorder includes abnormal sexual psychology, sexual perversion, and sexual abnormality.

[0021] In some preferred embodiments, the intellectual disability includes intellectual disability, expressive language disorder, receptive language disorder, specific reading disorder, and childhood autism.

[0022] In some preferred embodiments, the childhood and adolescent behavioral, conduct, or emotional disorders include social conduct disorder, childhood separation anxiety disorder, childhood generalized anxiety disorder, selective mutism, non-organic enuresis, and stuttering.

[0023] In some preferred embodiments, the mental disorder is a stress-related disorder.

[0024] In some preferred embodiments, the ritonavir or its derivatives are used for:

[0025] (i) Treatment of post-traumatic stress disorder; and / or

[0026] (ii) Prepare drugs for treating post-traumatic stress disorder.

[0027] In some preferred embodiments, ritonavir or its derivatives prevent and / or treat mental disorders by inhibiting the formation of the Syn2a-Syngr-3 complex.

[0028] In some preferred embodiments, ritonavir or its derivatives prevent and / or treat mental disorders by promoting the formation of the VAMP2-Syntaxin-SNAP25 trimer complex.

[0029] In some preferred embodiments, ritonavir or its derivatives prevent and / or treat mental disorders by promoting the release of presynaptic membrane vesicles from neurons.

[0030] In some preferred embodiments, ritonavir or its derivatives promote the release of presynaptic membrane vesicles from neurons by promoting the formation of the VAMP2-Syntaxin-SNAP25 trimer complex.

[0031] A second aspect of the present invention provides a method for treating mental disorders, the method comprising the steps of:

[0032] Administer a therapeutically effective dose of ritonavir or its derivatives to the test subjects.

[0033] In some preferred embodiments, ritonavir or its derivatives are administered to the test subject at a dose of 0.1-100 mg / kg.

[0034] In some preferred embodiments, ritonavir or its derivatives are administered to the subject orally or by injection.

[0035] In some preferred embodiments, ritonavir or its derivatives are formulated into tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, or injections and administered to the test subjects.

[0036] Compared with the prior art, the present invention has at least the following advantages:

[0037] This invention unexpectedly discovered mice (AtLAS) that have difficulty fading fear memories. - / -Intraperitoneal injection of ritonavir or its derivatives significantly restored the rigidity rate in model mice. Further immunoblotting and co-precipitation confirmed that ritonavir or its derivatives could significantly block the binding of Syn2a and Syngr-3, and promote the formation of VAMP2, Syntaxin, and SNAP25 trimers, thereby promoting the normal release of presynaptic membrane vesicles in neurons, thus restoring the rigidity rate in mice with refractory rigidity, and achieving the treatment of mental disorders such as stress-related disorders.

[0038] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0039] One or more embodiments are illustrated by way of example with reference to the accompanying drawings, and these illustrative descriptions do not constitute a limitation on the embodiments.

[0040] Figure 1 This is an immunoprecipitation image of HEK 293T cells in which the binding of Syn2a and Syngr3 was disrupted, according to an embodiment of the present invention.

[0041] Figure 2 This is a schematic diagram of the behavioral experiment process of fear memory extinction according to an embodiment of the present invention;

[0042] Figure 3 This is a graph showing the change in the rigidity rate of fear memory expiration in mice according to an embodiment of the present invention;

[0043] Figure 4 This is a statistical chart of the total protein immunoblotting results of Syn2a / b according to an embodiment of the present invention;

[0044] Figure 5 This is a statistical graph of the immunoblotting results after co-precipitation of Syn2a and Syngr3 proteins according to an embodiment of the present invention.

[0045] Figure 6 This is an immunoprecipitation diagram of VAMP2 and Syntaxin, SNAP25 proteins according to an embodiment of the present invention;

[0046] Figure 7 This is a diagram showing the changes in spontaneous excitatory postsynaptic currents in the mouse brain region according to an embodiment of the present invention;

[0047] Figure 8 This is an electron micrograph of a presynaptic membrane vesicle according to an embodiment of the present invention;

[0048] Figure 9 This is a statistical diagram of the number of vesicles on the presynaptic membrane according to an embodiment of the present invention. Detailed Implementation

[0049] Existing drugs have limited efficacy and significant side effects in treating post-traumatic stress disorder (PTSD). In our research, we discovered that ritonavir (RTV), primarily used to treat adult HIV-1 infection, or its derivatives, can effectively block the biological action of synapsin IIa (Syn2a) binding to synaptogyrin-3 (Syngr-3), restoring presynaptic vesicle release to some extent and thus reducing the relapse rate in AtLAS mice. - / - Fear memory in mice (a mouse model of persistent fear memory) is therefore an effective drug for the prevention / treatment of mental disorders, especially stress-related disorders.

[0050] Uses of compounds

[0051] This invention relates to novel uses of ritonavir or its derivatives for: (i) treating mental disorders; (ii) preparing medicaments for treating mental disorders; (iii) promoting the release of presynaptic vesicles from neurons; (iv) inhibiting the formation of the Syn2a-Syngr-3 complex; and / or (v) promoting the formation of the vesicle-associated membrane protein 2 (VAMP2)-syntaxin-25kD synaptosome-associated protein (SNAP25) trimer complex.

[0052] In embodiments of the present invention, ritonavir or its derivatives prevent and / or treat mental disorders by influencing the neurocytosis process. Specifically, during neurocytosis, the body rapidly secretes neurotransmitters or hormones by forming a soluble trimer complex of SNAP-25, syntaxin, and vesicle-associated membrane protein (VAMP). Ritonavir or its derivatives can promote the formation of the VAMP2-Syntaxin-SNAP25 trimer complex, thereby promoting the release of presynaptic vesicles from neurons / restoring the release of presynaptic vesicles from neurons to normal, thus achieving the prevention and / or treatment of mental disorders.

[0053] In embodiments of the present invention, ritonavir or its derivatives can reduce the rigidity rate in mice with difficulty expiration of fear memories (AtLAS- / - mice), preferably reducing the rigidity rate by at least 10%, preferably at least 15%, more preferably at least 20%, and even more preferably at least 25%.

[0054] In embodiments of the present invention, ritonavir or its derivatives prevent and / or treat mental disorders by inhibiting the formation of the Syn2a-Syngr-3 complex.

[0055] In a preferred embodiment of the invention, ritonavir or a derivative thereof is used for: (i) treating stress-related disorders; and / or (ii) preparing a medicament for treating stress-related disorders.

[0056] In a preferred embodiment of the invention, ritonavir or its derivatives are used for: (i) treating post-traumatic stress disorder; and / or (ii) preparing a medicament for treating post-traumatic stress disorder.

[0057] As used in this invention, the term "ritonavir (RTV)" refers to a commercially available, orally effective inhibitor of human immunodeficiency virus-1 (HIV-1) and human immunodeficiency virus-2 (HIV-2) aspartic protease, used to treat HIV-1 infection in adults. The chemical name of ritonavir is (2S,3S,5S)-5-[N-[N-[[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]amino]carbonyl]valine]amino]-2-[N-[(5-thiazolyl)methoxycarbonyl]amino]-1,6-diphenyl-3-hydroxyhexane, CAS number 155213-67-5, and its structural formula is shown in Formula I below.

[0058]

[0059] As used herein, the term "ritonavir derivative" refers to pharmaceutically acceptable salts, isomers, corresponding isomers, prodrugs, and ritonavir analogs of ritonavir. In this invention, the term "ritonavir analog" refers to a series of compounds obtained by pharmaceutically acceptable modifications (e.g., insertion, substitution, deletion of groups) based on ritonavir.

[0060] As used in this invention, the term "mental disorder" refers to a pathological abnormality of the brain characterized by identifiable symptoms of cognitive, emotional, mood, or affective disturbances caused by various factors (including biological, psychological, and social factors). In this invention, mental disorders include schizophrenia (e.g., paranoid schizophrenia, simple schizophrenia, post-schizophrenic depression, travel-related psychosis, peripheral psychosis), affective disorders (e.g., mania, dysthymia, bipolar disorder, type I bipolar disorder, type II bipolar disorder, cyclothymic disorder, depression), stress-related disorders (hysterical amnesia, hysterical fugue, hysterical psychosis, hysterical somatic disorder, acute stress disorder, post-traumatic stress disorder, adjustment disorder, phobias, anxiety disorders, obsessive-compulsive disorder, etc.), and psychogenic physiological disorders (anorexia nervosa, bulimia nervosa, insomnia, hypersomnia, sleep disorder). Sleep-wake rhythm disorders, decreased libido, vaginismus, etc.), personality disorders (e.g., paranoid personality disorder, schizoid personality disorder, obsessive-compulsive personality disorder), habit and impulse control disorders (e.g., pathological gambling, trichotillomania, fetishism, transvestism), psychosexual disorders, intellectual disability (mental retardation, expressive language disorder, receptive language disorder, specific reading disorder), childhood and adolescent psychological developmental disorders (e.g., childhood autism), childhood and adolescent behavioral, conduct, or emotional disorders (e.g., antisocial conduct disorder, childhood separation anxiety disorder, childhood generalized anxiety disorder, selective mutism, non-organic enuresis, stuttering), etc.

[0061] As used in this invention, the term "stress-related disorders," also known as reactive psychosis, refers to the psychological and physiological inability of an individual to effectively cope with various sudden events that have a significant impact on their mental or physical health, such as war, fire, flood, earthquake, infectious disease outbreaks, major traffic accidents, and other disasters. Examples of stress-related disorders in this invention include hysterical amnesia, hysterical fugue, hysterical psychosis, hysterical somatic disorders, acute stress disorder, post-traumatic stress disorder, adjustment disorder, phobias, anxiety disorders, and obsessive-compulsive disorder.

[0062] As used in this invention, the term "posttraumatic stress disorder (PTSD)" refers to a delayed and persistent psychological stress response in an individual caused by a sudden, threatening, or catastrophic life event.

[0063] Treatment

[0064] The present invention also relates to a treatment method for mental disorders, the method comprising the steps of:

[0065] A therapeutically effective dose of ritonavir was administered to the subjects.

[0066] As used herein, the term "object" is defined as including animals, such as mammals, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In a particular embodiment, the object is a human.

[0067] As used herein, the term "treatment" refers to the eradication or improvement of a disease or condition, or one or more symptoms associated with such disease or condition. In one embodiment, such symptoms are known to those skilled in the art to be associated with the disease or condition to be treated. In certain embodiments, the term refers to minimizing the spread or aggravation of a disease or condition by administering one or more preventative or therapeutic agents to a subject suffering from such a disease or condition. In some embodiments, the term refers to the administration of the compound of the present invention, with or without other additional active agents, after the onset of symptoms of a particular disease.

[0068] As used herein, the term "therapeuticly effective amount" refers to the amount of a compound sufficient to provide a therapeutic effect in the treatment or control of a disease or disorder, or sufficient to delay or minimize one or more symptoms associated with that disease or disorder. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other therapies, can provide a therapeutic effect in the treatment or control of a disease or disorder. The term "therapeuticly effective amount" may include amounts that improve overall therapy, reduce or avoid symptoms or causes of a disease or disorder, or enhance the therapeutic efficacy of another therapeutic agent. In some embodiments of the invention, the therapeutically effective amount is 0.1-100 mg / kg (mice), preferably 0.1-10 mg / kg, more preferably 1-10 mg / kg, for example 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg.

[0069] In a preferred embodiment of the present invention, ritonavir is administered to the test subject at a dose of 0.1-100 mg / kg.

[0070] In this invention, the method of administering ritonavir to the test subjects is not limited; it can be administered orally, parenterally, or locally in a single dose or in divided doses. For example, it can range from continuous (intravenous infusion) to several oral doses per day, and can include oral, local, parenterally, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancer), buccal, sublingual, and suppository administration, as well as other routes of administration. In a preferred embodiment of the invention, ritonavir is administered to the test subjects orally or by injection.

[0071] In this invention, ritonavir can be prepared into any dosage form commonly used in the art, such as oral solid dosage forms or parenteral dosage forms. Oral solid dosage forms include tablets, pills, powders, granules, capsules, etc., and are prepared by mixing at least one excipient (e.g., starch, calcium carbonate, sucrose or lactose, gelatin, etc.) with one or more compounds. In addition to simple excipients, lubricants (e.g., magnesium stearate and talc) are also used. Liquid dosage forms for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and may include various excipients such as wetting agents, sweeteners, flavorings, and preservatives, in addition to water and liquid paraffin (which are commonly used simple diluents). Parenteral dosage forms include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), injectable esters (e.g., ethyl oleate), etc., can be used as non-aqueous solvents and suspension solvents. In a preferred embodiment of the present invention, tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, and injections are selected for application.

[0072] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the present invention is further described below in conjunction with specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. Unless otherwise specified, the experimental materials and reagents used in the following embodiments are commercially available.

[0073] Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. It should be noted that the terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the exemplary embodiments of this application.

[0074] In the following examples, the experimental subjects were male C57 / BL mice (WT mice, purchased from Beijing Vital River Laboratory Animal Co., Ltd.) and AtLAS- / - mice, 8 weeks old, SPF grade, weighing 20-22 grams, and housed in a routine environment.

[0075] Example 1

[0076] In this embodiment, it was demonstrated that ritonavir disrupts the binding of Syn2a and Syngr-3 in HEK 293T cells.

[0077] HEK 293T cells were co-transfected with plasmids expressing EGFP-Syn2a and HA-Syngr3. Forty-eight hours after transfection, cells were incubated with 0, 1, and 2.5 μM ritonavir for 12 hours, and then cell proteins were collected. The overexpressed Synapsin 2a (Syn2a) protein is a fusion protein of Synapsin 2a and EGFP. Cell proteins were precipitated with anti-EGFP antibody, and the precipitated protein was detected with anti-HA antibody. The black blot on the NC membrane indicated the interaction between Syngr3 and Syn2a. After administration of 2.5 μM ritonavir, the corresponding protein on the NC membrane was almost undetectable by the anti-HA antibody, suggesting that 2.5 μM ritonavir could interrupt the interaction between Syn2a and Syngr3. In contrast, the 0 μM control group showed a significant detection of HA protein, indicating that 2.5 μM ritonavir could interrupt the binding of Syn2a and Syngr3. Figure 1 As shown.

[0078] Example 2

[0079] In this embodiment, a behavioral test on the extinction of fear memory in mice confirmed that ritonavir reduced the rigidity rate of extinction of fear memory in mice.

[0080] Six normal C57 mice and six AtLAS- / - mice were randomly selected and injected intraperitoneally with PBS solution. The other six normal C57 mice and seven AtLAS- / - mice were injected intraperitoneally with 5 mg / kg ritonavir solution. These injections were repeated four times. Figure 2 Subsequent fear memory testing showed that administering 5 mg / kg ritonavir solution to normal C57 mice did not significantly alter the rate of fear memory extinction rigidity, while administering 5 mg / kg ritonavir solution to mice with persistent fear memory (AtLAS- / - mice) significantly reduced the rate of fear memory extinction rigidity (see details). Figure 3 ).

[0081] Example 3

[0082] In this embodiment, the Syn2a / b on the membrane of the mouse mPFC brain region was quantified by immunoblotting.

[0083] After the fear memory extinction behavioral experiment in Example 2, mice were euthanized by decapitation due to cervical dislocation. Brain tissue was quickly removed and placed in PBS at 0-4℃. Bilateral mPFCs were rapidly separated, and total protein was extracted according to standard procedures. Protein content was measured and used for later use. The Syn2a / b content in mice in the ritonavir group and the control group was measured separately. GAPDH was used as an internal control band to demonstrate the consistency of protein loading. Comparison revealed that the Syn2a / b protein content in mice injected with 5 mg / kg ritonavir solution did not change significantly compared to the control group. Figure 4).

[0084] Example 4

[0085] In this embodiment, ritonavir was found to block the binding of Syn2a and Syngr-3 in the mouse mPFC brain region by immunoprecipitation.

[0086] After collecting the proteins from Example 3, tissue proteins were precipitated with anti-Syn2a antibody, and the precipitated proteins were detected with anti-Syngr3 antibody. The black blot on the NC membrane indicated the binding of Syn2a and Syngr3. Mice injected with 5 mg / kg ritonavir solution showed a significantly reduced amount of the corresponding protein detected by anti-Syngr3 antibody on the NC membrane compared to the control group, suggesting that ritonavir can block the interaction between Syn2a and Syngr3 to some extent in vivo. Figure 5 ).

[0087] Example 5

[0088] In this embodiment, ritonavir was found to improve the release of presynaptic vesicles by immunoprecipitation.

[0089] After collecting the proteins from Example 3, tissue proteins were precipitated with anti-VAMP2 antibody, and the precipitated proteins were then detected with anti-Syntaxin and SNAP25 antibodies. The black blot on the NC membrane indicated the binding of VAMP2 to Syntaxin and SNAP25. Mice injected with 5 mg / kg ritonavir solution showed a significantly increased amount of the corresponding proteins detected on the NC membrane by anti-Syntaxin and SNAP25 antibodies compared to the control group, suggesting that ritonavir can improve AtLAS. - / - Release of presynaptic membrane vesicles in mice Figure 6 ).

[0090] Example 6

[0091] In this embodiment, spontaneous postsynaptic potentials (sEPSCs) in mouse brain slices were detected by electrophysiological experiments, confirming that ritonavir can increase the frequency of sEPSCs.

[0092] Mice were euthanized by cervical dislocation and decapitation after anesthesia. Brain tissue was quickly removed and placed in frozen artificial cerebrospinal fluid (aCSF). Brain regions were separated according to experimental requirements, and the tissue was sliced ​​into 300 μm thick sections using a vibratory microtome and incubated at room temperature for 1 hour. Subsequently, the tissue was treated with 2.5 μM ritonavir solution or PBS solution for 30 minutes. Spontaneous excitatory aftercurrents (sEPSCs) in the mPFC brain region were recorded by selecting appropriate stimulation and recording electrode positions. 3-6 cells were recorded per brain slice.

[0093] Experiments showed that treatment with 2.5 μM ritonavir solution significantly increased the frequency of sEPSCs compared to the control group, demonstrating enhanced presynaptic transmission of neurons. Figure 7 ).

[0094] Example 7

[0095] In this embodiment, electron microscopy was used to photograph the distribution of synaptic vesicles in the presynaptic membrane region and the number anchored to the presynaptic membrane. It was found that the number of vesicles anchored to the presynaptic membrane also increased significantly after ritonavir treatment.

[0096] Mice were euthanized by cervical dislocation and decapitation after anesthesia, and brain tissue was quickly extracted for electron microscopy. Electron microscopy revealed that, compared to the control group, ritonavir-injected AtLAS- / - mice showed a significantly increased accumulation of presynaptic vesicles in the presynaptic membrane region, and a significantly increased number of vesicles anchored to the presynaptic membrane. Figure 8 and Figure 9 ).

[0097] Those skilled in the art will understand that the above embodiments are specific examples of implementing the present invention, and in practical applications, various changes in form and detail may be made without departing from the spirit and scope of the present invention.

Claims

1. The use of ritonavir, characterized in that, Drugs for the preparation of post-traumatic stress disorder.

2. The use according to claim 1, characterized in that, The ritonavir was formulated as tablets, pills, powders, granules, capsules, suspensions, or oral solutions and administered to test subjects.

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