Application of behavioral pharmacology hologram spectrum in drug research and development

Abstract

The invention relates to application of a brand new behavioral pharmacology hologram spectrum in medicine research and development. More specifically, as a novel experimental data analysis method and technology, the method can comprehensively and accurately reflect and display modes, characteristics and laws in which drugs act on behaviors of animals or people, so as to observe, analyze and research pharmacological and / or toxicological effects of the drugs on central and peripheral nervous systems.

Description

1. Technical Field

[0001] The present invention relates to the application of a new behavioral pharmacology hologram in drug research and development. More specifically, as a new experimental data analysis method and technology, the new behavioral pharmacology hologram can be used to study and evaluate the pharmacological activity and toxicological effects of various substances. 2. Background Technology

[0002] Psychopharmacology or behavioral pharmacology is an important part of pharmacology, which aims to study the effects of drugs on human psychological processes and psychological characteristics, and to develop therapeutic drugs for abnormal psychological processes and psychological characteristics. Human psychological processes include cognitive processes, emotional processes, and volitional processes. Mental disorders are mainly characterized by obvious and persistent abnormalities in the patient's psychological processes (cognition, emotion, will, and behavior) and psychological characteristics, as well as severe impairment of social and mental functions. Common clinical mental illnesses include schizophrenia, depression, anxiety, obsessive-compulsive disorder, etc.

[0003] Drugs are the main means and methods for the clinical treatment of mental disorders. Drugs for the treatment of mental disorders mainly include antipsychotics, antidepressants, antianxiety drugs, mood stabilizers, sedatives and hypnotics, etc. The research and development of modern drugs for the treatment of mental disorders depends on the establishment of animal models of mental disorders. Therefore, the research and establishment of new experimental methods, new animal models, and new experimental data analysis methods and technologies can promote the development and application of drugs related to mental disorders.

[0004] There are insurmountable obstacles between humans and animals in verbal and emotional communication. Therefore, it is difficult for researchers to make accurate judgments and evaluations on the pharmacological effects of drugs on animal psychological processes (cognition, emotion, and will). However, behavioral pharmacology uses the external behavioral performance of animals as an objective evaluation indicator, establishes specific animal models to simulate human psychological or psychopathological states, and evaluates the pharmacological effects and activities of drugs on the central and peripheral nervous systems by observing the effects of drugs on animal behavior. In addition, behavioral pharmacology not only plays an important role in the research and development of drugs for the treatment of mental disorders, but also has an important role in evaluating the side effects of drugs on the nervous system such as antihypertensive, antitumor, anti-infection, anti-allergic, antidiabetic, antipyretic and analgesic. Behavioral pharmacology has an irreplaceable position and role in research fields such as medicine, pharmacy, life sciences, and military medicine, and is increasingly receiving widespread attention.

[0005] The English translation of behavioral pharmacology is "Behavioral pharmacology", which is rather cumbersome to write. The Chinese translation of "Ethology" is "behaviorology", and the Chinese translation of "Pharmacology" is "pharmacology". According to the English word formation principle, the present invention creatively forms a new term noun, namely "Etho+pharmacology=Etho-pharmacology", which is translated into "behavioral pharmacology (Etho-pharmacology)" in Chinese, and its adjective form in English is "Etho-pharmacological (behavioral pharmacology)".

[0006] The present invention adopts artificial intelligence (AI) and omics research strategies to collect relevant data on the pharmacological effects of drugs, especially neuropsychiatric drugs and psychoactive substances on animal behavior to the maximum extent, forming a behavioral data set (Behavioral data cluster) and a behavioral pharmacological hologram (Etho-pharmacological hologram). Through data modeling, heat map analysis, factor analysis, cluster analysis, omics analysis, artificial intelligence analysis and other methods, the behavioral pharmacological effects of drugs are finely and accurately portrayed and described, providing a new experimental data analysis method and technology for behavioral pharmacology research. The core content of the present invention is the behavioral pharmacology hologram. So far, there is no record of the application of the behavioral pharmacology hologram in drug research and development, no related research papers have been published, and no reports on related research work and results have been seen. The behavioral pharmacology hologram is a brand-new concept, a brand-new theory, and a brand-new experimental data analysis method and technology.

[0007] The behavioral pharmacology hologram refers to a statistical map obtained by linear analysis of animal or human behavioral data sets related to drug effects. It can comprehensively and accurately reflect and display the pattern, characteristics and rules of the pharmacological effects of drugs on animal or human behavior.

[0008] The establishment of the behavioral pharmacology hologram is based on behavioral pharmacology experiments and linear analysis of behavioral data sets, following the three basic principles of systematicity, characteristic and stability to ensure the standardization, specification and objectivity of the hologram, which is conducive to its wide application in drug research and development. The three basic principles for the establishment of the behavioral pharmacology hologram are: (1) Systematicity. Collect as much relevant information and data as possible on the pharmacological effects of drugs, especially neuropsychiatric drugs or psychoactive substances on animal behavior to form a behavioral data set. Mainly including: (1) Spatiotemporal data; (2) Ethological representation; (3) Physiological indicator; (4) Biochemical index. The indicators collected and analyzed by the behavioral pharmacology hologram include data with (P<0.05) and without (P>0.05) statistically significant differences. This method and strategy is a major breakthrough in the analysis of behavioral pharmacology experimental data. It can obtain important information from data with or without statistically significant differences (P>0.05), and comprehensively and accurately analyze and interpret the behavioral pharmacology action mode (pattern), characteristics (characteristic) and rules (rule) of drugs. It must be pointed out that on the basis of the above principles, all drugs, including neuropsychiatric drugs, psychoactive substances, antihypertensive drugs, antitumor drugs, anti-infective drugs, antiallergic drugs, antidiabetic drugs, antipyretic analgesics, etc., can be tested and analyzed by the behavioral pharmacology hologram, and a powerful database of behavioral pharmacology holograms of various drugs can be established to provide pharmacological and / or toxicological consultation and guidance for the research and development of various drugs. (2) Characteristic. In addition to reflecting the drug-dose relationship in classical pharmacology, the behavioral pharmacology hologram can also analyze the characteristics of the hologram, such as positive peak, positive peak position, positive peak value, positive area under the curve, positive characteristic peak, negative peak, negative peak position, negative peak value, negative area under the curve, negative characteristic peak, etc. (3) Stability. Stability refers to the repeatability and reproducibility of the established behavioral pharmacology hologram under the prescribed methods and conditions. The behavioral pharmacology holograms made repeatedly by the same experimenter, different experimenters, and different laboratories should be within the allowable error range, reflecting the objectivity, universality, and practicality of the behavioral pharmacology hologram. It is required that the entire process of drug preparation, laboratory conditions (such as light, room temperature, humidity, noise, etc.), instruments and equipment, experimental process, data collection, processing, and analysis should be standardized. In addition, a corresponding evaluation agency can be established to evaluate objectivity and repeatability. III. Summary of the invention

[0009] 1. Purpose of the Invention

[0010] The purpose of the present invention is to provide a new experimental data analysis method and technology with practical value, and to apply it in drug research and development.

[0011] 2. Brief description of the invention

[0012] The present invention provides a behavioral pharmacology hologram experimental data analysis method and technology. Through research, it has been clearly found that the behavioral pharmacology hologram experimental data analysis method and technology can comprehensively and accurately test and evaluate the pharmacological and / or toxicological effects of drugs on animals (such as mice, rats, zebrafish, etc.). The behavioral pharmacology hologram can be used for drug screening, identification, evaluation and development.

[0013] Therefore, the first aspect of the present invention relates to the application of behavioral pharmacology holograms in the research and development of drugs for the treatment of mental disorders, including but not limited to antipsychotics, antidepressants, antianxiety drugs, mood stabilizers, and sedatives and hypnotics.

[0014] Another aspect of the present invention relates to the application of behavioral pharmacology hologram in the evaluation, identification and research of psychoactive substances, including but not limited to opioids, central nervous system stimulants, central nervous system depressants, alcohol, nicotine, caffeine, and cannabinoids.

[0015] Another aspect of the present invention relates to the application of behavioral pharmacology holograms in the research and development of drugs for treating neurological diseases, including but not limited to anti-epileptic drugs, anti-Alzheimer's disease drugs, and anti-Parkinson's disease drugs.

[0016] Another aspect of the present invention relates to the application of behavioral pharmacology holograms in the research and development of other drugs, including but not limited to antihypertensive drugs, antiarrhythmic drugs, antitumor drugs, anti-infective drugs, antiallergic drugs, antidiabetic drugs, and antipyretic analgesics. 3. Summary of the invention

[0018] According to the present invention, the term "behavioral pharmacology hologram" used in the present invention refers to a statistical map obtained by linear analysis of animal or human behavioral data sets related to drug effects, which can comprehensively and accurately reflect the patterns, characteristics and laws of drug effects on animal or human behavior, thereby observing, analyzing and studying the pharmacological and / or toxicological effects of drugs on the central and peripheral nervous systems.

[0019] According to the present invention, the term "patient" as used herein refers to a human being.

[0020] According to the present invention, the term "mental disorder" used in the present invention includes anxiety, depression, mania, bipolar disorder, schizophrenia, post-traumatic stress disorder, psychogenic mental disorder, aggressive behavior disorder, etc.

[0021] According to the present invention, the term "drugs for treating mental disorders" used in the present invention includes antianxiety drugs, antidepressants, antimanic drugs, mood stabilizers, antipsychotics, anti-aggressive behavior drugs, sedatives and hypnotics, etc.

[0022] According to the present invention, the term "animal" used in the present invention includes mice, rats, zebrafish and the like.

[0023] According to the present invention, the term "drug" used in the present invention refers to a substance with pharmacologically active therapeutic effects, including small molecule compounds, proteins, nucleic acids, polypeptides, traditional Chinese medicines, traditional Chinese medicine extracts, traditional Chinese medicine components, and pharmaceutical compositions.

[0024] According to the present invention, the term "behavioral pharmacology experiment" used in the present invention includes Liang's situational stress box test, elevated plus maze test, open field test, eight-arm maze test, water maze test, forced swimming test, tail suspension test, self-administration test, drug identification experiment, conditioned place preference experiment, social behavior experiment, light-dark box experiment, hot plate experiment, freezing behavior experiment, etc.

[0025] According to the present invention, the term "behavioral data set" used in the present invention includes spatiotemporal parameters (such as latency, residence time, activity distance, movement speed, activity level, immobility time, interval exploration, etc.), behavioral representations (such as Liang's panic posture, standing, protective probe, non-protective probe, self-grooming, flat plate falling, etc.), physiological indicators (such as fecal particle number, loose stool characteristics, body temperature changes, weight changes, heart rate, respiratory rate, etc.), biochemical indexes (such as serum corticosterone, blood sugar, plasma lactate, etc.), etc.

[0026] According to the present invention, the term "behavioral pharmacology hologram characteristics" used in the present invention includes positive peak, positive peak position, positive peak value, area under the positive peak curve, positive characteristic peak, positive peak similarity, negative peak, negative peak position, negative peak value, area under the negative peak curve, negative characteristic peak, negative peak similarity, factor peak, total similarity of the hologram, etc.

[0027] The following examples are provided to illustrate the present invention in more detail and are not intended to limit the present invention in any way.

[0028] The "behavioral pharmacology hologram" of the embodiment of the present invention is produced by collecting 45 spatiotemporal parameters and 50 behavioral indicators of mice using the Liang situational stress box. IV. Description of the drawings

[0029] Figure 1 It is a holographic atlas of the behavioral pharmacology of diazepam.

[0030] Figure 2 It is a holographic atlas of alcohol behavioral pharmacology.

[0031] Figure 3 It is a holographic map of the behavioral pharmacology of buspirone.

[0032] Figure 4 It is a heat map of the behavioral pharmacological effects of diazepam, alcohol, and buspirone.

[0033] Figure 5 Diagram of the similarity between diazepam and alcohol behavioral pharmacology heat map analysis (A1) The number of indicators significantly increased by the drug (A2) The number of indicators significantly decreased by the drug.

[0034] Figure 6 This is a diagram of the similarity of the behavioral pharmacology heat map analysis of diazepam and buspirone. (B1) The number of indicators significantly increased by the drug (B2) The number of indicators significantly decreased by the drug.

[0035] Figure 7 This is a similarity diagram of the heat map analysis of behavioral pharmacology of alcohol and buspirone. (C1) The number of indicators significantly increased by the drug (C2) The number of indicators significantly decreased by the drug.

[0036] Figure 8 This is a schematic diagram of the similarity of the behavioral pharmacology heat map analysis of diazepam, alcohol and buspirone. (A) The number of indicators significantly increased by the drugs (B) The number of indicators significantly decreased by the drugs. V. Specific implementation methods

[0037] Example 1: Spatiotemporal parameters of mice in Liang's contextual stress box.

[0038] Table 1. Spatiotemporal parameters of mice in Liang's situational stress box (45 items)

[0039] Table1.Spatiotemporal data in Liang's contextual-stress box in mice(45items)

[0040]

[0041]

[0042]

[0043] Example 2: Behavioral indicators of mice in Liang's situational stress box.

[0044] Table 2. Behavioral indicators of mice in Liang's situational stress box (50 items)

[0045] Table 2.Ethological judgment in Liang's contextual-stress box inmice(50items)

[0046]

[0047]

[0048]

[0049]

[0050] Example 3: Analysis of behavioral pharmacology holographic spectrum indications

[0051] Table 3. Analysis of behavioral pharmacology holographic atlas indications

[0052] Table 3.Characteristics analyzes on etho-pharmacological hologram

[0053]

[0054]

[0055] Example 4: Effects of the antianxiety agent diazepam on behavioral observation indicators of mice

[0056] The experiment used ICR mice, adult males, weighing 13-15g, and kept in cages of 4 mice. The room temperature of the animal room was 23±1℃, the relative humidity was 45±10%, and the light was on a 12h day and night cycle (lighting time 08:00-20:00). Before the experiment, the mice were adaptively raised in the laboratory for 7 days, with free access to water and food. The room temperature of the experimental operation room was 23±1℃, the light intensity was 10-15lux, and noise interference was isolated. The experiment was carried out between 11:00 and 20:00 to eliminate the influence of biological circadian rhythm. It was transferred from the animal room to the experimental operation room 1 hour in advance to adapt to environmental changes. Each mouse was used only once.

[0057] The mice were randomly divided into three groups and injected intraperitoneally (ip) with 5% DMSO in saline or antianxiety agent diazepam (0.25 mg kg -1 , 0.5mg·kg -1 , 1.0mg·kg -1 ), and 30 minutes later, they were placed in the Liang situational stress box and allowed to explore freely for 15 minutes. During this period, behavioral detection software was used to track spatiotemporal data and manually record behavioral indicators.

[0058] Data processing: ① Analysis of variance: All experimental data were expressed as mean ± standard error (Mean ± SEM), and SPSS27.0 statistical analysis was used. The main statistical methods were one-way analysis of variance (One-Way ANOVA) and Bonferroni correction. ② Data standardization: Calculate the change rate of each index in different dose groups compared with the control group, and the expression is:

[0059]

[0060] In one indicator, is the mean value of the i-dose group (i = 0.25, 0.5 or 1.0), is the average value of the control group. The change rate approaches infinity and cannot be calculated, so the cutoff value is 200%, represented by a. If the change rate>200%, the cutoff value is 200%, represented by b.

[0061] Statistical graph drawing: ① The bar graph was drawn using Prism 8.0. ② The spectrum graph was drawn using Prism 8.0 and Adobe Illustrator.

[0062] Figure 1 The behavioral pharmacology hologram of diazepam showed that in the 0.25 mg / kg dose group, the PA activity distance and PA high-speed movement time indicators were significantly increased compared with the control group of normal saline containing 5% DMSO.

[0063] In the 0.5 mg / kg dosage group, the total activity distance, PA activity distance, total average movement speed, CA average movement speed, PA average movement speed, OGA average movement speed, total high-speed movement time, CA high-speed movement time / CA dwell time, PA high-speed movement time, PA high-speed movement time / PA dwell time, OGA high-speed movement time, OGA high-speed movement time / OGA dwell time, total high-speed movement time / total low-speed movement time, CA high-speed movement time / CA low-speed movement time, OGA high-speed movement time / OGA low-speed movement time, total activity, and PA activity indices were significantly increased compared with the normal saline control group containing 5% DMSO; the CA low-speed movement time / CA dwell time, OGA low-speed movement time, OGA low-speed movement time / OGA dwell time, Liang's panic posture duration, Liang's panic posture frequency, CA Liang's panic posture duration, CA Liang's panic posture frequency, and OGA Liang's panic posture duration indices were significantly decreased compared with the normal saline control group containing 5% DMSO.

[0064] In the 1.0 mg / kg dose group, the total activity distance, CA activity distance, PA activity distance, OGA activity distance, total average movement speed, CA average movement speed, PA average movement speed, OGA average movement speed, total high-speed movement time, CA high-speed movement time, CA high-speed movement time / CA dwell time, PA high-speed movement time, PA high-speed movement time / PA dwell time, OGA high-speed movement time, OGA high-speed movement time / OGA dwell time, total high-speed movement time / total low-speed movement time, CA high-speed movement time / CA low-speed movement time, ratio of PA high-speed movement time / PA low-speed movement time, OGA high-speed movement time / OGA low-speed movement time, total activity, CA activity, PA activity, number of entries into CA, number of interval shuttling, and CA non-protective exploration were significantly decreased. The head frequency, OGA self-grooming duration, and OGA self-grooming frequency indices were significantly increased compared with the normal saline control group containing 5% DMSO; the total low-speed movement time, CA low-speed movement time / CA dwell time, PA low-speed movement time / PA dwell time, OGA low-speed movement time, OGA low-speed movement time / OGA dwell time, Liang's panic posture duration, Liang's panic posture frequency, protective probe duration, protective probe frequency, CA Liang's panic posture duration, CA Liang's panic posture frequency, OGA Liang's panic posture duration, OGA Liang's panic posture frequency, OGA protective probe duration, OGA protective probe frequency, OGA self-grooming latency, and PA Liang's panic posture duration were significantly decreased compared with the normal saline control group containing 5% DMSO.

[0065] Example 5: Effects of alcohol on behavioral observation indicators of mice

[0066] The experiment used ICR mice, adult males, weighing 13-15g, and kept in cages of 4 mice. The room temperature of the animal room was 23±1℃, the relative humidity was 45±10%, and the light was on a 12h day and night cycle (lighting time 08:00-20:00). Before the experiment, the mice were adaptively raised in the laboratory for 7 days, with free access to water and food. The room temperature of the experimental operation room was 23±1℃, the light intensity was 10-15lux, and noise interference was isolated. The experiment was carried out between 11:00 and 20:00 to eliminate the influence of biological circadian rhythm. It was transferred from the animal room to the experimental operation room 1 hour in advance to adapt to environmental changes. Each mouse was used only once.

[0067] The mice were randomly divided into three groups and injected intraperitoneally (ip) with saline or alcohol (0.5 g kg -1 , 1.0g·kg -1 , 1.5g·kg -1), and 30 minutes later, they were placed in the Liang situational stress box and allowed to explore freely for 15 minutes. During this period, behavioral detection software was used to track spatiotemporal data and manually record behavioral indicators.

[0068] Data processing: ① Analysis of variance: All experimental data were expressed as mean ± standard error (Mean ± SEM), and SPSS27.0 statistical analysis was used. The main statistical methods were one-way analysis of variance (One-Way ANOVA) and Bonferroni correction. ② Data standardization: Calculate the change rate of each index in different dose groups compared with the control group, and the expression is:

[0069]

[0070] In one indicator, is the mean value of the i-dose group (i=0.5, 1.0 or 1.5), is the average value of the control group. The change rate approaches infinity and cannot be calculated, so the cutoff value is 200%, represented by a. If the change rate>200%, the cutoff value is 200%, represented by b.

[0071] Statistical graph drawing: ① The bar graph was drawn using Prism 8.0. ② The spectrum graph was drawn using Prism 8.0 and Adobe Illustrator.

[0072] Figure 2 The alcohol behavioral pharmacology hologram showed that in the 1.0g / kg dosage group, the total activity distance, exit area activity distance, total average movement speed, CA average movement speed, total high-speed movement time, CA high-speed movement time / CA stay time, PA high-speed movement time / PA stay time, OGA high-speed movement time, CA high-speed movement time / CA low-speed movement time, self-grooming latency, and PA self-grooming latency indicators were significantly increased compared with the normal saline control group; the total low-speed movement time, Liang's panic posture duration, and OGA Liang's panic posture duration indicators were significantly decreased compared with the normal saline control group.

[0073] In the 1.5g / kg dose group, CA residence time, total activity distance, CA activity distance, PA activity distance, OGA activity distance, total average movement speed, CA average movement speed, PA average movement speed, OGA average movement speed, total high-speed movement time, CA high-speed movement time, CA high-speed movement time / CA residence time, PA high-speed movement time, PA high-speed movement time / PA residence time, OGA high-speed movement time, OGA high-speed movement time / OGA residence time, total high-speed movement time / total low-speed movement time, CA high-speed movement time / CA low-speed movement time, PA high-speed movement time / PA low-speed movement time, OGA high-speed movement time / OGA low-speed movement time, total activity, CA activity, OGA activity, number of entries into CA, zone The number of shuttling times, non-protective probe frequency, self-grooming latency, CA non-protective probe duration, CA non-protective probe frequency, and PA self-grooming latency were all significantly increased compared with the normal saline control group; the PA stay time, total low-speed movement time, PA low-speed movement time, PA low-speed movement time / PA stay time, OGA low-speed movement time / OGA stay time, total immobility time, PA immobility time, PA immobility time / PA stay time, Liang's panic gesture duration, Liang's panic gesture frequency, CA Liang's panic gesture duration, CA Liang's panic gesture frequency, OGA Liang's panic gesture duration, OGA Liang's panic gesture frequency, PA Liang's panic gesture duration, and PA Liang's panic gesture frequency were all significantly decreased compared with the normal saline control group.

[0074] Example 6: Effects of the antianxiety agent buspirone on behavioral observation indicators of mice

[0075] The experiment used ICR mice, adult males, weighing 13-15g, and kept in cages of 4 mice. The room temperature of the animal room was 23±1℃, the relative humidity was 45±10%, and the light was on a 12h day and night cycle (lighting time 08:00-20:00). Before the experiment, the mice were adaptively raised in the laboratory for 7 days, with free access to water and food. The room temperature of the experimental operation room was 23±1℃, the light intensity was 10-15lux, and noise interference was isolated. The experiment was carried out between 11:00 and 20:00 to eliminate the influence of biological circadian rhythm. It was transferred from the animal room to the experimental operation room 1 hour in advance to adapt to environmental changes. Each mouse was used only once.

[0076] The mice were randomly divided into three groups and injected intraperitoneally (ip) with normal saline or the anxiolytic buspirone (1.0 mg kg -1 , 3.0mg·kg -1 , 9.0mg · kg -1), and 30 minutes later, they were placed in the Liang situational stress box and allowed to explore freely for 15 minutes. During this period, behavioral detection software was used to track spatiotemporal data and manually record behavioral indicators.

[0077] Data processing: ① Analysis of variance: All experimental data were expressed as mean ± standard error (Mean ± SEM), and SPSS27.0 statistical analysis was used. The main statistical methods were one-way analysis of variance (One-Way ANOVA) and Bonferroni correction. ② Data standardization: Calculate the change rate of each index in different dose groups compared with the control group, and the expression is:

[0078]

[0079] In one indicator, is the mean value of the i-dose group (i=1.0, 3.0 or 9.0), is the average value of the control group. The change rate approaches infinity and cannot be calculated, so the cutoff value is 200%, represented by a. If the change rate>200%, the cutoff value is 200%, represented by b.

[0080] Statistical graph drawing: ① The bar graph was drawn using Prism 8.0. ② The spectrum graph was drawn using Prism 8.0 and Adobe Illustrator.

[0081] Figure 3 The behavioral pharmacology hologram of buspirone showed that in the 1.0 mg / kg dosage group, the duration of Liang's panic posture, the frequency of Liang's panic posture, the duration of protective probe, the duration of OGA Liang's panic posture, the frequency of OGA Liang's panic posture, and the duration of OGA protective probe were significantly decreased compared with the normal saline control group.

[0082] In the 3.0 mg / kg dosage group, Liang's panic posture duration, Liang's panic posture frequency, protective probe duration, protective probe frequency, self-grooming latency, OGA Liang's panic posture duration, OGA Liang's panic posture frequency, OGA protective probe duration, and OGA protective probe indexes were significantly decreased compared with the saline control group.

[0083] In the 9.0 mg / kg dosage group, PA low-speed movement time / PA stay time, total immobility time, PA immobility time, PA immobility time / PA stay time, protective probe latency, self-grooming duration, self-grooming frequency, OGA protective probe latency, PA self-grooming duration, and PA self-grooming frequency indicators were significantly increased compared with the normal saline control group; PA activity distance, PA average movement speed, PA high-speed movement time, Liang's panic posture duration, Liang's panic posture frequency, protective probe duration, protective probe frequency, self-grooming latency, CA Liang's panic posture duration, CA Liang's panic posture frequency, OGA Liang's panic posture duration, OGA Liang's panic posture frequency, OGA protective probe duration, OGA protective probe frequency, PA Liang's panic posture duration, PA Liang's panic posture frequency, and PA self-grooming latency indicators were significantly decreased compared with the normal saline control group.

[0084] Example 7: Similarity of heat map analysis of the behavioral pharmacology holograms of diazepam, buspirone and alcohol

[0085] Heat map analysis similarity calculation formula:

[0086]

[0087] The number of commonly changed indicators refers to the number of indicators that can be significantly changed (significantly increased or significantly decreased) in the same direction by two drugs, and the number of total changed indicators refers to the number of indicators that can be significantly changed (significantly increased or significantly decreased) by any drug.

[0088]

[0089] A and B represent different drugs or doses.s represent significantchange caused by drug, which includes significant increase and significantdecrease. represents the number of the indicators changed significantly by both two drugs / doses. represents the number of the indicators changed significantly by either of two drugs / doses.

[0090] Table 4. Similarity of heat map analysis of diazepam and alcohol behavioral pharmacology holograms

[0091] Table 4.Similarity of etho-pharmacological hologram between diazepamand ethanol in heatmap analysis

[0092] drug Number of projects with significant increase Significantly decreased number of projects Diazepam (1.0 mg / kg, ip) 27 14 Alcohol (1.5 g / kg, ip) 30 16 total 57 30 Common change index 24 10 Total change index 33 20 Similarity (%) 72.7 50.0

[0093] Table 5. Similarity of heat map analysis of behavioral pharmacology holograms of diazepam and buspirone

[0094] Table 5.Similarity of etho-pharmacological hologram between diazepam and buspirone in heatmap analysis

[0095] drug Number of projects with significant increase Significantly decreased number of projects Diazepam (1.0 mg / kg, ip) 27 14 Buspirone (9.0 mg / kg, ip) 10 17 total 37 31 Common change index 0 9 Total change index 37 22 Similarity (%) 0 40.9

[0096] Table 6. Similarity of heat map analysis of alcohol and buspirone behavioral pharmacology holograms

[0097] Table 6.Similarity of etho-pharmacological hologram between ethanoland buspirone in heatmap analysis

[0098] drug Number of projects with significant increase Significantly decreased number of projects Alcohol (1.5 g / kg, ip) 30 16 Buspirone (9.0 mg / kg, ip) 10 17 total 40 33 Common change index 0 8 Total change index 40 25 Similarity (%) 0 32.0

[0099] Table 7. Similarity of heat map analysis of behavioral pharmacology holograms of diazepam, alcohol, and buspirone

[0100] Table 7.Similarity of etho-pharmacological hologram between diazepam, ethanol and buspirone in heatmap analysis

[0101]

[0102]

[0103] Figure 4 The pharmacological effects of diazepam, alcohol, and buspirone on 95 observed parameters and indicators of mice in the Liang contextual stress box were summarized by using the behavioral pharmacological effect heat map analysis method. Figure 5 The data of heat map analysis similarity showed that the similarity of spatiotemporal parameters and behavioral indicators of diazepam and alcohol behavioral pharmacology holograms significantly increased was 72.7%, and the similarity of significantly decreased observation indicators was 50.0%. Figure 6 The heat map analysis method was used to calculate the similarity of the behavioral pharmacology holograms of diazepam and buspirone, among which the similarity of the significant increase in spatiotemporal parameters and behavioral indicators was 0%, while the similarity of the significant decrease in observation indicators was 40.9%. Figure 7 Heat map analysis of the behavioral pharmacology holograms of alcohol and buspirone showed that the similarities of the significantly increased and decreased observation indicators were 0% and 32.0%, respectively. Figure 8 The similarities of behavioral pharmacology heat map analysis between three drugs, diazepam, alcohol, and buspirone, were analyzed and summarized.

[0104] The present invention proposes the concept and theory of behavioral pharmacology hologram for the first time, and provides experimental data analysis methods and technologies with practical value. It has very important academic value and theoretical significance in drug research and development, and presents a wide range of application prospects. Example 1-2 lists in detail the spatiotemporal parameters (45 items) and behavioral indicators (50 items) observed and recorded in the Liang situational stress box experiment, totaling 95 items, and established a related behavioral data set, providing an experimental basis for the establishment of a behavioral pharmacology hologram. Example 3 lists in detail the indications for analyzing the behavioral pharmacology hologram, and proposes a technical route and method for analyzing the behavioral pharmacology hologram based on databases, computer programs and software, artificial intelligence, heat maps, behavioral genomics research and analysis. Example 4-6 uses Liang's situational stress box behavioral pharmacology experimental method to observe and record the effects of antianxiety agents diazepam and buspirone and psychoactive substance alcohol on 45 spatiotemporal parameters and 50 behavioral indicators of mice, establish a behavioral data set, make a behavioral pharmacology hologram, and perform relevant statistical analysis. Example 7 uses a heat map analysis method to calculate the similarity of the behavioral pharmacology holograms of diazepam, buspirone, and alcohol, compares the similarities or differences of the behavioral pharmacological effects of the three drugs, and evaluates, identifies, and judges. It can be seen that the behavioral pharmacology hologram is the first cornerstone for artificial intelligence and big data models to calculate and predict the behavioral effects of drugs on animals and / or humans. For the first time, it provides a scientific research strategy for comprehensive and accurate observation and evaluation of the behavioral pharmacological effects and activities of drugs on animals and / or humans, breaking through the traditional classic research model of behavioral pharmacology "one experimental method to study one (type) of drug (One test, one drug)". The promotion and application of behavioral pharmacology holograms can greatly promote drug research and development.

Claims

1. Behavioral pharmacology hologram refers to the statistical map obtained by linear analysis of behavioral data sets of animals (mice, rats, zebrafish, etc.) or humans related to drug effects. It can comprehensively and accurately reflect and display the patterns, characteristics and laws of the pharmacological effects of drugs on animal or human behavior. It is a new experimental data analysis method and technology for research and development of drugs.

2. According to claim 1, the application of behavioral pharmacology holograms in the research and development of drugs for the treatment of mental disorders, including but not limited to antipsychotics, antidepressants, antianxiety drugs, mood stabilizers, and sedatives and hypnotics.

3. According to claim 1, the application of behavioral pharmacology holograms in the evaluation, identification and research of psychoactive substances, including but not limited to opioids, central nervous system stimulants, central nervous system depressants, alcohol, nicotine, caffeine, and cannabinoids.

4. According to claim 1, the application of behavioral pharmacology holograms in the research and development of drugs for treating neurological diseases, including but not limited to anti-epileptic drugs, anti-Alzheimer's disease drugs, and anti-Parkinson's disease drugs.

5. According to claim 1, the behavioral pharmacology hologram is used in the research and development of other drugs, including but not limited to antihypertensive drugs, antiarrhythmic drugs, antitumor drugs, anti-infective drugs, antiallergic drugs, antidiabetic drugs, and antipyretic analgesics.

6. The database and data analysis methods and techniques researched and developed based on the behavioral pharmacology hologram as described in claims 1 to 5.

7. The computing program and analysis software developed based on behavioral pharmacology holograms according to claims 1 to 5.

8. According to claims 1 to 5, the artificial intelligence model and its data analysis methods and technologies studied and developed based on the behavioral pharmacology hologram.

9. The heat map analysis method and technology researched and developed based on behavioral pharmacology hologram according to claims 1 to 5.

10. The omics analysis methods and technologies researched and developed based on behavioral pharmacology holograms according to claims 1 to 5.

Images