CN114432461A - Method for evaluating nicotine addiction degree or evaluating influence of drug to be tested on nicotine addiction degree - Google Patents
Method for evaluating nicotine addiction degree or evaluating influence of drug to be tested on nicotine addiction degree Download PDFInfo
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- CN114432461A CN114432461A CN202111492044.7A CN202111492044A CN114432461A CN 114432461 A CN114432461 A CN 114432461A CN 202111492044 A CN202111492044 A CN 202111492044A CN 114432461 A CN114432461 A CN 114432461A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
- A01K67/027—New breeds of vertebrates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/465—Nicotine; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
Abstract
The present invention provides a method for evaluating a degree of nicotine addiction or evaluating an influence of a drug to be tested on the degree of nicotine addiction, which comprises S1) providing an aqueous solution containing nicotine as a sole water source for a test animal, feeding and recording the number of times the test animal licks the aqueous solution containing nicotine, and obtaining a test animal model for nicotine addiction when the number of times the test animal licks the aqueous solution containing nicotine is stable; s2) replacing the water source with water solution without nicotine to obtain test animal model for nicotine withdrawal; s3) evaluating the degree of nicotine addiction by evaluating the number or frequency of licking the water source by the test animal that produced the nicotine withdrawal, or by evaluating the effect of the test animal on the degree of nicotine addiction by licking the water source after administering the test animal with the test drug. The preparation method of the animal model is very simple, does not need surgical procedures, and can quantitatively evaluate the addiction and withdrawal degree of the test animal.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a method for evaluating nicotine addiction degree or evaluating influence of a to-be-tested medicine on nicotine addiction degree
Background
Nicotine is a main addictive substance in tobacco, and is also a main addictive ingredient in nicotine electronic cigarette tobacco tar in the market at present. At present, the medicine for treating nicotine addiction is seriously lacked in clinic at home and abroad, and the research on the nicotine addiction is beneficial to the research and development of the medicine for quitting smoking and is beneficial to more smoking crowds to get rid of the dependence of tobacco and electronic cigarettes. Therefore, there is a great market and social need for evaluation and research of nicotine addiction. However, the currently used method is a nicotine intravenous self-administration method to evaluate and study nicotine addiction, and although the nicotine addiction can be well quantified by this method, this method has several drawbacks and disadvantages as follows. (1) In this method, a jugular catheterization procedure is required to insert a catheter into the heart of the test animal, and the other end of the catheter is placed subcutaneously on the back or head. The vein catheterization operation is more traumatic to the test animal, requires careful care after the operation, and the test animal needs at least one week to recover. In addition, intravenous catheterization requires a high level of skill on the experimenter. (2) The catheter embedded under the skin of the test animal can be damaged along with time, gaps and the like appear, so that the experiment can not be continued, the experiment efficiency is influenced, and the elimination rate of the test animal is high. (3) In intravenous self-administration experiments, test animals must be individually placed in a control box. Since rats and mice are social animals, independent experiments inevitably cause stress, and the stress has been proved to have great influence on addictive behaviors, so that the mode interferes with experimental results and influences research conclusions. (4) The system used for the intravenous self-administration experiment is expensive, and the instrument and equipment occupy larger space. The invention aims to develop a technical method for evaluating and researching nicotine addiction, which does not need to perform operations on test animals, is simple, easy to operate and efficient.
Disclosure of Invention
In order to solve the problem that nicotine addiction and withdrawal are difficult to evaluate in the prior art, the invention provides a novel method for evaluating and researching nicotine addiction. The method of the invention does not need to carry out surgical operation on the test animal, reduces the test difficulty, can quantify the degree of addiction of nicotine, and is suitable for evaluating the addiction and withdrawal of nicotine.
One aspect of the invention provides a method for assessing the degree of nicotine addiction or assessing the effect of a test drug on the degree of nicotine addiction, comprising the steps of:
s1) providing the aqueous solution containing nicotine as the only water source for the test animal, feeding the test animal for 1-5 weeks, recording the times of the test animal licking the aqueous solution containing nicotine, and obtaining the test animal model of nicotine addiction when the times of the test animal licking the aqueous solution containing nicotine are stable for 3-5 consecutive days;
s2) replacing the water solution containing nicotine with the water solution without nicotine as the only water source, and continuously feeding the test animal for 2-5 days to obtain the test animal model for producing nicotine withdrawal;
s3) evaluating the degree of nicotine addiction by evaluating the number or frequency of licking the water source by the test animal that produced the nicotine withdrawal, or by evaluating the effect of the test animal on the degree of nicotine addiction by licking the water source after administering the test animal with the test drug.
In another aspect of the present invention, there is provided a method for preparing an animal model having nicotine addiction, comprising the steps of:
s11) providing the aqueous solution containing nicotine as the sole water source for the test animal, feeding the test animal for 1-5 weeks, recording the number of times the test animal suffering from nicotine addiction per day licks the aqueous solution containing nicotine, and obtaining an animal model having nicotine addiction when the number of times the test animal licks the aqueous solution containing nicotine is stable for 3-5 consecutive days.
In still another aspect of the invention, the animal model with nicotine addiction prepared by the method is provided.
In another aspect of the invention, there is provided a method of making an animal model for nicotine withdrawal comprising the steps of:
s21) providing the aqueous solution containing nicotine as the sole water source for the test animal, feeding the test animal for 1-5 weeks, recording the number of times the test animal suffering from nicotine addiction per day licks the aqueous solution containing nicotine, and obtaining an animal model having nicotine addiction when the number of times the test animal licks the aqueous solution containing nicotine is stable for 3-5 consecutive days.
S22) replacing the aqueous solution containing nicotine with an aqueous solution containing no nicotine as the sole water source and continuing to feed the test animals for 2-5 days to obtain a test animal model producing nicotine withdrawal.
In a further aspect, the invention provides an animal model for nicotine withdrawal prepared by the above method.
Further, the content of nicotine in the aqueous solution containing nicotine is preferably 0.1-1mg/L, more preferably 0.5 mg/L.
Further, in step S1), S11) or S21), the test animal is fed with the aqueous solution containing nicotine as the only water source for the test animal for 2.5 to 3 weeks.
Further, in steps S1), S11), or S21), the number of times the test animal licks the aqueous solution was stabilized such that there was no significant difference between the number of times the test animal licks the aqueous solution for a fixed period of time per day for 3-5 days.
Further, the test animal is selected from the group consisting of mouse, rat, dog, non-human primate, rabbit.
Further, the form of nicotine in the nicotine solution comprises a salt solution of nicotine, preferably benzoate, tartrate, lactate, levulinate, malate and citrate.
Further, a flavoring agent, such as saccharin sodium, may also be added to the nicotine solution.
In yet another aspect, the present invention provides a method for screening a drug for reducing nicotine dependence and reducing nicotine stage symptoms, the method comprising the steps of:
s31 administering a drug to be screened in the above animal model,
s32) detecting the number or frequency of licking of the water source by the test animal after administration,
s33), the test animal licking the water source more frequently or frequently, with higher licking indicating a higher craving of the test animal for nicotine.
In a further aspect of the invention there is provided a method of assessing the level of addiction of an addictive product or the effect of a test drug on the level of addiction to an addictive product, which method is the same as the method described above except that nicotine is replaced by another addictive product or a product which may produce addiction, preferably the other addictive product is selected from the group consisting of drugs, alcohol, areca, caffeine and tea polyphenols.
In a further aspect of the invention there is provided a method of preparing an animal model of addiction to an addictive product, which method is the same as the method described above, except that nicotine is replaced by another addictive product, preferably the other addictive product is selected from the group consisting of drugs, alcohol, areca, caffeine and tea polyphenols.
In a further aspect of the invention there is provided a method of preparing an animal model for the development of withdrawal from addictive products, the method being the same as the method described above except that nicotine is replaced by other addictive products, preferably selected from the group consisting of drugs, alcohol, betel nut, caffeine and tea polyphenols.
In a further aspect, the invention provides the use of the animal model described above for assessing the degree of addiction to an addictive product or for assessing the degree of addiction to an addictive product of a test drug.
Advantageous effects
1) The method adopted in the invention evaluates nicotine addiction through nicotine drinking times, and can quantify nicotine addiction or withdrawal degree.
2) In the model, the test animal does not need surgical operation, so that the influence of surgical trauma and postoperative infection on the test animal is avoided; the catheter is not required to be embedded, so that the failure of the experiment caused by the defect of the catheter is avoided, and the experiment efficiency is improved; a plurality of mice can be placed in the test box at the same time, so that the stress caused by single test is avoided; the used instruments and equipment are simple, low in price and convenient to use.
3) The methods of the invention may be used in a variety of applications, such as for assessing the level of addiction to nicotine or other potentially addictive substances, for assessing the severity of withdrawal symptoms, and for screening drugs for use in reducing addiction or the level of withdrawal, among others.
Drawings
FIG. 1 is a mouse nicotine drinking water addiction model. A, water lick test device used in the experiment. B, water licking condition of control group mice. C, water licking condition of nicotine group mice. After 72 hours of nicotine withdrawal, the number of licking times of the nicotine group mice to the nicotine water solution is obviously increased. While the control mice did not change significantly. 0.0001; one-way anova.
Figure 2 is a graph showing that the technical method of the invention finds that the number of relapse times of the rannickine after nicotine withdrawal is remarkably reduced. In a fixed-length experiment of 4 hours per day for three consecutive days, the number of licks and aspirations per mouse was recorded. The average number of licks for three days was used as the baseline for the number of licks in mice. After 72 hours of withdrawal, the number of licks and suckers in the nicotine group of mice increased significantly, which is reflected in nicotine reward and nicotine addiction levels. A single injection of Vannicline (1mg/kg, i.p.) 10 minutes prior to the test significantly reduced the number of licks after withdrawal. While valnemulin did not affect the number of licks and aspirations in the control group. The statistic adopts Two-way ANOVA, p is less than 0.01; pc 0.001.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, specific embodiments thereof are described in detail below, but the present invention is not to be construed as being limited to the implementable range thereof.
Example 1 establishment of quantifiable nicotine addiction model by Nicotine Drinking Water count test
The feasibility of the method is proved by counting the nicotine drinking water of the mice. In this experiment, there were 2 groups (experimental and control) of 8 week old mice, 15 per group.
First, an addictive period test is conducted. The only water source of the mice in the experimental group in the feeding environment was a mixed aqueous solution containing sodium saccharin and nicotine, the concentration of sodium saccharin in the mixed aqueous solution was 2g/L, i.e., 2g of sodium saccharin per liter of aqueous solution, and the concentration of nicotine was 0.5mg/L, i.e., 0.5mg of nicotine per liter of water, and the sodium saccharin was added to cover the bitter taste of nicotine. The only water source for the control mice in the feeding environment was an aqueous solution containing sodium saccharin at a concentration of 2 g/L. Both the saccharin sodium salt and nicotine are dissolved in an aqueous solution at a pH of about 7.0.
Then, an adaptability test was performed. The adaptive experiment aims to make the mouse more adaptive to the water bottle capable of counting, and in some other embodiments, the counting water bottle can also be used in the addiction period, so that the adaptive experiment time is reduced, or the adaptive experiment is cancelled.
After drinking the above water source for three weeks, the mice of the experimental group and the control group were continuously placed in counting experimental cages for three days, 1 hour each day, and each mouse was individually placed in the counting experimental cage, wherein fig. 1A shows the structure of the counting experimental cage, the experimental cage contained a water bottle as the only water source, and a sensor was provided on the water bottle to count the number of times the mouse licks the water source. The water solution in the water bottle of the experimental group mouse in the adaptability test stage is the same as the water source in the addiction period and is a mixed water solution containing saccharin sodium and nicotine, the concentration of saccharin sodium in the mixed water solution is 2g/L, and the concentration of nicotine is 0.5 mg/L. The water solution in the water bottle in the adaptability test stage of the control group of mice is the same water solution containing saccharin sodium in the water source of the addiction period, and the concentration of the saccharin sodium is 2 g/L. In some other examples, multiple mice were tested in the same cage and total licking times were recorded and shown to be consistent with the data from the individual tests.
A baseline phase count test was then performed. The water licking counting test is carried out on the day after the adaptability test is finished, each mouse is independently placed in a counting test cage for 4 days continuously every 4 hours, and the water licking times of each mouse in the test process can be recorded.
The water licking times of the experimental group and the control group are shown in fig. 1B and C (day one to day four), and the water licking times of the two groups of mice per day can be stably maintained at a higher level in the continuous four-day test, and there is no significant difference between the four-day reference times.
Withdrawal tests were then performed. At the end of the fourth day test, the only water source for the experimental mice was changed to 2g/L aqueous saccharin sodium solution, resulting in nicotine withdrawal, while the water source for the control group remained unchanged. The only water sources of the control group and the test group on the fifth day and the sixth day are aqueous solutions with saccharin sodium concentration of 2 g/L. The water licking test was repeated for 4 hours on the seventh day, and the nicotine group was administered with the same water source as the water source for the addiction period as the mixed aqueous solution containing sodium saccharin and nicotine, and the control group was administered with the same water source as the water source for the addiction period as the aqueous solution containing sodium saccharin.
The test results are shown in fig. 1B and C (seventh day results), and the results show that the times of licking and sucking of the mice in the experimental group are obviously higher than the baseline, and have significant difference. While control mice did not differ from baseline in the seventh day test. This indicates that nicotine withdrawal after 72 hours resulted in increased craving and relapse of nicotine (fig. 1B, C). It is therefore feasible that the counts in the present invention can be taken to quantify nicotine addiction.
Example 2 evaluation of quantifiable nicotine addiction model Using withdrawal drugs
We further used the technical method of the present invention to verify the effect of clinical smoking cessation drug, Vannicline (FIG. 2). In this experiment, there were 2 groups of 8 week old mice, 15 per group. The only water source for the experimental mice in the feeding environment was 0.2% saccharin sodium +0.5mg/kg nicotine solution; the only water source in the feeding environment for control mice was 0.2% saccharin sodium. After drinking the water source for three weeks, mice were individually placed in the corresponding water licking apparatus filled with sodium saccharin or sodium saccharin + nicotine solution for three days, one hour per day. The licking count test was performed starting on day four and the number of licks per mouse was recorded in a fixed duration experiment of 4 hours per day for three consecutive days. The average number of licks for three days was used as the baseline for the number of licks in mice. Then, at the end of the third day test, the only water source for the saccharin sodium + nicotine group mice was changed to a 0.2% aqueous saccharin sodium solution, resulting in nicotine withdrawal while the water source for the control group remained unchanged. The test was stopped on the fourth and fifth days. The water licking times test is carried out again on the sixth day, and the water licking times of the saccharin sodium + nicotine group mice on the nicotine + saccharin sodium + nicotine water solution are obviously higher than the baseline. A single injection of Vannicline (1mg/kg, i.p.) 10 minutes prior to the test significantly reduced the number of licks after withdrawal. While valnemulin did not affect the number of licks in the control group.
Claims (10)
1. A method of assessing the degree of nicotine addiction or assessing the effect of a test agent on the degree of nicotine addiction, said method comprising the steps of:
s1) providing the aqueous solution containing nicotine as the only water source for the test animal, feeding the test animal for 1-5 weeks, recording the times of the test animal licking the aqueous solution containing nicotine, and obtaining the test animal model of nicotine addiction when the times of the test animal licking the aqueous solution containing nicotine are stable for 3-5 consecutive days;
s2) replacing the water solution containing nicotine with the water solution without nicotine as the only water source, and continuously feeding the test animal for 2-5 days to obtain the test animal model for producing nicotine withdrawal;
s3) evaluating the nicotine addiction degree by evaluating the frequency or frequency of licking the water source by the test animal producing nicotine withdrawal, or evaluating the influence of the test animal on the nicotine addiction degree by licking the water source frequency or frequency after the test animal is administered with the test drug;
preferably, in step S1), the test animal is raised for 2.5-3 weeks with an aqueous solution containing nicotine as the sole water source for the test animal;
preferably, in step S1), the number of times the test animal licks the aqueous solution is stabilized to be within 3-5 days, and there is no significant difference between the number of times the test animal licks the aqueous solution within a fixed period of time per day;
preferably, the test animal is selected from the group consisting of a mouse, rat, dog, non-human primate, rabbit;
preferably, the form of nicotine in the nicotine solution comprises a salt solution of nicotine, more preferably benzoate, tartrate, lactate, levulinate, malate and citrate;
preferably, a flavoring agent is also added to the nicotine solution.
2. A method for preparing an animal model with nicotine addiction, comprising the steps of:
s11) providing the aqueous solution containing nicotine as the sole water source for the test animal, feeding the test animal for 1-5 weeks, recording the number of times the test animal suffering from nicotine addiction per day licks the aqueous solution containing nicotine, and obtaining an animal model having nicotine addiction when the number of times the test animal licks the aqueous solution containing nicotine is stable for 3-5 consecutive days;
preferably, in step S11), the test animal is raised for 2.5-3 weeks with an aqueous solution containing nicotine as the sole water source for the test animal;
preferably, in step S11), the number of times the test animal licks the aqueous solution is stabilized to be within 3-5 days, and there is no significant difference between the number of times the test animal licks the aqueous solution within a fixed period of time per day;
preferably, the test animal is selected from the group consisting of a mouse, rat, dog, non-human primate, rabbit;
preferably, the form of nicotine in the nicotine solution comprises a salt solution of nicotine, more preferably benzoate, tartrate, lactate, levulinate, malate and citrate;
preferably, a flavoring agent is also added to the nicotine solution.
3. An animal model with nicotine addiction made according to the method of claim 2.
4. A method of preparing an animal model for nicotine withdrawal comprising the steps of:
s21) providing the aqueous solution containing nicotine as the sole water source for the test animal, feeding the test animal for 1-5 weeks, recording the number of times the test animal suffering from nicotine addiction per day licks the aqueous solution containing nicotine, and obtaining an animal model having nicotine addiction when the number of times the test animal licks the aqueous solution containing nicotine is stable for 3-5 consecutive days;
s22) replacing the aqueous solution containing nicotine with an aqueous solution containing no nicotine as the sole water source and continuing to feed the test animals for 2-5 days to obtain a test animal model producing nicotine withdrawal.
S21) providing the aqueous solution containing nicotine as the sole water source for the test animal, feeding the test animal for 1-5 weeks, recording the number of times the test animal suffering from nicotine addiction per day licks the aqueous solution containing nicotine, and obtaining an animal model having nicotine addiction when the number of times the test animal licks the aqueous solution containing nicotine is stable for 3-5 consecutive days;
preferably, in step S21), the test animal is raised for 2.5-3 weeks with an aqueous solution containing nicotine as the sole water source for the test animal;
preferably, in step S21), the number of times the test animal licks the aqueous solution is stabilized to be within 3-5 days, and there is no significant difference between the number of times the test animal licks the aqueous solution within a fixed period of time per day;
preferably, the test animal is selected from the group consisting of a mouse, rat, dog, non-human primate, rabbit;
preferably, the form of nicotine in the nicotine solution comprises a salt solution of nicotine, more preferably benzoate, tartrate, lactate, levulinate, malate and citrate;
preferably, a flavoring agent is also added to the nicotine solution.
5. An animal model for nicotine withdrawal prepared by the method of claim 4.
6. A method of screening for a drug that reduces nicotine dependence and nicotine withdrawal symptoms, comprising the steps of:
s31) administering a drug to be screened of the animal model of claim 3 or 5,
s32) determining the number or frequency of licking of the water source by the test animal after administration of the drug to be screened,
s33) obtaining the effect of the drug by analyzing the frequency or frequency of licking the water source by the test animal, wherein a higher frequency of licking the water source after administration of the drug indicates a higher craving of the test animal for nicotine.
7. A method for assessing the degree of addiction of an addictive product or for assessing the effect of a test drug on the degree of addiction of an addictive product, comprising the steps of:
s41) providing an aqueous solution containing the addictive product as the sole water source for the test animal, feeding the test animal for 1-5 weeks, recording the number of times the test animal licks the aqueous solution containing the addictive product, and obtaining a test animal model of nicotine addiction when the number of times the test animal licks the aqueous solution containing nicotine is stable for 3-5 consecutive days;
s42) replacing the water solution containing the addiction product with the water solution without the addiction product as the only water source, and continuing to feed the test animal for 2-5 days to obtain a test animal model for giving up the addiction product;
s43) evaluating the addiction degree of the addictive product by evaluating the frequency or frequency of licking the water source by the test animal which produces the withdrawal of the addictive product, or evaluating the influence of the test animal on the addiction degree of the addictive product by licking the water source by the test animal after the test animal is administered with the test drug;
preferably, in step S41), the test animal is kept for 2.5-3 weeks with the aqueous solution containing the addictive product as the sole water source for the test animal;
preferably, in step S41), the number of times the test animal licks the aqueous solution is stabilized to be within 3-5 days, and there is no significant difference between the number of times the test animal licks the aqueous solution within a fixed period of time per day;
preferably, the test animal is selected from the group consisting of a mouse, rat, dog, non-human primate, rabbit;
preferably, the addictive product is selected from drugs, alcohol, areca, caffeine, tea polyphenols or products of unknown addiction.
8. A preparation method of an animal model with addiction to an addictive product is characterized by comprising the following steps:
s51) providing an aqueous solution containing the addictive product as the sole water source for the test animal, feeding the test animal for 1-5 weeks, recording the number of times the test animal suffering from addiction to the addictive product licks the aqueous solution containing the addictive product per day, and obtaining an animal model having addiction to the addictive product when the number of times the test animal licks the aqueous solution containing nicotine is stable for 3-5 consecutive days;
preferably, in step S51), the test animal is kept for 2.5-3 weeks with the aqueous solution containing the addictive product as the sole water source for the test animal;
preferably, in step S51), the number of times the test animal licks the aqueous solution is stabilized to be within 3-5 days, and there is no significant difference between the number of times the test animal licks the aqueous solution within a fixed period of time per day;
preferably, the test animal is selected from the group consisting of mouse, rat, dog, non-human primate, rabbit;
preferably, the addictive product is selected from the group consisting of drugs, alcohol, areca, caffeine, tea polyphenols.
9. A method of preparing an animal model for the development of withdrawal from addictive products comprising the steps of:
s61) providing the aqueous solution containing nicotine as the sole water source for the test animal, feeding the test animal for 1-5 weeks, recording the number of times the test animal suffering from nicotine addiction per day licks the aqueous solution containing nicotine, and obtaining an animal model having nicotine addiction when the number of times the test animal licks the aqueous solution containing nicotine is stable for 3-5 consecutive days;
s62) replacing the water solution containing nicotine with the water solution without nicotine as the only water source, and continuously feeding the test animal for 2-5 days to obtain the test animal model for producing nicotine withdrawal;
preferably, in step S61), the test animal is raised for 2.5-3 weeks with an aqueous solution containing nicotine as the sole water source for the test animal;
preferably, in step S61), the number of times the test animal licks the aqueous solution is stabilized to be within 3-5 days, and there is no significant difference between the number of times the test animal licks the aqueous solution within a fixed period of time per day;
preferably, the test animal is selected from the group consisting of a mouse, rat, dog, non-human primate, rabbit;
preferably, the addictive product is selected from the group consisting of drugs, alcohol, areca, caffeine, tea polyphenols.
10. Use of the animal model prepared by the preparation method of any one of claims 8 or 9 for evaluating the degree of addiction to an addictive product or for evaluating the degree of addiction to an addictive product of a test drug.
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