Self-administering drug device in laboratory mice

Abstract

The self-administration device is a standard chamber for laboratory mice designed to simulate the injection of addictive substances in humans. This device has two parts: hardware and software. The hardware part includes five structures: the chamber, the infusion pump, the food dispenser, the stimulator, and the controller (interface). The software part controls the hardware parts and records events automatically. The chamber has three keys, each of which can be assigned to one of the effectors. To do this, we define in the device software that pressing one key by the animal activates the infusion pump, another key activates the feeder, and the third key does nothing in particular so that the animal's overall motor activity can be measured with it. Above each key, there is an indicator lamp that, if programmed in the software, lights up each time the animal presses that key, signaling to the animal that the drug is being injected or that the truffle has been deposited in the bowl. In this way, in the long term, the animal learns which key to press if it wants to inject itself with a drug, and which key to press if it wants to eat a truffle. In this way, the state of addiction to substances or food, as well as their interactions and the neural mechanisms associated with them, can be studied.

Description

Description of the invention Title of the invention Self-administering drug device for laboratory mice Technical background of the relevant invention This invention relates to the field of medical research in the field of drug and psychotropic drug addiction. The present invention is a device that simulates the state of addiction in laboratory mice, the innovative aspect of which is that it can provide the animal with the desired and selective consumption of injectable addictive substances and eating food or sweets. Technical problem and stating the objectives of the invention According to official statistics announced by the Iranian Ministry of Health, the number of drug addicts in the country who use it daily is about two million two hundred thousand people. Therefore, drug dependence is one of the most important health problems in our country and research in this field is one of the country's health priorities. Unfortunately, despite numerous studies conducted around the world and over many years, a suitable treatment solution for addiction has not yet been found, one of the main reasons for which is the lack of suitable animal models for this problem. Two common animal models in preclinical studies of addiction are the conditioned place preference method and the self-administration method, the latter method being superior to the former method due to the use of operant conditioning instead of classical conditioning. However, in current self-administration devices, no solution has been seen to investigate the mutual effect of addictive substances and natural rewards on the neural circuit of the brain.Therefore, it is not possible to examine how the animal's desire to consume drugs changes in the presence of natural pleasurable factors such as food. Previous studies have also shown that the use of morphine or heroin increases the desire to eat sweet foods, while withdrawal from these drugs in the acute phase reduces the desire for sweets, which is a manifestation of anhedonia. Anhedonia is one of the disorders associated with addiction in which the patient does not get enough pleasure from natural rewards such as eating and sexual activity, etc. (the pleasure threshold increases), which in turn can affect the high rate of relapse to drug use. In the current self-administration method, the pleasure associated with taking or quitting drugs cannot be measured. This is while any treatment strategy proposed for addiction, in addition to reducing drug use and reducing the likelihood of relapse, should also be able to reduce pleasure. Accordingly, we developed a device that is capable of simultaneously measuring the level of craving for addictive drugs and the craving for food (or sweets). A description of the state of the prior art and the history of developments related to the claimed invention. Drug self-administration devices are used to investigate the neural and biological bases of addiction in animal models. A self-administration system consists of a data collection system, computer-controlled systems, operant chambers, food dispenser, constant-rate infusion pump, and an intravenous infusion channel. The operant chamber (30 × 25 × 32 cm) is made of stainless steel and provides a sound-attenuated environment so that the noise of the environment and other animals does not affect the concentration and activity of the animal being tested. The chamber is ventilated and its temperature is maintained at around 21 °C. There are two levers or nose-poke holes approximately 14 cm apart: an active key and an inactive key. The keys can be opened and closed and can be accessed or removed. Whenever the animal presses the active key (or touches its nose to the sensor embedded in the active hole in the wall of the apparatus), it automatically receives an intravenous injection of a certain amount of narcotic or psychotropic drug. The inactive key is used to measure unconditioned behaviors (or to design more complex conditions for receiving a reward). Four centimeters above each key or muzzle hole is a red or white stimulus light, and there is a tone for each key.In some models, sixteen light beams are placed in the chamber to measure horizontal and vertical movements. A swivel joint minimizes the animal's movement restriction and prevents kinking of the delivery tubing, damage to the intravenous catheter, and irritation of the catheter attachment point in the animal's skin, which can lead to scratching. A balance arm holds the delivery tubing taut to prevent the animal from manipulating or chewing it. An infusion pump rapidly (usually less than 10 seconds) delivers a specified amount of material into the animal's vein after the animal has made a sufficient response (such as pressing a key a certain number of times). All responses to each key are recorded by an electromechanical counter and event recorder. In some models, food is provided to the animal instead of an injection of material when the active key is pressed. To deliver an electric shock to the sole of the foot, there is a barbed plate on the floor of the chamber connected to a current / voltage source (stimulator). A patent for a self-administration device has been registered in Iran with the number 89643 on 1 / 6 / 1395. A review of the specifications of this device shows that it is designed and manufactured for inhalation self-administration of substances and does not include capabilities related to oral and intravenous self-administration of substances. The specifications of this device are as follows: The device is made of plexiglass and is equipped with 2 keys (active and inactive), a red light above the active key, a roof without holes, 2 fans (blower and suction) and a hot plate. Metal rods are installed in the bottom of the chamber to be able to create foot shock and stress the animal. The inhalation self-administration section of the device includes a 3 cc syringe containing a drug solution of a certain concentration. By pressing the active key, this solution is poured onto the hot plate located adjacent to the chamber and, after evaporating, is blown into the chamber by the blower fan. This fan operates for 15 seconds and after it turns off, the suction fan removes the hot air from the hot plate so that the animal is not disturbed. The absence of holes and vents in the ceiling of the chamber prevents the dispersion of drug vapors in the room. In 2018, Zhang Shanshan of ANHUI DONGSHI SOFTWARE TECHNOLOGY filed a patent in China under the numbers CN108243977 and CN208129163, which designed a self-administration device for rats or mice, similar to the classic type but designed for longer-term experiments. There was no possibility of oral administration of food or substances in this device. In 2016, Michael M. Scott from the University of Virginia, USA, registered an invention with the number US20160287366 that has the ability to self-administer inhaled substances in response to a specific behavior from laboratory mice, thus being able to measure the animal's behavioral and physiological response to the administered substance. In 2018, LIU HANQING and colleagues from Peking University registered a device with the number CN107582211, which is used for self-inhalation administration of atomized medicine to rodents. In 2007, Mead Andy N. and colleagues from the University of Virginia patented a device with patent numbers US20070006814 and WO2004066705A2 that can administer medication to laboratory mice as an intranasal spray after sensing the presence of an animal in a target chamber. In 2014, José Antonio LÓPEZ MORENO from the Universidad Complutense de Madrid patented a device with patent number ES2439816A1 that allows for self-administration of inhaled substances in laboratory animals. Based on what was said above, although the inhalation method of drug administration in animals can in itself simulate one of the methods of drug consumption in addicted patients, so far, a device that can provide simultaneous administration of drug (in the form of intravenous injection) and food / drug / sweets (orally) in an animal model of addiction has not been developed. Providing a solution to an existing technical problem along with an accurate, sufficient, and integrated description of the invention To solve the problem of simultaneous assessment of drug craving and food craving in the addiction model, this device uses three keys instead of two: (1) a key for intravenous injection, (2) a key for food delivery, and (3) a passive key. In general, this device has two parts: hardware and software. The hardware part includes five chamber structures, an infusion pump, a food dispenser, a stimulator, and a controller or interface (Figures 1 and 2). The software part controls the hardware parts and records events automatically. 1. Hardware section 1-Room The chamber of the device is where the laboratory rat is placed to measure addictive behavior. The body of the chamber is made of dark opaque plexiglass with a thickness of 8 mm and dimensions of 30 × 30 × 30 cm. The connection of the walls is completely solid and non-slip. The walls of the chamber are supported from the outside by aluminum columns. On the front view of the chamber, there is a hinged door that opens outwards on the left wall and latches on the edge of the right wall so that the animal cannot leave the chamber. The floor of the chamber is covered with steel rods with a diameter of 1 cm, which are placed at a distance of 1 cm from each other as a railing. The floor of the cage is made as a sliding square frame that can be removed from the chamber for washing. When it is placed in its place, it is connected by pins to sockets embedded under the opposite wall, and thus connected to the stimulator located outside the chamber to apply an electric shock to the animal's feet if necessary.Under the floor of the cage is a removable, washable, and replaceable tray that collects the animal's waste during the experiment. The right wall has three steel pedal-shaped switches with a width of 4 cm and a distance of 3 cm from each other, which are placed at a height of 10 cm from the floor of the cage. Under the middle switch, at a distance of 2 cm from the floor of the cage, a cubic chamber with dimensions of 5 cm is installed as a food receiver, into which food is deposited by the dispenser. The switches can be opened and closed automatically by the software. The degree of mechanical hardness or softness of pressing the switches, as well as their response sensitivity, can be adjusted. Above each switch is a signal lamp with a different color light to signal the mouse. Pressing each of the keys by the animal results in a programmed response, such as intravenous injection of substances by an infusion pump, or food by a dispenser, or the application of an electric shock to the sole of the foot by a stimulator.A sound generator is located on the outer side of the right wall to emit a warning sound of a certain intensity and frequency when the drug is injected. In the upper wall of the chamber (roof), there is a narrow slit 1 cm wide in the midline from front to back, which leads to a circular hole with a diameter of 5 cm at the midpoint of the wall. This slit allows the animal to easily connect the infusion pump and catheter. The hole located in the middle minimizes the movement restriction of the animal. A lightweight single-jointed steel balancing arm is attached to the outer part of the left wall, its free end is located above the middle hole and keeps the swivel suspended by a retaining ring, so that as the mouse moves horizontally in the chamber, the arm moves up and down so that both the catheter connected to the jugular vein is not under excessive tension and the catheter is not accessible to the animal. The swivel is a piece that allows the catheter to rotate without bending or twisting as the animal rotates. It keeps the drug injection path open.A metal spring is located at the other end of the arm, which adjusts the amount of load required to move the arm. A spring leash, attached to the bottom of the swivel, holds the catheter in place and protects it from chewing by the animal, as well as providing easy and smooth rotation of the swivel. The opposite end of the leash is attached to a back plate that was previously placed under the skin between the animal's shoulder blades. The left wall of the chamber has a white chamber lamp to illuminate the chamber and a silent fan that prevents the temperature from rising in the chamber by providing proper ventilation. 2-Infusion pump The infusion pump consists of a syringe holding mechanism and a moving mechanism. The holding mechanism is used to hold the syringe stationary during pump operation, allowing for syringe replacement, and the moving mechanism includes a plunger on the finger portion of the syringe. The motor is connected to the plunger by a system, and there is a round knob to adjust the position of the plunger on the finger portion of the syringe. The motor's action causes the syringe piston to move. 3-Food distributor The food dispenser consists of a container and a dispensing mechanism. The food container is cylindrical in shape. The dispensing mechanism is a chamber (container) located inside the main container and connected by a shaft to the motor at the bottom of the main container. The container has 9 holes in the bottom with equal diameter and symmetrically on the edge of the plate. In the bottom of the main container, there is a hole in the edge of the container, the center of which is aligned with the center of the holes in the container, and when each hole in the container is opposite this hole, the food in the hole in the container is released from this hole and poured into the animal's food container in the main chamber through an intermediate tube. 4-Stimulator The stimulator is the mechanism that delivers the shock, which consists of an electronic unit and an electrode plate. The electronic unit generates a pulse upon receiving a command and sends it through a wire to the electrode plate. The electrode plate is a plate on the floor of the main chamber that consists of a row of evenly spaced rods that are connected to opposite poles, one after the other. 5-Controller The controller is an electronic unit that manages the entire system and includes a power supply, a microcontroller board, and a relay board. The power supply board supplies power to the device. The microcontroller board controls and manages communication with the software and hardware. The relay board controls (turns on and off) the chamber lamps and fan with commands received from the microcontroller board, and also controls and manages the infusion pump, food dispenser, stimulator, and chamber, and receives the necessary commands from the sensors (chamber switches). First, the controller unit is set up through the information it receives from the software, and based on these settings, the controller unit controls and manages the device. 2. Software section The software can automatically control all components of the device and record the animal's behavior. This software can: (1) individually turn each of the lamps on or off, open and close the switches, start or stop the pump, start or stop the stimulator, and play or stop the alarm sound, (2) record the number of times each of the keys is pressed and the number of times the drug is injected, (3) determine the active and inactive keys, (4) determine the behavior-response pattern with its details (fixed ratio or progressive ratio), i.e., specify how many times the active key is pressed to cause the device to respond (injection and its accompanying symptoms) and how the number of key presses should change to go from one injection to the next, (5) if sufficient response conditions are met, create a coordinated response, i.e., start the infusion pump to inject a specific volume of drug in a specific time (usually 5 to 10 seconds) and at a specified rate, and turn the indicator lamp above the active key on for a specific time (usually 5 to 10 seconds). seconds), turn on the chamber lamp for a specified period of time (usually 20 seconds)slow, play the alarm sound for a specified period of time (usually 5 to 10 seconds), record any additional pressing of the active key during these responses but do not cause a new response, and finally, when the specified time expires, disable the pump response, turn off the indicator lamp, turn on the chamber lamp, stop the alarm sound, and make the active key sensitive to subsequent presses. (6) If previously defined, deliver a food to the animal by pressing the key and produce responses similar to the previous case. (7) If previously defined, deliver an electric shock with specific characteristics in terms of duration, intensity, and frequency to the animal's foot by pressing the key. Or, deliver this shock without the animal pressing the key and according to the experimenter's instructions. To reduce complexity and produce a user-friendly product, a microcontroller was used for hardware management and Windows-based software for the user interface. Considering the product structure, we have the following two software sections: (1) Hardware management software (microcontroller) and (2) User software. 1-Hardware management software This part of the software is written in C language. Its main purpose is to manage the hardware part based on the information received from the user software and send the hardware status to the user software. The parts that this software controls are as follows: –Control the status of lights (4 pcs.) –Key status control (3 pcs.) –Fan status control (1 pc.) –Beezer control (1 pc.) –Food dispenser control (1 pc.) –Infusion pump control (1 pc.) – Stimulator control (1 pc.) The following data is also sent by the hardware driver software to the user software: –Change the status of the keys (keys in and out, 3 pieces) –Change the activation status of the keys (activated and deactivated keys, 3 pcs.) -Change the status of the lamps (4 pcs.) –Change fan status (1 pc.) –Change the status of the buzzer (1 piece) –Change the status of the food dispenser (1 unit) –Change the status of the infusion pump (1 unit) –Change the stimulator position (1 piece) The overall product process, which is controlled and managed by the hardware management software, is as follows: – The fan turns on during the test and turns off at the end of the test. -Turning on the main light of the chamber at the beginning of the test and managing its on and off during the test based on the activation of the keys or changing the position of the food dispenser or stimulator or infusion pump, according to the programming that the user has done in the user software, and turning off the main light at the end of the test. – Each key is on or off based on the user's programming before the test begins. -Turning on and off the light for each key at the start of the test and managing whether it is on or off during the test based on the activation of the keys or the change in the status of the food dispenser or stimulator or infusion pump, according to the programming that the user has done in the user software, and turning off all the lights at the end of the test. -Activation and deactivation of the food dispenser during the test based on the activation of the keys and according to the programming that the user has done in the user software. -Activation and deactivation of the infusion pump during the test based on key activation and according to the programming that the user has done in the user software. -Activation and deactivation of the stimulator during the test based on the activation of the keys or the change in the status of the food dispenser or infusion pump, according to the programming that the user has done in the user software or performs the stimulation directly during the test. 2-User software The user software is designed and written in C# on the Windows platform, and uses an Access database to store data. Excel is also used to provide output to the user. The main purpose of the user software is to store the initial test parameters, manage the entire test cycle, communicate with the hardware driver software, and send and receive data to control, manage, and record the data of each test, and provide reports to the user at each stage of the test cycle. The design also attempts to make the software environment user-friendly. The core of the user software has been developed based on the following criteria. –Test phases –Number of animals in each phase –Type of drug –Test time – Continuous or intermittent testing In intermittent testing, the time of being active and inactive –Activating and deactivating keys in each phase separately –Number of key presses (food, medicine, inert) -The key response pattern includes the following two types, depending on the key stimulation and the ability to be defined separately for each phase: Fixed ratio, in which a specific response is given based on a specific number of key presses. Progressive ratio, in which a specific response is given based on a stepwise increase in key presses at a specific slope. -Keypress response characteristics can be defined separately for each phase, including the following: Injection duration Amount of food waste Number of food spills The duration of the room lamp turning off  Duration of indicator light on The duration of sound generation is on Duration of shock application Interruption duration -How to receive food, medicine, and shock based on defined keys – Amount of food intake –Time intervals between two meals –Maximum number of meals received – Amount of medication received –Time intervals between two drug intakes –Maximum number of times the medicine is taken –Number of shocks received –Intervals of receiving shocks –Main lamp on and off time – Indicator lamp on and off time The software has two categories of windows, as follows: –The first series of windows, for general program settings and communication with hardware (Figure 3) – The second series of windows, for creating and opening an experiment (project), includes the following processes (Figure 4): Create experiment: capture and store initial experiment parameters Opening the experiment includes the following windows: oMain window (Figure 5) Main display of initial parameters Select current test specifications Executing tests (hardware communication) Test storage  Ability to be redirected to the initial parameters editing window  Ability to be redirected to the report window o Initial parameters editing window: Ability to edit all parameters oReport window (Figure 6): Ability to get a report of all data based on the main test specifications The software work process is as follows: The software first receives the test parameters from the experimenter in a window. This window has a number of tabs, each tab is defined based on a category, and on that basis it receives input values ​​from the user. To work with the device, after opening the software and then clicking on the File / Open menu, the experiment window opens. The program allows the user to activate the device by selecting the drug, animal number and test phase. After clicking on the Prepare Device button, then Start, the device starts operating. During the activation period, the device can be stopped with the Stop button. The results can be saved with the Save button and the window status can be set to the device preparation mode with the Cancel button. In this window, the number of key activations (food, drug and inert), the number of indicator lamps (food, drug and inert), the number of food deposits and the number of drug injections and the number of main lamp illuminations, stimulator illuminations and sound illuminations are displayed. All results are stored in the database and the user can export the data to Excel through the reporting window. Explanation of shapes, maps and diagrams Figure 1 shows the main hardware parts of the device, which are, respectively, 1: chamber; 2: syringe pump; 3: food dispenser; 4: stimulator; and 5: controller. Figure 2 shows the overall view of the device and the location of the hardware components from different directions. Figure 3 shows the user interface. A project (experimental procedure) can be defined from the File menu. After creating a project file, opening it takes the user to the experiment registration window (Figure 4). The settings menu allows the responding hardware components such as the infusion pump, dispenser, and stimulator to be programmed. For example, the infusion pump can be programmed for the volume and speed of each injection by specifying the size and volume of the syringe. Or the stimulator can be programmed for the voltage and frequency of the foot shock. Figure 4 shows the experiment registration window. In the different tabs of this window, you can specify the exact characteristics of each experiment and its execution process. Figure 5 shows the experiment window. During the experiment, when the animal is in the device and shows the agent's behavior on the keys, this window displays the progress of the work to the user at any moment. Figure 6 shows the reporting window. At the end of each animal, the experimental data is saved in the user software. If necessary, the user can use this window to output the data to an Excel file based on selected criteria. A clear and precise statement of the advantages of the claimed invention over prior inventions. In classic examples of this device, there are two switches, one active and one inactive. Pressing the active switch causes the injection of drug into the rat's jugular vein, but pressing the inactive switch does not cause any programmed response. The response on the active switch (the number of presses) is an indicator of the animal's craving for the drug, while the response on the inactive switch is an indicator of the animal's general, non-specific motor activity. The innovation of the present device is that by simultaneously providing an addictive drug and a natural food, it will provide a better animal simulation of addiction in humans. In the classic device, the laboratory animal can only choose whether to receive the addictive drug or not. However, in the present device, the animal can choose between two options, namely the drug or a food (food or sweets). Therefore, the function of the neural circuit responsible for pleasure in the brain can be examined when faced with pleasure from drugs or pleasure from natural rewards. For example, one of the characteristics of drug addiction is that the person involved does not get enough pleasure from natural rewards such as eating and seeks more pleasure from drugs or psychotropic substances. This condition is called anhedonia. To examine whether a drug treatment or research intervention can reduce the amount of drug intake, responses on the active key are considered. However, in the current classic device, there is no solution to answer whether that treatment or intervention has been able to improve anhedonia.To solve this problem, we used three switches in our design. An active switch for drug injection, an active switch for food reward such as truffles, and an inactive switch to examine nonspecific motor activity. Therefore, theoretically, an ideal treatment for drug abuse would be one that could reduce the animal's behavioral response to the drug switch while simultaneously increasing its behavioral response to the reward switch. Also, if a natural food is replaced with an addictive food, a situation of polydrug abuse can be examined. Description of at least one implementation method for implementing the invention To use this device, a number of rats in the weight range of 300 to 330 grams are used, which are kept in completely standard conditions with appropriate temperature and humidity, in a 12-hour reverse light and dark cycle, and with full access to water and sufficient food. The different stages of the experiment can vary depending on the research question in question. For example, the following steps can be performed: 1- Compatibility: Initially, rats adapt and become accustomed to laboratory conditions within a few days. 2-Learning to press the right key to get truffles: The right key of the chamber is opened and made available. The rat is placed in the chamber for two hours and allowed to roam freely. If the rat presses the right key, a truffle is deposited into the food bowl by the food dispenser for each press. This trial is repeated for several days. The criterion for learning at this stage is reaching a stable level of truffle intake (less than 20% variation) in three consecutive sessions. 3- Right jugular vein catheterization and 7-day recovery period: The animal is placed on its back and the jugular vein is located just above the clavicle. With a sterile surgical blade, a 1.5 to 2 cm long diagonal incision is made in the skin from below the vein upwards and outwards. The incision is opened using forceps, flushed with sterile saline and covered with sterile gauze. The animal is turned over onto its stomach and a 2 cm long longitudinal skin incision is made from the point between the two scapulae downwards. Using surgical forceps, separate the skin from the underlying tissues to provide space for the catheter base. Lift the skin edge with forceps and continue the incision upwards for another 5 mm with scissors. This should make the incision large enough to fit the catheter base without stretching the skin. The animal is turned over onto its back and with forceps, free the skin around the anterior incision from the underlying tissues. Then, with a pair of forceps, with the tip closed, we create a subcutaneous passage from the front incision to the back incision, and we remove the tip of the forceps from the back incision and keep it closed in the same position.Then, we open the forceps, grab the catheter with it, and advance it through the skin into the incision. Using fine, slant-headed forceps, we separate the tissues around the jugular vein and release a length of about 5 to 8 mm of the vein without tearing or damaging it. We pass a piece of suture thread under the vein and tie a knot on the side closest to the head to block blood flow from the brain. We pass another suture thread under the vein and tie a loop with a loose knot around it and hold it on the side closest to the heart. We open the forceps from the tip of the catheter and flush the catheter path with saline. We pass a fine metal rod with a diameter of 1 mm and a length of 5 cm under the vein and pull it upwards to provide a suitable bed for making an incision on the vein. Using fine scissors, make a small V-shaped incision in the vein and insert a needle, previously cut lengthwise and shaped into a funnel, 5 mm into the vein. Push the catheter through the funnel of the needle into the vein and then remove the needle. Flush the catheter path once more with saline to ensure patency.You can also aspirate the syringe a little to see if the catheter is open by seeing blood entering it. Then we tighten the suture knot, fix the catheter in place, and close the neck incision. Place the catheter base in the dorsal incision, fix the catheter in it, and then close the incision. We wash the catheter path with heparinized saline and put the cap on it. Then the mouse undergoes a 7-day recovery process. 4-Learning to self-prescribe morphine: At this stage, all three keys are available. Each press of the left key delivers morphine intravenously, and each press of the right key deposits a truffle. The learning criterion at this stage is to achieve a stable level of morphine intake with less than 20% variation over three consecutive sessions. The average intake over the final three sessions is taken as baseline intake. 5- Morphine intake stabilization phase: At this stage, all three keys are available. By pressing the left key 5 times, morphine is injected intravenously, and by pressing the right key, a truffle is deposited. The learning criterion at this stage is reaching the baseline level of morphine consumption. 6-Step to stop self-prescribing: In this stage, all keys are available. By pressing the left key 5 times, saline is injected intravenously instead of morphine, and with each press of the right key, a truffle is deposited. The criterion for learning in this stage is a reduction in the number of left key presses to less than 20% of the stabilization stage. The criterion for the presence of unpleasantness is a significant reduction in the number of right key presses compared to the final response seen in stage 2. 7- Self-prescription recovery stage: One day after the extinction phase, morphine-seeking behavior is reinstated by foot shocks delivered intermittently for 10 min. After the shock period, all three keys are made available. A response on the left key results in an injection of saline, and a response on the right key results in a truffle deposit. A response on the middle key results in no programmed consequences in all phases. Explicit mention of the industrial application of the invention This device is used for research laboratories of universities and educational and research centers that are especially active in the field of addiction studies. With this device, in addition to the animal's craving for addictive substances, it is possible to measure its desire to eat sweet truffles, and thus examine the mutual influence of drug rewards and natural rewards on each other in cases such as aversion. Also, if truffles are replaced with edible addictive substances, the state of multidrug abuse can be examined. In addition, since the device has the ability to deliver electric shocks, it is possible to simulate the desire to use drugs in difficult and stressful situations.

Claims

Complaint What is claimed: Claim 1) What is claimed is a device for simulating drug addiction in laboratory mice that, by having an operant switch and a conditioned light in addition to common models, can provide the animal with free choice between an injectable addictive substance and a natural oral reward, make it possible to examine the mutual influence of each on the other, and, if necessary, administer a painful and stressful electric shock to the animal simultaneously with the presentation of the addictive substance or oral reward.

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