CN114667963A

CN114667963A - Device for evaluating drug addiction of primates

Info

Publication number: CN114667963A
Application number: CN202011553692.4A
Authority: CN
Inventors: 熊志奇; 翟荣伟
Original assignee: Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences
Current assignee: Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences
Priority date: 2020-12-24
Filing date: 2020-12-24
Publication date: 2022-06-28
Anticipated expiration: 2040-12-24

Abstract

The invention provides a device for evaluating drug addiction of primates. In response to the technical drawback of not recognized in the art for evaluating drug addiction in primates, the present invention provides a device for evaluating drug addiction in primates, with which it is possible to evaluate whether a primate has addiction and strength to a drug to be tested in a short time.

Description

Device for evaluating drug addiction of primates

Technical Field

The invention belongs to the fields of neuroscience and mechanical devices; more particularly, the present invention relates to a device for primate drug addiction assessment.

Background

Drug addiction is a chronic recurrent brain disease characterized primarily by compulsive, uncontrolled drug use, and recurrent relapse. Repeated use of addictive substances by individuals will produce physical and/or mental dependence. Drug addiction has become a major public health and social problem that plagues human health and social development.

The scientific evaluation of drug addiction is helpful for preventing drug abuse and realizing clinical reasonable medication, and is an essential step for converting basic research into clinical application of new drugs. At present, the most effective animal model for researching drug addiction is a self-administration model, and the common model animal is a large mouse and a small mouse. Since the rodent has obvious difference from the primate in the anatomical structure, projection loop, neurotransmitter, receptor system and the like of brain areas related to drug addiction, the rodent model has obvious limitation in the aspects of popularization and transformation of addiction research results. Non-human primates are highly similar in anatomy, development, and function to the human nervous system. Therefore, the non-human primate self-administration model is the best model for evaluating primate drug addiction.

However, there is currently a lack of standard, widely accepted means for primate drug addiction assessment at home and abroad. The difficulties in developing such devices are found by those skilled in the art to be multifaceted, mainly including that the habits of non-human primates are not easy to catch, making it difficult for some research models to obtain consistent results; lack of typical, highly efficient monitoring metrics, etc.

In view of the above, there is a need in the art to develop a novel device for evaluating drug addiction in non-human primates in order to evaluate drug addiction in non-human primates in a controlled and standardized manner and to develop a relatively stable and reliable evaluation technique.

Disclosure of Invention

The invention aims to provide a device for evaluating drug addiction of primates.

In a first aspect of the present invention, there is provided a device for evaluating drug addiction in primates, comprising a main body of a console for accommodating a test animal, and an animal holding system; the operation box main body comprises: the system comprises an interaction module, an input module, an output module, a reward module, a monitoring module, a vital sign monitoring module and a recording-control module; the interaction module is used for interacting with animals and comprises an interaction panel, wherein a part of components (animal interaction related components) of the input module, the output module, the reward module or the monitoring module are arranged on the interaction panel; the reward module includes: a solid reward submodule, a liquid reward submodule and an automatic administration submodule.

In another aspect of the present invention, there is provided a use of the device for primate drug addiction assessment, for use in aspects including, but not limited to: self-administration strengthening training of primates; primate drug reward effect assessment; evaluating the incontrollable effect of the drug behavior of the primate; evaluation of drug craving degree of primates; evaluating drug tolerance effect of the primate; and/or, primate drug harm usage assessment.

Other aspects of the invention will be apparent to those skilled in the art in view of the disclosure herein.

Drawings

Fig. 1 is a perspective view of an embodiment of the primate addiction evaluation device of the present invention.

FIG. 2 is a schematic structural diagram of an embodiment of an interactive panel of the present invention.

Fig. 3 is a schematic structural diagram of one embodiment of the strut module of the present invention.

Fig. 4 is a front view of an embodiment of the primate addiction evaluation device of the invention.

Fig. 5 is a rear view of an embodiment of the primate addiction evaluation device of the invention.

FIGS. 6 a-j, results of evaluation of craving cynomolgus monkey in accordance with example 2 of the present invention for methamphetamine.

FIGS. 7a to c, the results of evaluation of craving cynomolgus monkey in physiological saline in example 3 of the present invention. In the figure, mg/kg/inj, ug/kg/inj refer to the amount of mg or ug per injection per kg animal body weight.

The reference numerals are explained below: 1-console box body, 2-recording-control module (computer recording and control module), 3-console box door, 4-vent, 5-lighting assembly (e.g. light lamp), 6-behavior monitoring submodule (e.g. camera), 7-temperature probe, 8-interaction panel, 9-strut module, 10-touch screen module, 11-warning lamp, 12-solid reward submodule, 13-head-face monitoring submodule, 14-horn (buzzer), 15-air-blow (air-puff) module, 16-liquid reward submodule, 17-automatic dosing submodule, 18-trough, 19-thermometric module (e.g. infrared thermometer), 20-probe hole (e.g. infrared probe hole), 21-slide rail, 22-pulley, 23-pressure bar box, 24-pressure bar plate, 25-microswitch, 26-bar box dynamometer and 27-microswitch supporting plate.

Detailed Description

The inventor of the invention has intensively studied and discloses a device for evaluating drug addiction of primates, which comprises an interaction module, an input module, an output module, a reward module, a monitoring module, a vital sign monitoring module and a recording-control module. Through intensive research and observation of a primate, the inventor organically combines and arranges each component at a proper position, thereby realizing stable and accurate evaluation of animal drug addiction.

As used herein, the term "operative communication" means that two or more components (assemblies) belonging to the apparatus (evaluation system) of the present invention can communicate with each other, such as information transmission, signal transmission and reception, signal feedback, signal storage, data processing/analysis, and the like, to realize orderly operation. For example, the "operative communication" may be achieved through a cable.

As used herein, the term "primate" includes non-human primates; preferred include animals selected from (but not limited to) the group consisting of: monkeys, gibbons, orangutans; preferably, said monkeys include monkeys selected from the group consisting of: rhesus monkey, cynomolgus monkey, Japanese macaque, green monkey, marmoset monkey, squirrel monkey.

As used herein, the term "animal interaction-related component" refers to a component of the apparatus of the present invention adapted to be integrated into the interaction panel to facilitate interaction with an animal; preferably, it comprises: a compression bar module and a touch screen module in the input module, a cue light in the output module, a solid reward submodule in the reward module, and/or a head and face monitoring submodule of the monitoring module.

Device for evaluating drug addiction

The invention provides a device for evaluating drug addiction of primates, which comprises an interaction module, an input module, an output module, a reward module, a monitoring module, a vital sign monitoring module and a recording-control module; preferably, the device further comprises an animal fixation system suitable for primates.

(1) Primate self-administration system assembly

The device of the present invention comprises a primate self-administration system assembly comprising a console body, an interaction module, an input module, an output module, a logging-control module (preferably a computer logging-control module), a reward module, a monitoring module, and a vital signs monitoring module.

The operation box main body of the invention is used for accommodating primates and is internally provided with experimental equipment for testing animal behaviors, cognition and the like. The operation box main body can be arranged to at least comprise an operation box door. In a preferred mode of the invention, the operating box door is designed to be a single-door opening design, and compared with a multi-door and/or multi-door opening design, the design is simpler in structure, low in cost and better in sound insulation effect, and can effectively reduce the interference of the outside on an experiment.

In a preferred mode of the invention, the box body wall of the operation box main body is provided with an air exchange opening, and an illumination component (such as an illuminating lamp), a behavior monitoring module (a camera) and a temperature probe are arranged in the operation box main body so as to monitor and control the temperature in the operation box and provide a comfortable experimental environment for the primates.

The present inventors have studied and observed the life habit of non-human primates and designed the size of the main body of the console suitable for non-human primates. In a preferred mode of the invention, the box body of the operation box main body has the length of 500-1200 mm, the width of 500-1200 mm and the height of 1000-2000 mm; preferably 650 to 1000mm in length, 650 to 1000mm in width and 1200 to 1800mm in height; more preferably 700-900 mm in length, 700-900 mm in width and 1350-1650 mm in height. The internal space can effectively avoid anxiety, tension and uneasy mood of primates caused by space problems, and can obtain more ideal and stable experimental test results.

In a preferred mode of the present invention, the console box main body of the present invention contains or is mainly prepared from a sound insulating material.

The interaction module is used for realizing interaction between the components of the administration system of the primates and the primates, comprises experimental equipment on an interaction panel and experimental equipment in a box main body, and can be connected with the recording-control module through a cable. In a preferred embodiment of the present invention, the interactive panel is located on a surface of the console box main body that is away from the door (i.e., on the right-side surface of the door). In a preferred embodiment of the present invention, the panel material may be a stainless material.

In a preferred mode of the present invention, the interactive panel of the present invention is provided with a pressure lever module and a touch screen module in the input module, a prompt lamp in the output module, a solid award module in the award module, and a head and face monitoring sub-module in the monitoring module. The experimental equipment on the interactive panel can be connected with the recording-control module through a cable. Preferably, the prompting lamps comprise at least one left prompting lamp and at least one right prompting lamp, the left prompting lamp and the right prompting lamp are respectively arranged on the left side and the right side of a vertical center line of the interactive panel, and at least one upper prompting lamp; preferably, the left prompt lamp and the right prompt lamp are respectively positioned above the left pressure lever and the right pressure lever; more preferably, the left cue light and the right cue light are different in color (e.g., selected from red or green), and the upper cue light is different in color (e.g., white) from the left cue light and the right cue light.

In a preferred mode of the present invention, the input module includes a stick module and a touch screen module. The pressure bar module comprises a left pressure bar and a right pressure bar which are respectively positioned on the left side and the right side of the vertical center line of the interactive panel. The pressure bar module comprises a pressure bar box, a pressure bar plate, a microswitch, a bar-shaped box dynamometer and a microswitch supporting plate. Preferably, the plunger case is mounted (e.g., bolted) to the interactive panel, the bar case dynamometer is mounted (e.g., bolted) to the plunger case, and the plunger plate is mounted in the plunger case by the bar case dynamometer and coupled to the micro switch. The bar-shaped box dynamometer can realize the resetting of the pressure bar plate, the pressure bar plate is partially exposed out of the interactive panel, and the exposed part of the pressure bar plate is positioned in the box body and is pressed by the primates. Preferably, the microswitch tray is mounted (e.g., bolted) within the plunger box below the plunger plate. Preferably, the microswitch is mounted on the microswitch support plate and is connected to a recording-control module (preferably a computer recording-control module) for transmitting the number of pressing rod times and the duration of a single pressing. The vertical distance between the lower edge of the strip-shaped box dynamometer shaft and the microswitch can be used for adjusting the resistance of the pressure lever, the adjustable range of the resistance is 0-10N, and the range is set according to the strength of forelimb strength of the nonhuman primates. The reward difficulty is obtained by adjusting the resistance of the pressure lever, so that the learning of the operation of the pressure lever is facilitated, and an index for obtaining the reward motivation in a visual and reliable quantification manner is provided. The inventor firstly carries out the design of the function of adjustable resistance of the pressure lever, which is not reported and disclosed in the field.

In a preferred mode of the invention, the touch screen module is located in the center of the interactive panel and between the double-sided pressure rods. The inventor firstly applies the touch screen module to evaluation of addiction of non-human primates, and compared with the evaluation mode of a single input module applying the compression bar module, the design adds a new visual input mode based on vision, the input mode realizes diversification of visual stimulation patterns and space positions, and the input mode can realize adjustment of task complexity and difficulty by combining with the compression bar module. Meanwhile, a classical experimental paradigm based on the design of a touch screen module can be used for dynamically monitoring the cognitive ability and motor ability states of a tested animal, the aspect is very important for animal behavior detection, and particularly relates to the ingestion of drugs and other addictive substances which can cause the change of acute cognitive ability and motor ability.

The touch screen is optimally set after deep behavior analysis is carried out on primates by the inventor. The visual stimulus output by the touch screen has the advantage of diversified spatial positions and patterns. Compared with a device without the touch screen module, the touch screen module has remarkable advantages, and meets the actual demand of output diversification faced by the current primate research.

In a preferred mode of the invention, the output module comprises a prompting lamp, a loudspeaker and an air-blowing (air-puff) module. The output module can also be matched with the visual stimulation output of the touch screen module.

In a preferred mode of the invention, the prompting lamps comprise a left prompting lamp and a right prompting lamp which are positioned on the interaction panel and are positioned on the left side and the right side of a vertical center line, and an upper prompting lamp which is positioned on the vertical center line and is close to the upper edge of the interaction panel. The prompting lamp is used for realizing light stimulation on primates; preferably, the left and right indicator lights are respectively positioned right above the left and right pressure levers, for example, one of red or green, but the colors of the two are different; it should be understood that other colors of light are possible, as long as the left and right colors are different; the upper cue light is located directly above the touch screen module and is generally a different color, preferably white, than the left and right cue lights.

The location of the horn is not particularly limited and may be located in the wall of the console box or in the interactive panel for outputting the sound stimulus.

In a preferred form of the invention, the insufflation (air-puff) module is located outside the cabinet and generates a flow of air of a specified duration, velocity and flow rate to effect air flow stimulation of the primate face through the connecting duct.

The recording-control module is positioned outside the box body, can be connected with an experimental instrument through a cable, and is used for recording data input of the input module, the monitoring module and the vital sign monitoring module and controlling the operation of the reward module and the output module.

In a preferred mode of the invention, the reward module comprises a solid reward submodule, a liquid reward submodule and an automatic administration (such as intravenous injection) submodule which can be connected with the recording-control module through a cable to realize the control of feeding, liquid reward or automatic administration of medicines to the primates. Preferably, the solid reward submodule comprises a pellet pump, a pipeline and a trough, the pellet pump and the pipeline are positioned outside the box body and controlled by the recording-control module to deliver a preset amount of solid food or drug pellets to the primate. Preferably, the trough is centrally located on the interactive panel. Preferably, the fluid reward submodule comprises a syringe/peristaltic pump and tubing, located outside the housing, the syringe/peristaltic pump being connected to the mouth of the primate via tubing and controlled by the recording-control module to deliver a predetermined amount of fluid to the primate. The automatic drug delivery sub-module comprises an injection pump/peristaltic pump and a pipeline, is positioned outside the box body, is connected to the body of the primate through the pipeline and is controlled by the recording-control module to inject preset drug amount to the body of the primate. In the invention, the three reward submodules are firstly used for training and evaluating animals, and diversified animal training and administration evaluation can be realized.

In a preferred mode of the invention, the monitoring module comprises a behavior monitoring submodule located on the wall of the box body and a head and face monitoring submodule located on the interactive panel. Preferably, the behavior monitoring sub-module is configured to monitor all behaviors of the primate, and the head and face monitoring sub-module is configured to monitor head movements and facial expressions (reflecting emotions such as happiness, anger, sadness, fear, and the like) of the primate. The data of head movements and facial expressions are not only part of the experimental data but also important parameters for controlling the progress of the experiment, as the facial fear expression of the primate is monitored during the experiment, the recording-controlling module will immediately terminate the experimental procedure.

In a preferred form of the invention, the vital signs monitoring module is located outside the console box and includes a thermometry module (e.g., an infrared thermometer) and a probe hole in the wall of the console box. The temperature measuring module (such as an infrared thermometer) can dynamically monitor the body temperature of the primate in real time, the data not only serve as part of experimental data, but also serve as important parameters for controlling the experimental process, and if the body temperature of the primate exceeds the range of normal values in the experimental process, the recording-control module immediately terminates the experimental procedure. The invention provides the application of the vital sign monitoring module for the first time, and the vital sign monitoring module is organically combined in an integral evaluation system.

In a preferred form of the invention, the automatic drug delivery module further comprises a line having one end located within the body surface skin of the primate and the other end connected to the syringe pump.

In a preferred form of the invention, the operating box has a slide rail at the bottom for pushing in and pulling out the primate fixing system, and the operating box has a pulley.

(2) Animal fixation system

The device of the present invention further comprises an animal immobilization system for coordinating the training of the animal and/or the evaluation of the medication of the animal.

In a preferred form of the invention, the animal holding system is a chair assembly comprising a frame, side panels, front and rear panels and a base enclosing a seating space into which the primate can enter. Preferably, the support is formed by splicing four round/square columns which are vertically and upwards fastened at four corners of the base respectively and a plurality of transverse round/square pipes, and the connected round/square pipes are fixed through a detachable buckle clamp (a connecting assembly between the pipes). Preferably, the seat assembly further comprises an upper panel for securing the primate neck, which is mounted on top of the holder by the clamp (connection assembly). Preferably, the seating assembly further comprises a primate seat assembly secured to the lower portion of the frame by the clip retainer and positioned above the base. Preferably, the chair assembly further comprises a primate bilateral forelimb arm fixing assembly fixed in the middle of the frame by the clasper and located above the seat assembly. Preferably, the side panels and panels are secured to the seat assembly by removable clamps (attachment assemblies); the front panel and the rear panel are single-door and are respectively used for the primate to go in and out and experimenters to carry out experiment-related operations on the back of the primate. The primate seat assembly is simple and firm in structure and convenient to mount, adjust and dismount, can adjust the fixed height and the inclination angle of the neck of the primate, can adjust the forelimb arm of the primate in three directions (front and back, left and right and up and down), can adjust the height of the primate seat, allows the forelimb of the primate to move freely so as to facilitate experiment operations such as a pressure lever, a touch screen and the like, allows an experimenter to operate the back of the primate, and further facilitates safe and reliable related experiment research. The primate seat assembly is pushed into or pulled out of the operation box through a sliding rail arranged at the bottom of the operation box body. The primate seat component has good universality and is suitable for scientific research experiments of primates of various ages and body types.

Applications of the device of the invention

The invention also provides application of the primate drug addiction evaluation device. It may be applied to uses including but not limited to the following group: self-administration strengthening training of primates; primate drug reward effect assessment; evaluating the incontrollable effect of the drug behavior of the primate; evaluation of drug craving degree of primates; evaluating drug tolerance effect of the primate; primate drug hazard use assessment.

(1) Self-administration enhanced training of primates

As an evaluation mode, the primate can sit on the seat assembly to complete self-administration tasks, the primate can obtain a reward (the reward can be natural reward such as solid food, liquid fruit juice, water and the like and also can be addictive drugs such as heroin and ice poison) by pressing one pressure lever of the left and right pressure levers for a certain number of times, and the reward cannot be obtained by pressing the other pressure lever, so that sound and light stimulation are presented while the reward is given. At the beginning, the primate random compression bar is trained for a period of time, the compression efficiency and frequency of the primate reward-object-associated side compression bar are greatly improved, and the strengthening effect of the reward objects is reflected. During training, a dose gradient for a single award presentation can be set to fully evaluate the potentiating effect of the award, while a single day maximum award acquisition number can be defined to prevent excessive intake of medication.

As a preferred mode of the invention, the training success criteria are as follows: the number of single-day reward article acquisitions and the amount of compression bar for primates varied within a range of + -20% over 3 consecutive days. The end conditions of the training task on the same day are as follows: a. the maximum time of the training task is reached, such as 120 minutes; b. the maximum number of prizes is reached in advance; c. no compression bar operation is carried out for 30 minutes continuously; d. the face of the primate has emotions such as fear; e. primate body temperatures are outside the normal range.

(2) Evaluation of primate drug reward effects

As a means of assessment, the device of the present invention can be used to assess primate drug reward effects. As a preferred approach, the primate's operative conditioned reflex to natural reward is first established: primates placed in the primate seat assembly and in the primate self-medication system assembly, trained to press the left and right press bars on the interactive panel, giving a food reward (solid particles, similar in shape to pills) when the left press bar is pressed, while presenting a sound and red/green light stimulus; a juice reward is given when the right side plunger is depressed, with simultaneous sound and green/red light stimulation. The selection percentage of each reward and the number of presses of the double-sided pressure bar were recorded. Next, when the selection ratio is stable on the day of occurrence (criterion described later), the following steps are performed: a. setting a dose gradient of the drug to be tested (e.g. 5 gradients can be selected, the first dose is zero, the third dose is the optimal dose for the drug in clinical or animal studies, the second is one third of the third, the fourth is three times the third, and the fifth is three times the fourth); b. the method comprises the following steps of (1) substituting the original solid or liquid reward for a medicine to be tested (if the medicine to be tested is a solid pill, selecting a right side pressure rod to be associated, namely pressing the right side pressure rod for a fixed number of times (namely a Fixed Ratio (FR) value), giving a pill instead of original fruit juice as a reward object once; c. the maximum test duration per day for each primate may be 120 minutes, including five blocks of 20 minutes duration (the number of blocks equals the number of dose gradients of the drug), with a maximum number of rewards of 10 in each block, which will be prematurely ended when the maximum reward is reached, with a 5 minute interval between blocks. The five blocks are different only in dosage of the drug to be detected given once, the dosages of the drugs from block1 to block5 are increased progressively, and the dosage in each block is unchanged; d. allowing the primates to freely select between the drug to be tested and the natural reward material, and counting the respective selection percentages and the number of compression bars; e. the evaluation was ended when the data change satisfying the selection percentage and the number of struts for three consecutive days was within 20%.

(3) Evaluation of Effect of primate drug on uncontrolled behavior

As an evaluation mode, the device of the present invention can be used to evaluate the uncontrolled behavior effects of primate drugs. As an embodiment, comprising: a. drawing a dose response curve of the drug to be tested, and selecting the dose with the highest compression bar frequency (namely the primate intends to pay more compression bar operations for the dose) as the application dose for evaluating the behavior runaway effect of the primate; b. the primates can freely select between the medicine to be tested and the natural reward material, the maximum training time of a single day is 120 minutes, the maximum reward times is determined according to the safety dosage of the medicine, and the training is finished on the day when the maximum value is reached; c. the interval between the phase dials is set to 1 minute; the FR value is calculated according to the ratio of the pressing times of a certain side pressure lever to the corresponding reward times obtained in the previous day, the FR initial value can be set manually according to the actual situation, and the FR value is unchanged in the current day; e. before 120 minutes of daily detection, a 10-minute craving detection task is added, and within 10 minutes, the primate compression bar operation does not produce any outputs of reward sound, light stimulation and the like, but compression bar behavior is still recorded. Evaluation end conditions: assessment will be terminated prematurely when the FR value exceeds three times its average three days prior to a sharp increase, or when the FR value exhibits an "S" shaped increase, otherwise up to a maximum length of time (4 weeks).

(4) Evaluation of drug craving in primates

As an evaluation mode, the device of the present invention can be used to evaluate primate drug craving. As an embodiment, comprising: after repeated ingestion of the test drug for a period of time, administration is stopped and the primate's craving for the test drug is evaluated. The assessment task is similar to the described method for assessing the effects of uncontrolled behaviour of primate drugs, except that: the FR value is constant and the operation of the compression bar does not yield any reward and medication, and presents sound, light, etc. outputs. The craving degree of the primate on the medicine to be tested is quantified through the pressing amount of the primate on the medicine to be tested-related lateral pressure rod.

(5) Evaluation of drug tolerance effects in primates

As a means of evaluation, the device of the present invention can be used to evaluate primate drug tolerance effects. As an embodiment, comprising: recording the single-day intake amount of the drug to be tested in the process of self-administration strengthening training, evaluation of drug reward effect of the primate or evaluation of behavior runaway effect of the primate drug, and analyzing the change rule of the intake amount along with time to evaluate the tolerance effect of the primate on the drug to be tested.

(6) Evaluation of primate drug harmful use

As a means of evaluation, the device of the present invention can be used to evaluate the extent of harmful use of primate drugs. As an embodiment, comprising: recording the drug intake amount to be measured in a single day, the weight and the food intake amount in the same day in the process of self-administration strengthening training, estimation of drug reward effect of the primate or estimation of behavior runaway effect of the primate drug, analyzing the change rule of the drug intake amount along with time, and carrying out regression analysis on the relation between the weight/the food intake amount and the accumulated drug intake amount to estimate the harmful use degree of the primate on the drug to be measured.

The device of the present invention is capable of performing a series of addiction related animal training regimens including, but not limited to, the following:

(i) training of addiction models of various addict drugs, such as morphine, heroin, cocaine, methamphetamine and other primates, comprises self-administration, strength of foraging behavior and the like.

(ii) Withdrawal training of various addiction drugs, such as morphine, heroin, cocaine, methamphetamine and other primate addiction models, observation of acute/chronic withdrawal symptoms and the like.

(iii) The withdrawal training of the addiction models of various addiction drugs, such as morphine, heroin, cocaine, methamphetamine and other primates, comprises natural withdrawal, accelerated/slowed withdrawal by means of drug/physical intervention and the like.

(iv) The relapse of various addiction drugs, such as morphine, heroin, cocaine, methamphetamine and other primate addiction models, comprises drug induction, clue induction, environmental induction and the like.

The device of the present invention is capable of performing a series of clinical animal training protocols with relevant drugs including, but not limited to:

(i) antibiotic drugs that can be administered orally (solid pills, tablets, etc., liquid drug solutions) or intravenously are evaluated for their addiction, tolerance, etc. in primates.

(ii) Therapeutic drugs such as cardiovascular diseases, neurological and psychiatric diseases, immune system diseases, urinary system diseases, respiratory system diseases, digestive system diseases, hematological diseases, reproductive system diseases, and tumor diseases, which can be administered orally (solid pills, tablets, etc., liquid drug solutions) or intravenously, are evaluated for addiction to primates, tolerance, and the like.

(iii) Addiction, tolerance, and the like in primates were evaluated for sedative-hypnotic drugs that can be administered orally (solid pills, tablets, etc., liquid drug solutions) or intravenously.

The device of the present invention is capable of performing animal training protocols including, but not limited to, several pre-clinical transformation-related drugs:

With the present invention, several food-related animal training protocols including, but not limited to, the following can also be performed: primates are evaluated for addiction, tolerance, etc. to solid, liquid foods.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer.

The present invention provides a device for evaluating primate drug addiction comprising a primate self-administration system component and a primate seat component. See in particular the summary section.

In the description of the present invention, it is to be understood that the terms "center", "lateral", "longitudinal", "front", "rear", "left", "right", "upper", "lower", "vertical", "horizontal", "top", "bottom", "inner", "outer", and the like indicate orientations or positional relationships based on orientations or positional relationships shown in the drawings, and are used merely for convenience in describing the present invention and to simplify the description, but do not indicate or imply that the device or element referred to must have a particular orientation, be of particular construction and operation, and therefore, should not be taken as limiting the scope of the present invention.

Example 1 an apparatus for evaluating drug addiction in primates

A device for evaluating drug addiction of primate is shown in figure 1, figure 4-figure 5, and comprises a main body 1 of a console box for accommodating a tested animal; the operation box main body 1 includes: the system comprises an interaction module, an input module, an output module, a reward module, a monitoring module, a vital sign monitoring module and a computer-based recording-control module 2. The interaction module comprises an interaction panel 8 on which are arranged: a compression bar module 9 and a touch screen module 10 in the input module, a prompt lamp 11 in the output module, a solid reward submodule 12 in the reward module, and a head and face monitoring submodule 13 of the monitoring module; and a plurality of sub-modules arranged on the interaction module are communicated with the recording-control module 2 through cables.

The input module comprises a pressure lever module 9 which comprises a left pressure lever and a right pressure lever which are respectively positioned on the left side and the right side of the vertical central line of the interactive panel. The depression bar module includes depression bar box 23, depression bar board 24, micro-gap switch 25, bar box dynamometer 26, the depression bar box sets up on interactive panel, bar box dynamometer 26 and micro-gap switch 25 are located depression bar box 23, depression bar board 24 passes in depression bar box 23's antetheca stretches into depression bar box 23, with bar box dynamometer 26 and micro-gap switch linkage mutually, the animal is through pressing depression bar board 24 and then starting micro-gap switch 25, measures and adjusts required pressing force size (fig. 2 ~ fig. 3) through bar box dynamometer 26. The microswitch 25 is arranged on a microswitch supporting plate 27, and the microswitch supporting plate 27 is positioned below the inner part of the box of the pressure bar plate 24; the microswitch 25 is communicated with the recording-control module 2 through a cable and is used for transmitting the times of the pressure lever and the time length data of single pressing. The vertical distance between the lower edge of the strip-shaped box force measuring shaft and the micro switch is used for adjusting the resistance of the pressure rod, and the reward difficulty is obtained by adjusting the resistance of the pressure rod.

The input module comprises a touch screen module 10, which is located in the center of the interactive panel 8 and between the left and right press rods of the press rod module 9.

The output module comprises a prompting lamp 11, a loudspeaker 14 and an air-blowing (air-puff) module 15. The prompting lamps comprise a left prompting lamp, a right prompting lamp, a left side and a right side which are respectively arranged on the vertical center line of the interactive panel, and an upper prompting lamp which is close to the upper edge of the interactive panel. And the left prompt lamp and the right prompt lamp are respectively positioned above the left pressure lever and the right pressure lever. The left prompt lamp and the right prompt lamp are different in color and are red and green respectively, and the upper prompt lamp is white.

The horn 14 is located on the inner wall of the console box body 1.

The insufflation (air-puff) module 15 is located on the wall of the cabinet body 1 and can deliver air flow stimulation of a specific duration, speed and flow to the face of the animal inside the cabinet body 1.

The reward module includes a solid reward submodule 12, a liquid reward submodule 16, an automatic dosing submodule 17. Preferably, it communicates with the recording-control module 2 via a cable to control feeding, liquid reward, or automatic administration of medication to the animal. The solid reward submodule 12 comprises a particle pump, a pipeline and a trough, wherein the particle pump is positioned outside the operation box main body 1 and is communicated with the trough 18 positioned in the operation box main body 1 through the pipeline; preferably, it communicates with the recording-control module 2 via a cable, controlling the delivery of a preset amount of solid food or drug particles to the animal, the trough being located on the interactive panel 8. The liquid reward submodule 16 comprises a syringe pump/peristaltic pump located outside the cabinet body 1, which is connected by a pipe to the mouth of the animal located inside the cabinet body 1, which is connected by a cable to the recording-control module 2, controlling the delivery of a preset amount of liquid to the animal. The automatic drug delivery sub-module 17 comprises an injection pump/peristaltic pump positioned outside the operation box main body, which is communicated with an animal body positioned inside the operation box main body 1 through a pipeline, and is communicated with the recording-control module 2 through a cable to control the injection of a preset amount of drugs into the animal.

The monitoring module includes: a behavior monitoring sub-module 6 and a head and face monitoring sub-module 13. The behavior monitoring submodule 6 is located in the operation box main body 1, and the head and face monitoring submodule 13 is located on the interaction panel 8. The behavior monitoring submodule or the head and face monitoring submodule is a camera.

The vital sign monitoring module comprises a temperature measuring module (infrared thermometer) 19 which is communicated with the recording-control module 2 through a cable and used for transmitting animal body temperature information. The temperature measuring module 19 is positioned outside the operation box main body 1 and measures temperature through a probe hole 20 positioned on the wall of the operation box main body 1.

In the operation case main part 1, still include the subassembly: an illumination assembly (illumination lamp) 5; the temperature probe 7 is used for measuring and/or monitoring the temperature in the operation box main body; and an air exchanging opening 4.

The inner bottom of the operation box main body 1 is also provided with a slide rail 21 which can be matched with an animal fixing system provided with a pulley, so that the animal fixing system can move along the slide rail conveniently.

The operation box main body 1 comprises an operation box door 3 which is a single door and is opposite to the front surface of the interaction panel.

The length of the box body of the operation box main body is 800mm, the width of the box body is 800mm, and the height of the box body is 1500 mm.

The bottom of the operation box main body 1 is also provided with a pulley 22 so that the operation box main body 1 can be moved.

The operation box main body 1 is surrounded by sound insulation materials to prevent internal animals from being interfered.

The console box main body 1 of the present invention further includes a primate seat unit; it comprises a bracket, two side plates, a front plate, a back plate and a base, which are mutually connected in a surrounding way to form a seat space suitable for primates. The support is formed by splicing four round/square upright posts which are vertically and upwards fastened at four corners of the base respectively and a plurality of transverse round/square tubes, and the connected round/square tubes are fixed by a detachable buckle clamp (a connecting assembly between the tubes); the seat assembly further comprises an upper panel for securing the primate neck, mounted on top of the support by a clamp; the seat assembly further comprises a fixing assembly for fixing bilateral forelimb arms of the animal, wherein the fixing assembly is fixed in the middle of the bracket through a fastener and is positioned above the primate seat assembly; the side panels and panels are secured to the seat assembly by removable retainers; the front panel and the rear panel are single-door.

Example 2 training of cynomolgus monkeys and evaluation of their dosing

In this example, cynomolgus monkeys were used as an animal model, and training and drug administration evaluation thereof were performed using the apparatus of example 1.

1. Establishing an operative conditioned reflex of a cynomolgus monkey on a natural reward

The program setting for obtaining a natural reward immediately after the natural reward is obtained by utilizing the instinct of environmental exploration of the cynomolgus monkey, the favor of fruit juice and the pressing rod operation establishes the correlation between the pressing rod operation of the cynomolgus monkey and the natural reward, namely, the operational conditioning (operating conditioning). The cynomolgus monkey sits on the primate seat assembly to complete task training, and forelimbs on two sides have equal opportunity to press the lever, but the special structure of the primate seat assembly determines that the forelimb on one side of the cynomolgus monkey can only press the compression bar on the same side but cannot press the compression bar on the opposite side. A food reward (solid particles, similar in shape to pills) is given when the left strut is pressed by the cynomolgus monkey and a juice (liquid) reward is given when the right strut is pressed. The selection percentage of each prize and the number of presses of the double-sided pressure bar were recorded.

The behavioral training of this stage uses a Fixed Ratio (FR) enhancement procedure. During training, the inventors gradually increased the FR value to a fixed value, here for example 30 (increasing sequence: 1, 3, 5, 8, 13, 20, 30). Training 5 days per week, 2 hours per day, conditions for early termination of training tasks: the natural reward is given for the maximum number of times (85 times) and the operation without pressure rod is continued for 30 min. The flow and parameter settings for a single trial are as follows: when the real is started, the white room lamp is turned on, if the frequency of the left side pressure lever of the cynomolgus monkey reaches a specified value, a solid reward is given immediately, the room lamp is turned off during the reward giving period, the red LED lamp above the left side pressure lever flickers (500 ms for turning on and off respectively) and the buzzer sounds intermittently (500 ms for turning on and off respectively), and the reward is finished. If the frequency of the press rod on the right side of the cynomolgus monkey reaches a specified value, a fruit juice reward (2ml) is given immediately, a room lamp is turned off during the fruit juice giving period, a green LED lamp above the press rod on the right side flickers (500 ms respectively in on and off) and a buzzer sounds intermittently (500 ms respectively in on and off), and the fruit juice giving is finished. The 60s Time-out phase is then entered, during which and during which the cynomolgus monkey's lever operation does not count as a valid lever number to obtain juice, but is still recorded by the software.

The operative conditioned reflex of the cynomolgus monkey on the natural reward can be considered to be successfully established when the following two conditions are met, and the subsequent experiment is started: 1) at FR30, the reward award amount stabilized for 3 consecutive days (data change was within 10% of mean); 2) bonus awards and Time-out phases without pressure bars.

Experiments were performed on batches of cynomolgus monkeys, and the learning curves for some of the cynomolgus monkeys are shown in fig. 6 a. The results show that with the device of the invention, cynomolgus monkeys are able to establish stable operational conditioned reflexes over an average time of 10-15 days.

FIG. 6b is a graph showing the cumulative number of lever presses of the cynomolgus monkey over 30 min. The results show that with the device of the invention, the cynomolgus monkey can reach the following goals in an average time of 10-15 days: 1) high-frequency pressing of the prize-associated side pressing rod after the start of the trim; 2) reward awards and no-press operation of the Time-out phase.

2. Assessment of the reward Effect of Methamphetamine on cynomolgus monkeys

(a) Cynomolgus monkey vein intubation operation experiment

Determining the intake mode of the cynomolgus monkey according to the mode of using the medicine to be tested by the human. Intravenous administration is exemplified herein. A retention tube was chronically embedded in the femoral or jugular vein of the animal and the injection tip was introduced subcutaneously to the back for long-term administration. The procedure is briefly described as follows: under general anesthesia, the skin is cut 2cm above the femoral vein or jugular vein, the vein vessel is separated, the puncture needle is inserted into the vessel, then the implanted vein cannula is guided into the vein vessel by about 8-10cm along the puncture needle, and the vessel and the vein cannula are fixed. The other end of the venous cannula was passed subcutaneously to the back, the skin was cut 3cm, the venous catheter and the injection lumen were connected, and two incisions were sutured. And monitoring the physiological indexes of the experimental animals in real time during the operation. And (3) postoperative care: the postoperative care is carried out by professional animal technicians, analgesic drugs and antibiotics are injected once to twice every day three days before the operation, the first major debridement is carried out on the seventh day, the operation part and the periphery are cleaned, the suture line is removed, and the debridement work with the frequency of 2 days is ensured after seven days. After the postoperative is completely recovered, the operation can be continued.

(b) Plotting the dose-response curve of the cynomolgus methamphetamine

According to the previous test results, the single injection dose of the methamphetamine is set to 5 dose gradients of 0, 3.2, 10, 32 and 100 mug/kg, and the methamphetamine is associated with the left pressure rod instead of the original solid reward. The maximum testing time of each cynomolgus monkey per day is 120 minutes, the maximum reward times in each block are 10, when the maximum reward is reached, the blocks are ended in advance, and the blocks are separated by 5 minutes. The difference between the five blocks is only that the doses of the drugs to be tested are different in a single administration, the doses of the drugs in the blocks 1 to 5 are increased in an incremental manner, and the dose in each block is not changed. The flow and parameter settings for a single trial are as follows: when the trial starts, the white chamber lamp is turned on, if the number of times of the left side pressure lever of the cynomolgus monkey reaches the specified value, methamphetamine is immediately given once, the chamber lamp in the giving period is turned off, the red LED lamp above the left side pressure lever flickers (the lamp flickering frequency is different according to different methamphetamine doses, the lamp is turned on and off for 500ms respectively when the dose is 0 mug/kg ', the lamp is turned on and off for 400ms respectively when the dose is 3.2 mug/kg', the lamp is turned on and off for 300ms respectively when the dose is 10 mug/kg ', the lamp is turned on and off for 200ms respectively when the dose is 32 mug/kg', the lamp is turned on and off for 100ms respectively when the dose is 100 mug/kg ') and the buzzer sounds continuously (the sounding frequency of sounds is different according to different methamphetamine doses, the lamp is turned on and off for 500ms respectively when the dose is 0 mug/kg', the lamp is turned on and off for 400ms when the dose is 3.2 mug/kg ', and the lamp is turned on and off respectively 300ms when the dose is 10 mug/kg', open and close for 200ms each when the dose is "32 μ g/kg" and 100ms each when the dose is "100 μ g/kg"), the reward ends for the finished lot. If the frequency of the press rod on the right side of the cynomolgus monkey reaches a specified value, a fruit juice reward (2ml) is given immediately, a room lamp is turned off during the fruit juice giving period, a green LED lamp above the press rod on the right side flickers (500 ms respectively in on and off) and a buzzer sounds intermittently (500 ms respectively in on and off), and the fruit juice giving is finished. Allowing the primates to freely select between the drug to be tested and the natural reward material, and counting the respective selection percentages and the number of compression bars; e. this step ends when the data variation satisfying the selection percentage and the number of struts for three consecutive days is within 20%. And drawing a dose-response curve according to the compression bar behaviors of the cynomolgus monkey to different dose gradients and the single daily dose. And from this curve, the dose with the largest response was selected as the dose for subsequent evaluation.

Figure 6c is a graph of the percentage of methamphetamine and fruit juice selection by cynomolgus monkeys at five methamphetamine doses. The results show that with the device of the invention, the reward effect value (relative to the juice) of methamphetamine on cynomolgus monkeys can be assessed comprehensively, objectively and accurately.

FIG. 6d is a graph showing the frequency of pressing the side strut in association with methamphetamine by a cynomolgus monkey under five methamphetamine dosing conditions. The results show that the device of the invention can objectively and accurately evaluate the dosage effect of methamphetamine on the cynomolgus monkey and obtain the maximum response dosage.

3. Evaluation of drug addiction behavior to be tested

(a) Assessing effects of behavioral runaway

A. When the selection percentages of the methamphetamine in different doses in the step 2 are different and the maximum value exceeds 50%, the step 3 is started, and the dose with the highest compression bar frequency is selected as the use dose for evaluating the behavior runaway effect;

B. continuously and freely selecting the machin between methamphetamine and fruit juice, wherein the testing time per day is still 120 minutes at the longest, but block is not divided, the dosage per administration is constant, the maximum reward times are determined according to the safety dosage of the medicine, and the testing on the day is finished when the times are reached;

C. the interval between the phase dials is set to 1 minute;

the FR value is calculated according to the ratio of the pressing times of a certain side pressure lever to the corresponding reward times obtained in the previous day, the FR initial value can be set manually according to the actual situation, and the FR value is unchanged in the current day;

E. before 120 minutes of daily detection, a 10-minute craving detection task is added, and within 10 minutes, the cynomolgus monkey compression bar operation does not produce any outputs such as reward sound and light stimulation, but the compression bar behavior is still recorded.

F. Evaluation end conditions: assessment will be terminated prematurely when the FR value exceeds three times its average three days prior to a sharp increase, or when the FR value exhibits an "S" shaped increase, for a maximum duration of 4 weeks.

(b) Assessment of withdrawal response (degree of craving):

the detection task paradigm is similar to step 3(a), except that: the FR value is constant and no bonus sounds, lights, etc. are output. The craving degree of the cynomolgus monkey on the methamphetamine is quantified by the pressing times of the cynomolgus monkey on the associated lateral compression bar of the drug to be tested.

(c) Assessment of relapse behavior

Detecting whether the intake of the small dose of the methamphetamine and the presentation of clues (cue) can cause the cynomolgus monkey to press the side pressure rod and the pressing amount of the methamphetamine again.

(d) Assessment of hazardous use:

the change of the weight of the cynomolgus monkey is recorded to reflect the harmful use of the drug to be tested.

Figure 6e is a graph of the percentage of selection of methamphetamine and fruit juice by cynomolgus monkey over time. The results show that the cynomolgus monkey can achieve objective and stable methamphetamine selection percentage within 3-5 days on average by using the device.

FIG. 6f is a graph showing the change in the amount of methamphetamine ingested by a cynomolgus monkey on a single day with time. The result shows that the device of the invention can objectively and accurately evaluate the uncontrolled effect of the cynomolgus monkey on the use amount of the methamphetamine.

FIG. 6g is a graph of FR values versus training days. The result shows that the device of the invention can objectively and accurately evaluate the uncontrolled effect of the cynomolgus monkey on the methamphetamine use behavior.

FIG. 6h is a graph showing the craving degree of methamphetamine by cynomolgus monkeys during withdrawal. The results show that the craving degree of the machin for the methamphetamine can be objectively and accurately evaluated by using the device of the present invention.

FIG. 6i is a graph of the data of the relapse of methamphetamine by cynomolgus monkeys. The results show that the device of the invention can objectively and accurately evaluate the relapse behavior of the machin on the methamphetamine.

FIG. 6j is a graph of weight of cynomolgus monkeys as a function of length of methamphetamine intake. The results show that the device of the invention can objectively and accurately evaluate the harmful use effect of the machin on methamphetamine.

4. Quantification of craving macaca fascicularis addiction to methamphetamine

Quantifying the reward effect, the behavioral runaway effect, the craving degree, the relapse behavior and the harmful use, respectively.

(a) Reward effect

The reward effect score is calculated based on a selected percentage value corresponding to the highest response dose of methamphetamine, specifically 0-25% is scored as 0, 25-50% is scored as 1, 50-75% is scored as 2, and 75-100% is scored as 3). In this example, the item score is 3.

(b) Effect of out of control of behavior

And (3) calculating the out-of-control behavior score according to the increase amplitude of the single daily dosage and the increase amplitude of the FR value, and recording the single daily dosage as 0 score, 1.25-2 scores 1 score, 2-3 scores 2 score and 3 scores when the single daily dosage is 1-1.25 times of the average value of the dosages in the first three days in the step 3 at the end of detection. According to the standard, the score of the item in the embodiment is 3 points; at the end of the test, the FR value is 1-1.25 times of the average value of three days before the rapid increase of the FR value and is marked as 0 point, 1.25-2 times of the FR value is marked as 1 point, 2-3 times of the FR value is marked as 2 points, 3 times of the FR value is marked as 3 points, and the point value in the embodiment is 3 points.

(c) Degree of craving

The craving degree score is calculated according to the ratio of the number of pressing rods in the withdrawal period to the number of pressing rods on the day of the last administration, and is 1 time or less and is marked as 0 point, 1-1.5 times and is marked as 1 point, 1.5-2 times and is marked as 2 points, and 2 times or more and is marked as 3 points. In this example, the item score is 2.

(b) Resorption behavior

The re-suction score is calculated according to the ratio of the number of pressing rods during the detection period of the re-suction behavior to the number of pressing rods on the day of the last administration, 0-0.25 time is marked as 0 score, 0.25-0.5 time is marked as 1 score, 0.5-0.75 time is marked as 2 score, and more than 0.75 time is marked as 3 score. In this example, the score of this item is 3 points.

(c) In a harmful use

In the aspect of harmful use, the weight is not reduced or reduced by 10 percent and is recorded as 0 point, 10 to 15 percent and is recorded as 1 point, 15 to 20 percent and is recorded as 2 points, and more than 20 percent and is recorded as 3 points. In this example, the item score is 2.

The above indexes are divided into 18 points (0 is no addiction, 1-6 is low addiction, 7-12 is medium addiction, and 13-18 is high addiction). In this example, the index score was 16 points, which is high in addiction.

Example 3 training of cynomolgus monkeys and assessment of their medication (saline solution)

In this example, cynomolgus monkeys were used as an animal model, and training and evaluation of medication (physiological saline) were performed using the apparatus of example 1.

The operating conditioned reflex, which is the association between the pressing bar operation of the cynomolgus monkey and the natural reward, is established by using the program setting that the cynomolgus monkey obtains the natural reward once after the instinct of the environmental exploration, the favor of the fruit juice and the pressing bar operation. The cynomolgus monkey sits on the primate seat assembly to complete task training, and forelimbs on two sides have the same chance to press the lever, but the special structure of the primate seat assembly determines that the forelimb on one side of the cynomolgus monkey can only press the compression bar on the same side but can not press the compression bar on the opposite side. A food reward (solid particles, similar in shape to pills) is given when the left strut is pressed by the cynomolgus monkey and a juice reward is given when the right strut is pressed. The selection percentage of each reward and the number of presses of the double-sided pressure bar were recorded.

Behavioral training at this stage uses a Fixed Ratio (FR) enhancement procedure. During training the inventors gradually increase the FR value to a fixed value, here for example 30 (increasing sequence: 1, 3, 5, 8, 13, 20, 30). Training 5 days per week, 2 hours per day, conditions for early termination of training tasks: the natural reward is given for the maximum number of times (85 times) and the operation without pressure rod is continued for 30 min. The flow and parameters of a single trial are set as follows: when the real is started, the white room lamp is turned on, if the frequency of the left side pressure lever of the cynomolgus monkey reaches a specified value, a solid reward is given immediately, the room lamp is turned off during the reward giving period, the red LED lamp above the left side pressure lever flickers (500 ms for turning on and off respectively) and the buzzer sounds intermittently (500 ms for turning on and off respectively), and the reward is finished. If the frequency of the press rod on the right side of the cynomolgus monkey reaches a specified value, a fruit juice reward (2ml) is given immediately, a room lamp is turned off during the fruit juice giving period, a green LED lamp above the press rod on the right side flickers (500 ms respectively in on and off) and a buzzer sounds intermittently (500 ms respectively in on and off), and the fruit juice giving is finished. The 60s Time-out phase is then entered, during which and reward awards, cynomolgus monkey strut operation is not counted as the number of effective struts to obtain juice, but is recorded by the software.

The following two conditions were met and the subsequent experiments were started: 1) at FR30, the reward award amount stabilized for 3 consecutive days (data change was within 10% of mean); 2) reward awards and Time-out phases are free of struts.

2. Evaluation of the rewarding Effect of physiological saline on cynomolgus monkeys

(a) Cynomolgus monkey vein intubation operation experiment

Determining the intake mode of the cynomolgus monkey according to the mode of using the medicine to be tested by the human. The intravenous administration is used as an example for illustration, and this step can be skipped if the administration is oral or other medication. A retention tube was chronically embedded in the femoral or jugular vein of the animal and the injection tip was introduced subcutaneously to the back for long-term administration. The procedure is performed by an experienced veterinarian. The procedure is briefly described as follows: under general anesthesia, the skin is cut 2cm above the femoral vein or jugular vein, the vein vessel is separated, the puncture needle is inserted into the vessel, then the implanted vein cannula is guided into the vein vessel by about 8-10cm along the puncture needle, and the vessel and the vein cannula are fixed. The other end of the venous cannula was passed subcutaneously to the back, the skin was cut 3cm, the venous catheter and the injection lumen were connected, and two incisions were sutured. And monitoring the physiological indexes of the experimental animals in real time during the operation. And (3) postoperative care: the technical animal technicians are subjected to daily care after the operation, the analgesics and antibiotics are injected once to twice every day three days before the operation, the first major debridement is carried out on the seventh day, the operation part and the periphery are cleaned, the suture line is removed, and the debridement work with the frequency of 2 days is guaranteed seven days later. After the postoperative is completely recovered, the operation can be continued.

(b) Plotting the dosage-response curve of the physiological saline of the cynomolgus monkey

According to the previous test results, the single injection dosage of the physiological saline is set to be 0, 0.1, 0.3, 1 and 3mg/kg for 5 dosage gradients, and the physiological saline is associated with the left pressure lever instead of the original solid reward. The maximum testing time of each cynomolgus monkey per day is 120 minutes, the maximum reward times in each block are 10, when the maximum reward is reached, the blocks are ended in advance, and the blocks are separated by 5 minutes. The difference between the five blocks is only that the doses of the drugs to be tested are different in a single administration, the doses of the drugs in the blocks 1 to 5 are increased in an incremental manner, and the dose in each block is not changed. The flow and parameter settings for a single trial are as follows: when the trial starts, the white room lamp lights up, if the times of the left compression bar of the cynomolgus monkey reach the specified value, physiological saline is given once immediately, the room lamp lights out during the administration, the red LED lamp right above the left compression bar flickers (the flickering frequency of the lamp corresponding to different physiological saline doses is different, 500ms is turned on and off when the dose is 0mg/kg ', 400ms is turned on and off when the dose is 0.1 mg/kg', 300ms is turned on and off when the dose is 0.3mg/kg ', 200ms is turned on and off when the dose is 1 mg/kg', 100ms is turned on and off when the dose is 3mg/kg ') and the buzzer is interrupted (the sounding frequency corresponding to different physiological saline doses is different, 500ms is turned on and off when the dose is 0 mg/kg', 400ms is turned on and off when the dose is 0.1mg/kg ', 300 is sounded when the dose is 0.3 mg/kg', 200ms each on and off when the dose is "1 mg/kg" and 100ms each on and off when the dose is "3 mg/kg"), the reward ends for the finished lot. If the frequency of the press rod on the right side of the cynomolgus monkey reaches a specified value, a fruit juice reward (2ml) is given immediately, a room lamp is turned off during the fruit juice giving period, a green LED lamp above the press rod on the right side flickers (500 ms respectively in on and off) and a buzzer sounds intermittently (500 ms respectively in on and off), and the fruit juice giving is finished. Allowing the primates to freely select between the drug to be tested and the natural reward material, and counting the respective selection percentages and the compression bar times; e. this step ends when the data variation satisfying the selection percentage and the number of struts for three consecutive days is within 20%. And drawing a dose-response curve according to the compression bar behaviors of the cynomolgus monkey to different dose gradients and the single daily dose. And from this curve, the corresponding maximum dose is selected as the dose for subsequent evaluation.

FIG. 7a is a graph of the percentage of selections of physiological saline and fruit juice by cynomolgus monkeys at five physiological saline doses. The results show that the reward effect value (relative to the juice) of the physiological saline on the cynomolgus monkey can be comprehensively, objectively, accurately and truly evaluated by using the device disclosed by the invention.

FIG. 7b is a graph showing the pressing frequency of the cynomolgus monkey against the physiological saline related side pressing bar under the five physiological saline dosage conditions. The results show that the dosage effect of the physiological saline can be objectively, accurately and truly evaluated on the cynomolgus monkey by using the device of the invention.

Figure 7c is a graph of the percentage of cynomolgus monkey selection versus physiological saline and juice selection as a function of time. The results show that the cynomolgus monkey can reach objective and stable physiological saline selection percentage within 3-5 days on average by using the device of the invention.

3. Evaluation of drug addiction behavior to be tested

(a) Assessing effects of behavioral runaway

A. When the selection percentages of the physiological saline with different dosages in the step 2 are different and the maximum value exceeds 50%, the step 3 is carried out, and the dosage with the highest compression bar frequency is selected as the dosage for evaluating the behavior runaway effect.

4. Quantification of craving macaque addiction to physiological saline

(a) Rewarding effect

The reward effect score is calculated from a selected percentage value corresponding to the highest response dose of saline, specifically 0-25% is scored as 0 point, 25-50% is scored as 1 point, 50-75% is scored as 2 points, and 75-100% is scored as 3 points). In this embodiment, the item score is 0.

(b) Effect of out of control of behavior

According to the method, the item score in this embodiment is 0.

(c) Degree of craving

According to the method, the item score in this embodiment is 0.

(d) Resorption behavior

According to the method, the item score in this embodiment is 0.

(e) In a harmful use

According to the method, the item score in this embodiment is 0.

The above indexes are divided into 18 points (0 is no addiction, 1-6 is low addiction, 7-12 is medium addiction, and 13-18 is high addiction). In this example, the index score is 0, and the drug is not addictive.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A device for evaluating drug addiction of primates, comprising a main body of a console for accommodating a subject animal and an animal holding system; the operation box main body comprises: the system comprises an interaction module, an input module, an output module, a reward module, a monitoring module, a vital sign monitoring module and a recording-control module; the interaction module is used for interacting with animals and comprises an interaction panel, wherein part of components of the input module, the output module, the reward module or the monitoring module are arranged on the interaction panel; the reward module includes: a solid reward submodule, a liquid reward submodule and an automatic administration submodule.

2. The apparatus of claim 1, wherein the input module is to receive behavioral information of an animal;

the output module is used for transmitting stimulation signals to animals;

the reward module is used for giving a reward to the animal;

the monitoring module is used for monitoring animals, and preferably comprises monitoring the behaviors and/or the head-face performance of the animals;

the vital sign monitoring module is used for monitoring vital signs of animals; and/or

The recording-control module is used for acquiring, recording, analyzing and/or transmitting the information of the input module, the output module, the reward module, the monitoring module and the vital sign monitoring module.

3. The apparatus of claim 1, wherein the input module comprises a strut module comprising a left strut and a right strut, located to the left and right, respectively, of a vertical centerline of the interactive panel; preferably, the depression bar module includes depression bar box, depression bar board, micro-gap switch, bar box dynamometer, the depression bar box sets up on mutual panel, bar box dynamometer and micro-gap switch are located the depression bar box, the depression bar board passes the antetheca of depression bar box and stretches into in the depression bar box, with bar box dynamometer and micro-gap switch looks linkage, the animal is through pressing the depression bar board and then starting micro-gap switch, measures and adjusts required pressing force size through bar box dynamometer.

4. The device of claim 3, wherein the microswitch is disposed on a microswitch tray that is located below the box interior portion of the ram plate; the microswitch is in operable communication with the recording-control module and is used for transmitting the times of the pressure lever and the time length data of single pressing; and/or

The vertical distance between the lower edge of the strip-shaped box force measuring shaft and the microswitch is used for adjusting the resistance of the pressure rod, and the reward difficulty is obtained by adjusting the resistance of the pressure rod; preferably, the adjustable range of the resistance is 0-10N.

5. The apparatus of claim 1, wherein the input module comprises a touch screen module located on an interactive panel; preferably located in the center of the interactive panel and between the left compression bar and the right compression bar of the compression bar module; the touch screen module is in operable communication with the recording-control module and transmits operation information of the animal on the touch screen.

6. The apparatus of claim 1, wherein the output module comprises a notification light, a speaker, a blowing module; each component is in operative communication with the recording-control module and receives information from the recording-control module.

7. The apparatus of claim 6, wherein the notification lights comprise at least one left notification light and at least one right notification light, disposed on the left and right sides of a vertical centerline of the interactive panel, and at least one upper notification light; preferably, the left prompt lamp and the right prompt lamp are respectively positioned above the left pressure lever and the right pressure lever; preferably, the left prompt lamp and the right prompt lamp are different in color, and the upper prompt lamp is different from the left prompt lamp and the right prompt lamp in color; or

The loudspeaker is positioned on the inner wall of the operation box main body or the interactive panel; or

The blowing module is positioned on the wall of the operation box main body and is communicated to the front of the animal face positioned in the operation box main body through a pipeline; preferably, it is in operative communication with the recording-control module to control the delivery of air flow stimuli to the animal's face for a preset specified duration, speed and flow rate.

8. The apparatus of claim 1, wherein said solid reward submodule, said liquid reward submodule, and said automatic administration submodule of said reward module are each in operative communication with said log-control module for controlling administration of a drug to an animal, for controlling administration of a liquid reward, or for controlling administration of a drug automatically.

9. The apparatus of claim 8, wherein the solid reward sub-module comprises a particle pump, a conduit and a food bowl, the particle pump is located outside the main body of the console, and the conduit communicates with the food bowl located inside the main body of the console; preferably, it is in operative communication with the recording-control module, controlling the delivery of a predetermined amount of solid food or drug particles to the animal; preferably, the trough is located on the interactive panel; or

The liquid reward submodule comprises an injection pump/peristaltic pump positioned outside the operation box main body and communicated to an animal mouth part positioned inside the operation box main body through a pipeline; preferably, in operative communication with the recording-control module, controls the delivery of a predetermined amount of liquid to the animal; or

The automatic dosing submodule comprises an injection pump/peristaltic pump positioned outside the operation box main body and communicated to an animal body positioned inside the operation box main body through a pipeline; preferably, in operative communication with said recording-control module, controls the injection of a predetermined amount of medication into said animal; more preferably, the injection is intravenous.

10. The apparatus of claim 1, wherein the monitoring module comprises: a behavior monitoring submodule and a head and face monitoring submodule; preferably, the behavior monitoring submodule is located in the operation box main body, or the head and face monitoring submodule is located on the interaction panel;

preferably, the behavior monitoring submodule or the head and face monitoring submodule is a camera.

11. The apparatus of claim 1, wherein said vital signs monitoring module includes a thermometry module in operative communication with said recording-control module for conveying animal temperature information; preferably, the temperature measuring module is located outside the operation box main body and measures temperature through a probe hole located on the wall of the operation box main body.

12. The device according to any one of claims 1 to 11, wherein an interaction panel of the interaction module is provided with: a compression bar module and a touch screen module in the input module, a prompt lamp in the output module, a solid reward submodule in the reward module and a head and face monitoring submodule of the monitoring module.

13. The apparatus of claim 1, wherein said console box body further comprises a component selected from the group consisting of:

a lighting assembly;

the temperature probe is used for measuring and/or monitoring the temperature in the operation box main body; and/or

And (7) air exchange ports.

14. The apparatus of claim 1, wherein the animal fixation system is a primate seat assembly; preferably, it comprises a support, two side panels, a front panel, a back panel and a base, which are mutually enclosed to form a seat space suitable for primates; preferably, the fixing component for fixing the arms of the bilateral forelimbs of the animal realizes that the forelimb on one side of the animal can only touch the pressure lever on the same side.

15. The device of claim 14, wherein the bracket is formed by splicing four circular/square columns vertically and upwardly fastened to four corners of the base respectively and a plurality of transverse circular/square pipes, and the connected circular/square pipes are fixed by a detachable fastener; and/or

The seat assembly further comprises an upper panel for securing the primate neck, mounted on top of the support by a clamp; and/or

The seat assembly further comprises a fixing assembly for fixing bilateral forelimb arms of the animal, wherein the fixing assembly is fixed in the middle of the bracket through a fastener and is positioned above the primate seat assembly; and/or

The side panels and panels are secured to the seat assembly by removable retainers; and/or

The front panel and the rear panel are single-door.

16. The apparatus as claimed in claim 1, wherein the inner bottom of the main body of the operation box is further provided with a slide rail, and the animal fixing system is provided with a pulley matched with the slide rail, so that the animal fixing system can move along the slide rail.

17. The apparatus of claim 1, wherein said cabinet body includes at least one cabinet door; preferably, it is provided as a single door; preferably, the operation box door is opposite to the front surface of the interaction panel; or

The length of a box body of the operation box main body is 500-1200 mm, the width of the box body is 500-1200 mm, and the height of the box body is 1000-2000 mm; preferably 650 to 1000mm in length, 650 to 1000mm in width and 1200 to 1800mm in height; more preferably 700 to 900mm in length, 700 to 900mm in width and 1350 to 1650mm in height; or

The bottom of the operation box main body is also provided with a pulley, so that the operation box main body can be moved; or

The operation box main body comprises a sound insulation material or is prepared from the sound insulation material.

18. Use of the device for primate drug addiction assessment according to any one of claims 1-17 for:

self-administration strengthening training of primates;

primate drug reward effect assessment;

evaluating the incontrollable effect of the drug behavior of the primate;

evaluation of drug craving degree of primates;

evaluating drug tolerance effect of the primate;

evaluation of harmfulness of primate drugs;

primate conditioned reflex training.

19. The use of claim 18, wherein the primate is a non-human primate; preferably, the primate comprises: monkeys, gibbons, orangutans; more preferably, said monkeys include monkeys selected from the group consisting of: rhesus monkey, cynomolgus monkey, Japanese macaque, green monkey, marmoset monkey, squirrel monkey.