CN112569355B - Application of imatinib and derivative thereof and addiction substance combined medicine or compound preparation in prevention and treatment of addiction and prevention and treatment of relapse - Google Patents

Abstract

The invention discloses application of imatinib and derivatives thereof and addiction substance proportion combined medicine or compound preparation in prevention and treatment of addiction and prevention and treatment of relapse. The medicinal preparation for treating drug addiction and behavior addiction comprises 100-dose-400 mg/day imatinib mesylate and addictive substance proportion combined administration or compound administration, and 100-dose-400 mg/day imatinib mesylate and environmental clues or substance clue proportion of addiction behavior combined administration, so that addiction can be prevented, relapse prevention and treatment can be realized, withdrawal symptoms can be relieved, and heart addiction can be completely eliminated. The invention utilizes a large number of animal experimental models to evaluate the drug efficacy and safety, proves that the drug efficacy and safety are good and high after the prescription or combined medication, and provides a new composition or combined medication preparation for the first-line clinical application of the drug for addiction treatment.

Description

Application of imatinib and derivative thereof and addiction substance combined medicine or compound preparation in prevention and treatment of addiction and prevention and treatment of relapse

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an application of imatinib and derivatives thereof in preparing a compound or combined preparation for preventing and treating addiction and preventing relapse by combining with an addictive substance and an addictive behavior.

Background

The drug problem is a public health problem which is urgently solved all over the world, the public society is seriously harmed to public security, and analgesic drugs such as ' Otherang ' event, fentanyl ' case and the like are abused, thereby bringing immeasurable consequences to the society and patients. Similarly, serious diseases and casualty events caused by substance dependence such as smoking and alcohol addiction problems are endless, and neuropsychiatric drug and analgesic drug addiction such as 'Oschardine' and the like severely limit the application of the medicine and bring irreversible adverse effects to the society and patients. The behavior addiction such as the internet addiction, the gambling addiction, the game addiction and the like brings more adverse consequences to the life of people. Drug addiction can have serious consequences, but the drug abuse trend is still getting more severe, and the first culprit behind this is "addiction". Any substance or action is difficult to quit once addicted, and so far the restraint is under the way all over the world. As is well known, the drug addiction is difficult to quit, no drug can be cured, and the drug is recovered. The key is the lack of effective drugs for the control and relapse prevention of 'addiction'.

The invention relates to the research and development of new drugs for treating addiction drugs. The invention adopts a brand new concept to discover that the drug imatinib mesylate, which is a specific and effective drug for drug rehabilitation and addiction treatment, is combined with addictive substances or addiction behaviors or prepared into a compound to have a good effect in addiction treatment, is expected to realize course-type cure of addiction treatment which is a direct abstinence and is substituted for the whole life, can prevent relapse, and provides a set of complete and effective drug treatment system for drug rehabilitation and addiction treatment.

Imatinib or a derivative imatinib mesylate, also called Gleevec or STI571, is a derivative of aminopyrimidine, developed by noval, switzerland for application to Chronic Myelocytic Leukemia (CML), approved by FDA in the us in 2001 to be on the market, and is called a new anticancer drug of the first molecular targeted tumorigenesis mechanism in humans, so the new anticancer drug is reviewed as a milestone by the journal "Science" and is listed as one of 10 major technological breakthroughs in the world in 2001 together with human genetic engineering and the like. At present, the targets of imatinib are mainly protooncogene c-Abl, stem cell factor receptor c-Kit and platelet-derived growth factor receptor recorded by Therapeutic Target Database (TTD), the protooncogene c-Abl exists in tumors such as chronic myelogenous leukemia and acute lymphatic leukemia, and the platelet-derived growth factor receptor mainly exists in connective tissues and blood vessels and plays an important role in tissue injury and repair. The addicted patient is normal body, except pathological change of nervous system, and has no tumor and tissue damage. Therefore, imatinib acts on the c-Kit mainly, and has weak effect on the protooncogene c-Abl and the platelet-derived growth factor receptor. The prior patents of application CN 105974131A and CN 106074555A have reported that c-Kit is activated in nucleus accumbens and the activity of rats is increased after acute morphine administration, and after the c-Kit inhibitor imatinib and derivatives thereof are administered, the formation of morphine condition preference and sensitization can be prevented, addiction memory can be blocked, and the recrudescence after withdrawal and the like can be prevented, so that the c-Kit can be used as a target for potential prevention and treatment of addiction and relapse after withdrawal, and the imatinib and derivatives thereof can specifically act against the c-Kit to prevent and treat addiction and relapse after withdrawal and can be used as a medicament for preventing and treating addiction.

In order to solve the problem of clinical addiction, the invention provides a new technology which is substantially advanced on the basis of the application of 'c-kit as a drug addiction treatment target' and 'new application of imatinib and derivatives thereof in treating addiction' applied for patents (CN 105974131A and CN 106074555A) and the invention, namely, a new dosage range, a new intervention paradigm, a new proportion and a new action mechanism are adopted. The imatinib mesylate dosage (100mg-400 mg/day/70 kg) used in the invention has few side effects in the clinical use process, is in the safe dosage range of clinical use, has good clinical effectiveness and safety, can be widely applied to the treatment of various clinical acute and chronic patients with combined addiction, and solves the bottleneck problem faced by clinical addiction at present. Aiming at the existing research foundation, the invention has the following substantial progress and differences:

the new dose is as follows: in the dose effect, the combination of imatinib and derivatives thereof with morphine is reported by Wang and Howard B.Gutstein, etc., that 5mg/kg of rat can be used for treating and preventing morphine tolerance, and the dose of 10 mu g GLEEVEC/10% CDSBE or 0.6nmolMS/10 mu g GLEEVEC in the patent (PCT/US2008/079198) is obviously different and different, and the invention discovers that the low dose of rat, i.e. 5mg/kg, can be used for treating and preventing morphine tolerance but can not prevent and treat addiction and relapse after withdrawal, and the dose higher than 10mg/kg can prevent and treat opioid tolerance and addiction and also can successfully prevent opioid and other substance addiction and relapse after withdrawal. The typical dose effect has similar examples in clinical application of the antipyretic analgesic aspirin, such as that aspirin is used for resisting thrombus at a small dose, used for resisting fever and pain at a medium dose, and used for resisting inflammation and rheumatism at a high dose, and the three types of clinical indications of antithrombotic, antipyretic analgesic, anti-inflammation and antirheumatic drugs have completely different effects and have substantial differences. Therefore, the dosage effect (more than 10mg/kg of rats, equivalent dosage of other species, and clinical dosage of more than 100 mg/day) of the invention is a substantial new discovery of imatinib mesylate in the field of addiction treatment, and the imatinib mesylate and drugs for addiction in the dosage range are combined or prepared into various compound preparations for preventing and treating addiction and relapse after withdrawal, so that the invention is the application of the drug in different indications in different dosage ranges, and is an invention which is substantially different from the application and progress of the prior invention.

The new proportion is as follows: the invention discovers that the imatinib mesylate is effective when being used for preventing and treating addiction and the dosage of CPP addiction in a certain proportion, wherein the morphine or cocaine dosage is effective according to the proportion of 2:1, and the dosage proportion of alcohol is more than or equal to 1: 50; in addition, the unconditionally induced dose also has a dose ratio, such as the effective ratio of morphine, cocaine and alcohol to the dose used in training CPP is less than 1: 3.

The new treatment strategy is: the invention has significant difference on the treatment strategy from the patents (CN 105974131A and CN 106074555A) applied by people before, the former two patents mainly intervene the treatment paradigm of the process of inducing memory and then consolidating by environmental clues, and the invention adopts the new intervention paradigm, namely the drug treatment of intervention after the process of inducing and consolidating by non-conditional clues. The intervention mode is easier to operate clinically, and the treatment effect is more effective.

The new mechanism is as follows: the imatinib mesylate composition has obvious difference in action mechanism, and the imatinib mesylate inhibits various signal transduction pathways such as PKC, PI3K-AKT, ERK and the like through blocking c-kit receptors to regulate kinase activity, protein expression, gene expression, regulation and control to start morphine reward, memory and neural plasticity processes, and blocks various effects generated by morphine, thereby achieving the effect of preventing and treating morphine addiction.

Disclosure of Invention

In view of the problems in the addiction treatment in the background, the invention aims to provide a new application of imatinib and derivatives thereof in the field of addiction treatment, wherein imatinib and derivatives thereof are used in combination with addictive substances or addictive behaviors or used together as a compound preparation to prevent or alleviate the symptoms of addiction and withdrawal after stopping use, and prevent and treat relapse.

The invention mainly carries out the following researches:

the imatinib and the derivative thereof are combined with addictive substances or addictive behaviors or compound preparations for preventing or treating addiction and mechanism and dosage effect thereof, and preventing and treating relapse after withdrawal.

In order to demonstrate that imatinib and its derivatives in combination with an addictive substance (morphine, cocaine, alcohol) (imatinib or its derivatives and the addictive substance are administered differently at 30 minutes intervals) or a combination preparation (imatinib or its derivatives is administered after mixing with the addictive substance) can prevent or treat addiction during the course of an addictive substance alone or an addictive behavior and have a dose-dependent effect, the present invention was accomplished by the following experiments.

(1) The change of c-kit activity of a mesolimbic dopamine system including VTA, nucleus accumbens, amygdala, hippocampus and prefrontal cortex is observed 60min after acute morphine administration, the change of c-kit phosphorylation level is observed by combining immunohistochemistry with western-blot, activated cell distribution is observed by immunofluorescence co-labeling, and a new molecular mechanism of morphine addiction and an action mechanism of imatinib mesylate for preventing and treating addiction are determined. Further using a CPP addiction model to observe the prevention, dosage effect and action mechanism of the imatinib mesylate on the formation of the addictive CPP. The experimental rats are administered 1, 5, 10, 20 and 30mg/kg of imatinib mesylate by 30mins in advance and then are subcutaneously injected with 5mg/kg and 10mg/kg of morphine (namely, combined administration), or mixed injections prepared by 1, 5, 10, 20 and 30mg/kg of imatinib mesylate and 5mg/kg and 10mg/kg of morphine are respectively administered, and the influence of imatinib mesylate on the formation of the conditioned place preference of rats is determined by classically evaluating the conditioned place preference of addicted rats.

(2) Acute administration and CPP addiction models are adopted to observe the prevention, dose effect and action mechanism of imatinib mesylate on the formation of cocaine addiction CPP.

(3) Acute administration and CPP addiction models are adopted to observe the prevention, dose proportion and action mechanism of the imatinib mesylate on the formation of the alcohol CPP. The alcohol dosage is 0.5g/kg and 0.75 g/kg; the dosage of the imatinib mesylate is 1, 5, 10, 15, 20 and 30 mg/kg.

(4) Dose effects on the effect on the foraging behavior of rats after morphine addiction following induction of unconditional stimulation with imatinib mesylate at 1, 5, 10, 20, 30mg/kg were observed using a model of CPP addiction. After the morphine CPPs were formed, rats were exposed to the CPP box before being administered 1, 5, 10, 20, 30mg/kg imatinib mesylate intraperitoneally and CPP values were measured on day 1 for drug dry prognosis to observe the effect on foraging behavior and on day 7 for drug dry prognosis.

(5) Using the CPP addiction model, dose effects of 1, 5, 10, 20, 30mg/kg imatinib mesylate unconditionally stimulated on post-foraging behavior following cocaine addiction in rats were observed.

(6) Using the CPP addiction model, the dose effect of 1, 5, 10, 15, 20, 30mg/kg imatinib mesylate unconditional stimulation on the effect on postprandial drug-seeking behavior following alcohol addiction in rats was observed.

(7) Using a model of CPP addiction, the effects of 30mg/kg of imatinib mesylate in combination with environmental cues, in combination with unconditional stimulation (different doses), and in direct use on the afterward drug-seeking behavior and relapse after morphine addiction in rats were observed, and after rat morphine CPP formation, imatinib mesylate was induced, induced or not induced by environmental cues. Wherein the environmental cues induce an impending addiction in the CPP box on the concomitant side to induce addictive memory followed by administration of imatinib mesylate; the unconditional stimulation elicits are given morphine (3, 4mg/kg), i.e. morphine in combination with imatinib mesylate, and divided into two groups of drug combination and compound preparation; no induction was performed, i.e., without placing in the CPP box and without administering morphine, and was treated directly with imatinib mesylate. CPP values were measured on day 1 for drug dry prognosis to observe effects on foraging behavior, CPP values were measured on day 7 for drug dry prognosis, and low dose (3mg/kg) morphine challenge and effects on relapse were observed for all rats given day 9 post-intervention.

(8) Using the CPP addiction model, the effects of 30mg/kg imatinib mesylate in combination with environmental cues, in combination with physical cues (different doses of cocaine), and directly on the craving behavior and relapse of cocaine in rats were observed.

(9) The CPP addiction model is used for observing the influence of 15 mg/kg and 30mg/kg of imatinib mesylate, environmental clues, physical clues (different doses of alcohol) and direct use on the drug seeking behavior and the drug relapse of rats after alcohol addiction.

(10) Using a model of CPP addiction, after formation of CPPs, imatinib mesylate was co-administered with morphine or co-administered with morphine, and the effect of different doses of imatinib mesylate on withdrawal symptoms was observed.

(11) Using a CPP addiction model, after cocaine CPP formation, imatinib mesylate is co-administered with cocaine or a combination thereof, and the effect of different doses of imatinib on withdrawal symptoms is observed.

(12) Using the CPP addiction model, after alcohol CPP formation, imatinib mesylate was co-administered with alcohol or a combination thereof, and the effect of different doses of imatinib mesylate on withdrawal symptoms was observed.

(13) The influence of different doses of imatinib mesylate on the formation and expression of morphine sensitization in rats was investigated using a sensitization model.

(14) The influence of different doses of imatinib mesylate on the sensitization formation and expression of cocaine in rats was explored using a sensitization model.

(15) The influence of different doses of imatinib mesylate on the formation and expression of alcohol sensitization in rats was investigated using a sensitization model.

(16) The dose effect of imatinib mesylate on the development of conditioned place preference for high-carbohydrate, high-lipid foods in rats was explored using a model of CPP addiction.

(17) The dose effect of imatinib mesylate on the formation of conditioned place preference for high-glucose and high-fat foods in rats followed by consolidation and relapse was investigated using a CPP addiction model.

(18) The dose effect of imatinib mesylate on the effects of gambling behaviour was explored using the rat gambling task.

The results show that after the acute morphine or cocaine is administrated, the co-labeling results of immunohistochemistry, western-blot and immunofluorescence show that the specific activation nucleus accumbens is not other brain area neuron c-kit receptors and ERK, AKT and PKMzeta signal pathways after the receptors; the imatinib mesylate inhibits the drug foraging behavior by blocking c-kit receptors and signal paths thereof, thereby achieving the effects of preventing morphine addiction and preventing and treating relapse. Similarly, the imatinib and the derivative thereof can be used in combination with morphine in a dosage ratio or compound preparation for preventing and treating morphine addiction and relapse after withdrawal.

Imatinib mesylate has blocking effects on the formation, formation and memory reinsolidation of morphine and cocaine CPP to different degrees. Either in combination or in a combination formulation, rats not administered imatinib mesylate had a conditioned place preference and sensitization, and when the dose of imatinib mesylate after administration is in the range of (10-30mg/kg) and the ratio of doses used in addiction to morphine or cocaine is 2:1 or greater, the conditioned place preference and sensitization formation is prevented; meanwhile, after the condition is favored and sensitized, when imatinib is directly administrated, 20 mg/kg and 30mg/kg can prevent the foraging behavior of rats after addiction, but can still be ignited, namely, the relapse cannot be prevented and controlled; when the rat is induced by environmental clues, 20 mg/kg and 30mg/kg can block the foraging behavior of the rat after addiction, and only 30mg/kg can prevent relapse; when the morphine or the cocaine is used at 3mg/kg, the foraging behavior and the relapse of rats after addiction can be prevented by 20 mg/kg and 30 mg/kg; at morphine or cocaine doses of 4mg/kg, the foraging behavior was inhibited only with 20, 30mg/kg imatinib mesylate, and relapse was not prevented.

Immunohistochemistry, western-blot and immunofluorescence co-labeling results after acute alcohol administration show that specific activation of nucleus accumbens is not a neuronal c-kit receptor in other brain regions. Imatinib mesylate (10, 15, 20, 30mg/kg) had varying degrees of inhibitory effect on alcohol formation and restorability after formation. The rats not administered with imatinib mesylate, whether co-administered or in a combination formulation, develop a conditional locus preference and sensitization, and prevent the development of the conditional locus preference when the dose of imatinib mesylate with alcohol is 1:50 or greater after administration of imatinib mesylate; meanwhile, after the condition position preference is formed, when imatinib mesylate and alcohol are directly administrated, the foraging behavior of rats after addiction can be prevented when the dose of imatinib mesylate and alcohol is more than or equal to 1:50, but the rat can be ignited, and the relapse cannot be prevented and controlled; when environmental clues are induced, the dosage of the imatinib mesylate and the alcohol is more than or equal to 1:50, so that the drug seeking behavior of rats after addiction can be prevented, but the dosage of only 30mg/kg can prevent relapse; when the unconditional stimulation is induced, the alcohol dosage is less than or equal to the CPP training dosage by 1:3, and the imatinib mesylate is greater than or equal to the alcohol CPP training dosage by 1:50, the compound preparation can prevent and treat foraging behavior and relapse of rats after addiction; at a non-conditionally stimulated alcohol dose of 0.5g/kg, the foraging behaviour was only inhibited with 20, 30mg/kg imatinib mesylate, which failed to prevent relapse. Therefore, the imatinib mesylate can inhibit the foraging behavior by blocking the c-kit receptor, thereby achieving the effects of preventing alcohol addiction and preventing relapse. Similarly, imatinib and its derivatives can be used in combination with alcohol in a dosage ratio or in a combination for preventing and treating alcohol addiction and relapse after withdrawal.

For addictive behaviors, the action effect of using imatinib mesylate is similar to that of using morphine, which indicates that the c-kit receptor has universality as an addictive treatment target and a therapeutic drug.

In clinical application, the equivalent dose conversion between human and animal according to the conversion of body surface area can be referred to pharmacological experimental methodology compiled by professor of xu Tertiary cloud:

for example: the dosage of the rat is Xmg/kg, and the converted clinical dosage of the adult is as follows:

since the clinical dose of human is Xmg/kg × 0.2kg/0.018 is 11.1 Xmg/day, the rat imatinib mesylate dose (1, 5, 10, 20, 30mg/kg) is converted into the clinical dose of adult 11, 55, 110, 220, 330 mg/day, respectively.

According to the marketed drug, glivectiminib

The published clinical trial data shows that 400 mg/day/70 kg has few side effects in the clinical use process, so 100-400 mg/day/70 kg is selected as the imatinib mesylate which is used as the clinical dose to be matched with the addictive substance, and the dose is in the safe range of the current clinical dose (figure 22).

Based on the research content, the invention provides the following technical scheme:

1. the imatinib mesylate or the derivative thereof and an addictive substance are compounded or combined to prepare a medicinal preparation for preventing and treating various addictions and preventing relapse.

2. The imatinib mesylate or the derivative thereof is used in combination with an addictive behavior, namely (1) the addictive food and the imatinib mesylate or the derivative thereof are used in a compound or combined way, and can be used for preventing and treating addiction and preventing relapse; (2) gambling behaviour, environmental cues induced by administering imatinib mesylate or a derivative thereof, for improving gambling behaviour.

3. The addictive substance refers to (1) narcotics, wherein the narcotics are also classified into opium, cocaine and cannabis, the opium comprises opium of natural source and effective component morphine extracted from the opium, and the product heroin obtained by processing the effective component, and an artificial synthetic product with similar opium function; (2) psychotropic drugs, which are classified into sedative-hypnotics and anxiolytics barbiturates, central stimulant amphetamines, hallucinogens ergotamine; (3) alcohol, tobacco and volatile organic solvents, and the like. When they are used for unconditional stimulation, the dosage is less than or equal to 1:3 dosage compared with the dosage used for training CPP.

4. The addiction behavior refers to (1) addiction food including high fat, sweet food, chocolate, and other palatable food; (2) gambling addiction, internet addiction and other addicts.

5. The imatinib and the derivative thereof have the dosage content of 100-400 mg/day.

6. Imatinib mesylate used for treating and preventing substance addiction relapse must be used in combination with an addictive substance or a compound preparation.

7. Imatinib mesylate, used for the treatment and prevention of addictive relapses in behaviour, must be used in combination with exposure to clues associated with addictive behaviour or in combination with a compound formulation.

8. The proportion of the imatinib mesylate is effective to prevent and treat addiction and prevent and treat substance use dosage during relapse and addiction formation, wherein the proportion of the imatinib mesylate and morphine or cocaine dosage is more than or equal to 2:1, and the proportion of the imatinib mesylate and morphine or cocaine dosage to alcohol dosage is more than or equal to 1: 50.

9. The addictive substance or the addictive behavior and the imatinib and the derivative thereof can be prepared into a compound single agent or a combined preparation within the dosage range.

10. The combination and compound preparation refers to that the opioid drug is matched with imatinib and derivatives thereof for use or is prepared into one of all formulations and specifications such as injections, infusion solutions, pills, subcutaneous implants, tablets, powders, granules, capsules, powders, oral liquids, sustained release agents, tinctures, suppositories, patches and the like; meanwhile, the use of the combination or the compound preparation in proportion also means that all medicaments used in the proportion for treating addiction or combination are included.

According to the invention, imatinib and derivatives thereof and addictive substances are prepared into various compound preparations or combined preparations for treating addiction according to clinical safe dose from the aspects of dose proportion, new intervention paradigm and new action mechanism for the first time, and the preparation is better suitable for clinical requirements, and the problem of preventing and treating addiction is promoted to a great extent on the basis. From the molecular structure, imatinib and addictive substances have no interactive groups, so that imatinib and derivatives thereof are combined with the addictive substances or prepared into compound preparations for carrying out addiction treatment, and the preparation method is effective, good in effect, high in safety and strong in clinical controllability and is a substantial progress of the addiction treatment.

Drawings

Figure 1 is a new molecular mechanism for the prevention of morphine addiction by imatinib mesylate.

FIG. 2 is a graph of the dose effect of imatinib mesylate in combination with morphine on the development of addiction in rats; wherein, A: the morphine and the imatinib mesylate are jointly administered for preventing the formation of the CPP, and the morphine dose for training the CPP is 5 mg/kg; b: the compound morphine and imatinib mesylate administration is used for preventing the formation of CPP, and the morphine dose for training the CPP is 5 mg/kg; c: the morphine and the imatinib mesylate are jointly administered for preventing the formation of the CPP, and the morphine dose for training the CPP is 10 mg/kg; d: the compound morphine and imatinib mesylate administration is used for preventing the formation of CPP, and the morphine dose for training the CPP is 10 mg/kg.

FIG. 3 is a novel molecular mechanism for the prevention of cocaine addiction by imatinib mesylate; wherein, A: immunohistochemistry shows that imatinib mesylate has obvious inhibition phenomenon on nucleus accumbens c-Kit increase, and other brain areas have no obvious influence; b: seven-color immunofluorescence co-labeling shows that seven key active molecules c-Kit, ERK, AKT and PKC are co-activated in nucleus accumbens after acute alcohol administration, and PDGF activity change is not obvious.

FIG. 4 is a graph showing the dose effect of imatinib mesylate in combination with cocaine on rat addiction; wherein, A: the cocaine and the imatinib mesylate are jointly administered for preventing the formation of the CPP, and the cocaine dose for training the CPP is 5 mg/kg; b: the cocaine and imatinib mesylate compound administration is used for preventing the formation of CPP, and the cocaine dosage for training the CPP is 5 mg/kg; c: the cocaine and the imatinib mesylate are jointly administered for preventing the formation of the CPP, and the cocaine dose for training the CPP is 10 mg/kg; d: the cocaine and imatinib mesylate compound administration is used for preventing the formation of CPP, and the cocaine dose for training the CPP is 10 mg/kg.

FIG. 5 is a molecular novel mechanism for the prevention of alcohol addiction by imatinib mesylate; wherein, A: immunohistochemistry shows that imatinib mesylate has obvious inhibition phenomenon on nucleus accumbens c-Kit increase, and other brain areas have no obvious influence; b: seven-color immunofluorescence co-labeling shows that seven key active molecules c-Kit, ERK, AKT and PKC are co-activated in nucleus accumbens after acute alcohol administration, and PDGF activity change is not obvious.

FIG. 6 is a graph of the dose effect of imatinib mesylate used in combination with alcohol on rat addiction; wherein, A: the combination administration of alcohol and imatinib mesylate is used for preventing the formation of CPP, and the alcohol dosage for training the CPP is 0.5 g/kg; b: the compound administration of alcohol and imatinib mesylate is used for preventing the formation of CPP, and the alcohol dosage for training the CPP is 0.5 g/kg; c: the combination administration of alcohol and imatinib mesylate is used for preventing the formation of CPP, and the alcohol dosage for training the CPP is 0.75 g/kg; d: the compound administration of alcohol and imatinib mesylate is used for preventing the formation of CPP, and the alcohol dosage for training the CPP is 0.75 g/kg.

Figure 7 is a dose response of imatinib mesylate in combination with morphine to the development of postprandial behavior and after morphine addiction in rats; wherein, A: the morphine and the imatinib mesylate are jointly administered to inhibit the foraging behavior, and the morphine dose for training the CPP is 5 mg/kg; b: the compound morphine and imatinib mesylate administration is used for inhibiting foraging behavior, and the morphine dose for training CPP is 5 mg/kg; c: the morphine and the imatinib mesylate are jointly administered to inhibit the foraging behavior, and the morphine dose for training the CPP is 10 mg/kg; d: the morphine and imatinib mesylate compound administration is used for inhibiting foraging behavior, and the morphine dose for training CPP is 10 mg/kg.

FIG. 8 is a graph of the effect of dose on the formation of the sum of the foraging behavior of imatinib mesylate when used in combination with cocaine on rat cocaine addiction; wherein, A: the cocaine and imatinib mesylate are jointly administered to inhibit foraging behavior, and the dosage of the cocaine for training the CPP is 5 mg/kg; b: the cocaine and imatinib mesylate compound drug delivery is used for inhibiting drug foraging, and the cocaine dose for training the CPP is 5 mg/kg; c: the cocaine and imatinib mesylate are jointly administered to inhibit the foraging behavior, and the dosage of the cocaine for training the CPP is 10 mg/kg; d: the cocaine and imatinib mesylate compound is used for inhibiting foraging behavior, and the dose of the cocaine for training the CPP is 10 mg/kg.

Figure 9 is a graph of the effect of dose of imatinib mesylate used in combination with alcohol on the development of postprandial drug behavior in rats after alcohol addiction; wherein, A: the combined administration of alcohol and imatinib mesylate is used for inhibiting drug-seeking behavior, and the alcohol dose for training the CPP is 0.5 g/kg; b: the compound administration of alcohol and imatinib mesylate is used for inhibiting drug foraging, and the alcohol dose for training CPP is 0.5 g/kg; c: the combined administration of alcohol and imatinib mesylate is used for inhibiting drug-seeking behavior, and the alcohol dose for training the CPP is 0.75 g/kg; d: the compound administration of alcohol and imatinib mesylate is used for inhibiting drug foraging, and the alcohol dose for training CPP is 0.75 g/kg.

Figure 10 is a dose effect of imatinib mesylate in combination with morphine upon environmental induction, unconditional stimulation, or direct administration on the formation of post-addiction to morphine and the repopulation of post-withdrawal effects in rats; wherein, A: unconditional stimulation, morphine dose is 3mg/kg, the influence of combined administration with imatinib mesylate on foraging behavior and relapse is achieved, and the morphine dose for training CPP is 10 mg/kg; b: unconditional stimulation, morphine dose is 3mg/kg, the influence of combined administration with imatinib mesylate on foraging behavior and relapse is achieved, and the morphine dose for training CPP is 10 mg/kg; c: unconditional stimulation, morphine dose is 5mg/kg, the influence of combined administration with imatinib mesylate on foraging behavior and relapse is achieved, and the morphine dose for training CPP is 10 mg/kg; d: unconditional stimulation is carried out, the morphine dose is 5mg/kg, the influence of compound administration of morphine and imatinib mesylate on the foraging behavior and the relapse is realized, and the morphine dose for training the CPP is 10 mg/kg; e: influence of imatinib mesylate on foraging behavior and relapse after environmental stimulation, and morphine dose for training CPP is 10 mg/kg; f: effect of direct administration of imatinib mesylate on foraging behavior and relapse, CPP was trained at a morphine dose of 10 mg/kg.

Figure 11 is a dose effect of imatinib mesylate and cocaine on the formation of post-opiate addiction foraging behavior and memory reintegration following withdrawal in environmentally induced, unconditional stimulation dosing or direct dosing in rats; wherein, A: unconditional stimulation, the cocaine dose is 3mg/kg, the influence of combined administration with imatinib mesylate on the foraging behavior and the relapse is avoided, and the cocaine dose for training the CPP is 10 mg/kg; b: unconditional stimulation is carried out, the cocaine dose is 3mg/kg, the influence of compound administration of cocaine and imatinib mesylate on the foraging behavior and the relapse is avoided, and the cocaine dose for training the CPP is 10 mg/kg; c: unconditional stimulation, the cocaine dose is 5mg/kg, the influence of combined administration with imatinib mesylate on the foraging behavior and the relapse is avoided, and the cocaine dose for training the CPP is 10 mg/kg; d: unconditional stimulation is carried out, the cocaine dose is 5mg/kg, the influence of compound administration of cocaine and imatinib mesylate on the foraging behavior and the relapse is avoided, and the cocaine dose for training the CPP is 10 mg/kg; e: influence of imatinib mesylate on foraging behavior and relapse after environmental stimulation, and the dose of cocaine for training the CPP is 10 mg/kg; f: effect of direct administration of imatinib mesylate on foraging behavior and relapse, CPP was trained with a cocaine dose of 10 mg/kg.

Figure 12 is a dose effect of imatinib mesylate in combination with alcohol upon environmental induction, unconditional stimulation, or direct dosing on the formation of drug-seeking behavior following alcohol addiction and the remembrance of memory following withdrawal in rats; wherein, A: unconditional stimulation, wherein the alcohol dose is 0.25g/kg, the influence of combined administration of imatinib mesylate on drug foraging behavior and relapse is avoided, and the alcohol dose for training the CPP is 0.75 g/kg; b: unconditional stimulation is carried out, the alcohol dose is 0.25g/kg, the influence of compound drug administration with imatinib mesylate on drug foraging behavior and relapse is avoided, and the alcohol dose for training the CPP is 0.75 g/kg; c: unconditional stimulation, wherein the alcohol dose is 0.5g/kg, the influence of combined administration of imatinib mesylate on drug foraging behavior and relapse is avoided, and the alcohol dose for training the CPP is 0.75 g/kg; d: unconditional stimulation is carried out, the alcohol dose is 0.5g/kg, the influence of compound drug delivery with imatinib mesylate on drug foraging behavior and relapse is avoided, and the alcohol dose for training the CPP is 0.75 g/kg; e: influence of imatinib mesylate on foraging behavior and relapse after environmental stimulation, wherein the alcohol dose for training the CPP is 0.75 g/kg; f: effects of direct administration of imatinib mesylate on foraging behavior and relapse, CPP was trained with an alcohol dose of 0.75 g/kg.

FIG. 13 is a graph of the effect of imatinib mesylate in combination with morphine on withdrawal response in rats; wherein, A: the effect of imatinib mesylate in combination with small doses of morphine on withdrawal symptoms (number of hops) after the formation of morphine CPP; b: the effect of imatinib mesylate in combination with small doses of morphine on withdrawal symptoms (number of hops) after the formation of morphine CPP; c: the effect of imatinib mesylate in combination with small doses of morphine on withdrawal symptoms (weight loss) after the formation of morphine CPP; d: effect of imatinib mesylate in combination with small doses of morphine on withdrawal symptoms (weight loss) after the formation of morphine CPP.

FIG. 14 is a graph showing the effect of imatinib mesylate in combination with cocaine on withdrawal response from rat addiction; wherein, A: the effect of imatinib mesylate on withdrawal symptoms (residence time in closed arms) following cocaine CPP formation; b: effect of imatinib mesylate on withdrawal symptoms (number of arm entries closed) following cocaine CPP formation.

FIG. 15 is a graph showing the effect of imatinib mesylate in combination with alcohol on withdrawal response in rats; wherein, A: the effect of imatinib mesylate on withdrawal symptoms (residence time in closed arms) after alcohol CPP formation; b: effect of Imatinib mesylate on withdrawal symptoms (number of arm entries closed) after alcohol CPP formation

Figure 16 is a dose effect of imatinib mesylate in combination with an opioid addict on the formation and expression of morphine sensitization in rats; wherein, A: the effect of imatinib mesylate in combination with morphine on the formation of sensitization to morphine; b: the influence of the imatinib mesylate and morphine compound medicine on the sensitization of the morphine; c: effect of imatinib mesylate on sensitizing expression of morphine.

FIG. 17 is a dose effect of imatinib mesylate in combination with an opioid addictive substance on the formation and expression of sensitization of cocaine in rats; wherein, A: the effect of imatinib mesylate in combination with cocaine on the formation of sensitization to cocaine; b: the influence of the compound administration of imatinib mesylate and cocaine on the sensitization formation of cocaine; c: effect of imatinib mesylate on the sensitization expression of cocaine.

FIG. 18 is a graph of the dose effect of imatinib mesylate in combination with an opioid addict on rat alcohol sensitization formation and expression; wherein, A: the effect of imatinib mesylate in combination with alcohol on the formation of alcohol sensitization; b: the influence of the compound administration of imatinib mesylate and alcohol on the formation of alcohol sensitization; c: effect of imatinib mesylate on alcohol-sensitized expression.

Fig. 19 is a graph of the dose effect of imatinib mesylate dosed with high-sugar, high-fat diet on addiction to rat high-sugar, high-fat diet, in a histogram, from left to right: high-sugar high-fat food + physiological saline, high-sugar high-fat food + imatinib mesylate 1, 5, 10, 20, 30 mg/kg.

FIG. 20 is a graph showing the effect of imatinib mesylate used in combination with a high-sugar, high-fat diet on the foraging and resolubilization of rats after addiction to the high-sugar, high-fat diet; wherein, A: the influence of imatinib mesylate on foraging and reabsorption of high-sugar and high-fat foods after unconditional stimulation; b: the influence of imatinib mesylate on foraging and reabsorption of high-sugar and high-fat foods after environmental cue stimulation; c: the effects of direct administration of imatinib mesylate on the foraging and resorption of high-carbohydrate and high-fat foods. The histogram includes, from left to right: high-sugar high-fat food + physiological saline, high-sugar high-fat food + imatinib mesylate 1, 5, 10, 20, 30 mg/kg.

FIG. 21 is a dose effect of imatinib mesylate on rat gambling tasks; wherein, A: environmental cues induce the effects of imatinib mesylate on gambling behavior; b: the effect of direct administration of imatinib mesylate on gambling behaviour.

FIG. 22 is a conversion of imatinib mesylate used dose to clinical dose.

Detailed Description

The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto. The addictive substance used in the examples below is morphine, which is widely representative, or cocaine, and one skilled in the art can reproduce similar findings with other addictive substances having similar mechanisms of action to morphine. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

Example 1: effect of imatinib mesylate dosage effect on rat morphine addiction formation and molecular mechanism

Experiment 1: novel mechanism for preventing morphine addiction by using imatinib mesylate

Acute morphine administration.

Animal grouping and treatment: the experimental rats were randomly divided into four groups, namely, a normal saline + normal saline, a normal saline + imatinib sulfonate administration group, a morphine + normal saline group, and morphine + imatinib mesylate (n ═ 10).

Injecting imatinib (30mg/kg) or physiological saline (1mL/kg) into abdominal cavity, injecting morphine (10mg/kg) subcutaneously half an hour later, and perfusing heart to take out brain tissue 1 hour later. Observing the change of c-kit activity of a mesolimbic dopamine system including VTA, nucleus accumbens, amygdala, hippocampus and prefrontal cortex, observing the change of c-kit phosphorylation level by immunohistochemistry combined with western-blot, observing activated cell distribution by immunofluorescence co-labeling, determining downstream activation target molecules by multicolor immunofluorescence co-labeling, and determining a new molecular mechanism of morphine addiction and an action mechanism of imatinib mesylate for preventing and treating addiction.

The results are shown in figure 1, after the acute morphine is administrated, the co-labeling results of immunohistochemistry, western-blot and multicolor immunofluorescence show that the nucleus accumbens is specifically activated but not other brain area neuron c-kit receptors and a plurality of signal transduction pathways such as PKC, PI3K-AKT, ERK and the like after the receptors regulate kinase activity, protein expression, gene expression and regulation and start morphine reward, memory and neural plasticity processes, and the nucleus accumbens c-kit receptors are the specific brain areas activated by the acute morphine administration; the imatinib mesylate can inhibit various signal transduction pathways such as PKC, PI3K-AKT, ERK and the like by blocking c-kit receptors to regulate kinase activity, protein expression, gene expression and regulation and start morphine reward, memory and neural plasticity processes, thereby achieving the effect of preventing morphine addiction.

Experiment 2: effect of imatinib mesylate dosing on rat morphine addiction formation

Materials (I) and (II)

Medicine preparation: morphine (Morphine, Qinghai pharmaceutical works), imatinib mesylate (Selleck Chemicals).

Experimental animals: SPF grade SD male rats weighing 180-220 g. Provided by lakan slyka laboratory animals ltd, the animal certification number is No.43004700040706, and the production license number: SCXK (Xiang) 2016-. Rat feed purchased from the laboratory animal center of Wuhan university. All animals were raised in the SPF environment of the animal experiment center of Wuhan university at 23 + -2 deg.C, 50 + -5% humidity, 6% light time: 00-18: 00, 12-hour light and shade alternation is adopted, the rats can freely obtain food and drinking water when being raised, and environmental adaptation within one week is provided before experiments (the same below).

An experimental instrument: conditional position preference apparatus (developed by the institute of medicine make internal disorder or usurp of Chinese academy of medical sciences): the experiment is automatically controlled by a computer. The device consists of a conditioned place preference box consisting of three boxes: two side chambers and a middle chamber. The three chambers are separated by a movable partition plate, and the inside and the outside are black. The box A and the box B are positioned on two sides of the middle box and have the same size, 9 squares capable of emitting yellow light diodes are arranged on the side wall of the box A, a bottom plate is made of stainless steel bars, and a bottom plate of the box B is made of stainless steel grids. The residence time and the number of times of entrance and exit of the rats in each box can be transmitted to a computer through data, and behavioural data are automatically collected and recorded.

Second, Experimental methods

Morphine Conditional Place Preference (CPP) model establishment.

And (3) testing a basic value: on day 1, the partition was removed, the three chambers were opened, the CPP program on the computer was started, the rat was placed in the middle chamber and allowed to move freely for 15 minutes in the three chambers, and the computer synchronously recorded the residence time in each chamber. Based on the test results, elimination and grouping were performed, and the concomitant drug side and non-concomitant drug side of each rat were distinguished.

After the baseline was tested, rats were divided into 24 groups (n-10) according to score:

conditional location preference training: and closing the channel between the three boxes on days 2 to 9. On days 2, 4, 6 and 8, the combined administration group was injected with different doses of imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) 30 minutes in advance, followed by morphine (5, 10mg/kg, s.c.), and placed on the concomitant drug side for 45 min; the control group was injected with physiological saline (1mL/kg, i.p.) + morphine (5, 10mg/kg, s.c.) at the corresponding time point and placed 45min on the non-concomitant side. The compound preparation is prepared by mixing imatinib mesylate with morphine at different doses, injecting, and placing in the concomitant drug side for 45 min; the control group was injected with a mixture of physiological saline (1mL/kg) and morphine (5, 10mg/kg, s.c.) and placed on the non-concomitant side for 45 min. On days 3, 5, 7 and 9, the rats in the drug administration group and the control group of the combined drug administration were injected with normal saline (1mL/kg, i.p.) + normal saline (1mL/kg, s.c.), the rats in the drug administration group and the control group of the combined drug administration group were injected with normal saline (2mL/kg, i.p.), the drug administration group was placed on the non-concomitant drug side, and the control group was placed on the concomitant drug side, all for 45 min. The concomitant side of each rat was fixed. After the experiment, each group of rats was returned to the rearing cage.

Morphine CPP test: on day 10, CPP testing, similar to the baseline testing phase. The channel between the three chambers was opened, without any injection, the CPP program on the computer was started, the rat was placed from the middle chamber and allowed to move freely in the chamber for 15 minutes, and the computer synchronously recorded the residence time in each chamber. CPP score (CPP score) is the difference between time on the concomitant side and time on the non-concomitant side. Comparing the measured value of the rat after the rat has the conditional position preference in the medicine accompanying box with the previously measured value to determine whether the rat has the conditional position preference.

Third, experimental results

The results are shown in fig. 2, and whether the combination or the compound preparation is adopted, the imatinib mesylate administration group has significant difference compared with the control group and is dose-dependent, after the intraperitoneal injection of imatinib mesylate (10, 20, 30mg/kg, i.p.), rats with 5mg/kg morphine training CPP have conditioned place preference which cannot be formed, but after the injection of imatinib mesylate (1, 5mg/kg, i.p.) still has the conditioned place preference; after the imatinib mesylate (20, 30mg/kg, i.p.) is injected intraperitoneally, rats trained by 10mg/kg morphine cannot form conditioned place preference, but after the imatinib mesylate is injected (1, 5, 10mg/kg, i.p.), the conditioned place preference still exists in non-administrated rats, and the conditioned place preference still exists, which indicates that the dose ratio of the imatinib mesylate to the morphine for training is more than 2:1, so that the rat morphine addiction can be inhibited.

Example 2: effect of imatinib mesylate dosage effect on cocaine addiction formation in rats and molecular mechanism

Similar results were obtained with respect to experiments 1, 2 of example 1, where the addictive drug morphine was replaced by cocaine (figures 3, 4).

Example 3: influence of imatinib mesylate dosage effect on rat alcohol addiction formation and molecular mechanism

Experiment 1: the alcohol dose was 0.75g/kg and the imatinib mesylate dose was 30mg/kg, the procedure being the same as in example experiment 2. Similar results were obtained as in experiment 2 of example 1 (fig. 5).

Experiment 2: the dosage of the alcohol is 0.5g/kg and 0.75g/kg, and the dosage of the imatinib mesylate is 1 mg/kg, 5mg/kg, 10mg/kg, 15 mg/kg, 20 mg/kg and 30 mg/kg; the procedure was as in example 1, experiment 1.

The results are shown in FIG. 6, when the alcohol dose used for training CPP is 0.5g/kg, 1, 5mg/kg imatinib mesylate has no significant effect on CPP formation; whereas 10, 15, 20, 30mg/kg imatinib mesylate can significantly attenuate CPP and present a dose effect; the non-administration group CPP can be formed; when the alcohol dosage used for training the CPP is 0.75g/kg, 1, 5 and 10mg/kg of imatinib mesylate has no significant influence on the formation of the CPP; and the imatinib mesylate of 15, 20 and 30mg/kg can obviously weaken CPP and has a dose effect; the non-administered group CPP can be formed. It is demonstrated that the formation of alcohol addiction can be prevented when the ratio of imatinib mesylate to the amount of alcohol used in the training of CPP is greater than 1: 50.

Example 4: effect of imatinib mesylate on the Across of unconditional stimulus-induced memory recall post-morphine addiction in rats on the onset of drug-seeking behavior

The effect of different doses (1, 5, 10, 20, 30mg/kg, i.p.) of imatinib mesylate on morphine-dependent post-foraging behavior was studied by establishing a morphine Conditional Place Preference (CPP) model.

Materials (I) and (II)

Medicine preparation: morphine (Qinghai pharmaceutical factory), imatinib mesylate (Novartis Pharmastein AG).

Experimental animals: SPF grade SD male rats weighing 180-220 g. Provided by lakan slyka laboratory animals ltd, the animal certification number is No.420110200001490, and the production license number: SCXK (Xiang) 2017-. Rat feed purchased from the laboratory animal center of Wuhan university.

An experimental instrument: the same as in example 1.

Second, Experimental methods

(1) Establishment of morphine CPP model

And (3) testing a basic value: on day 1, the three-compartment tunnel was opened, the CPP program on the computer was started, the rat was placed from the middle compartment and allowed to move freely in the three compartments for 15 minutes, and the computer synchronously recorded the residence time in each compartment.

After the baseline was tested, rats were divided into 12 groups (n-10) according to CPP score:

conditional location preference training: and closing the channel between the three boxes on days 2 to 9. On days 2, 4, 6, and 8, the administration group was subcutaneously injected with morphine (5, 10mg/kg) and placed on the concomitant drug side for 45 minutes: the control group was injected subcutaneously with physiological saline (1mL/kg) and placed on the non-concomitant side for 45 minutes. On days 3, 5, 7, and 9, the rats in the administration group and the control group were injected with physiological saline (1mL/kg), and the administration group was placed on the non-concomitant drug side and the control group was placed on the concomitant drug side for 45 minutes. The concomitant side of each rat was fixed. Each group of rats was then returned to the home cage.

Morphine CPP test: the same as in example 1.

(2) Detection of effect of imatinib mesylate on foraging behavior

On day 11 of the experiment, rats were placed back on the concomitant side for 15 minutes, then given different doses of imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.).

(3) Morphine CPP retest

The rats were tested for their preference for the concomitant medication box on day 1, day 12, and day 7, day 18 after imatinib mesylate administration for 15 minutes, similar to the basal test period.

Third, experimental results

The results are shown in FIG. 7, and the difference between the administered group and the control group is significant. For the administration group, 1, 5mg/kg imatinib did not show significant effect after administration of imatinib mesylate in the group with 5mg/kg morphine or the CPP trained, 10, 20, 30mg/kg imatinib mesylate significantly attenuated the condition site preference and was not ignited and dose-dependent; in the case of non-dosed rats, a conditioned place preference still exists. With the group of 10mg/kg morphine or training CPP, no significant effect was seen with 1, 5, 10mg/kg imatinib mesylate after administration, and 20, 30mg/kg imatinib mesylate significantly attenuated the conditioned place preference and was not ignited and dose-dependent; in the case of non-dosed rats, a conditioned place preference still exists. The ratio of the imatinib mesylate to the morphine is more than or equal to 2:1, so that the foraging behavior after addiction can be blocked, the psychological craving can be inhibited, and the afterburning behavior can be prevented and treated.

Example 5: effect of imatinib mesylate on the post-cocaine addiction unconditionally stimulated memory-induced recall post-foraging behavior in rats

Referring to example 4, similar results were obtained by exchanging the addictive drug morphine for cocaine (fig. 8).

Example 6: effect of imatinib mesylate on the unconditional stimulus-induced memory recall post-alcohol addiction in rats on drug-seeking behavior

Grouping: the total number of groups was 14 (n ═ 10).

The rest of the procedure was the same as in example 3.

The results are shown in fig. 9, and the difference between the administered group and the control group is significant. For the administration group, the CPP group trained with 0.5g/kg alcohol showed no significant effect of 1, 5mg/kg imatinib after imatinib mesylate administration, and 10, 15, 20, 30mg/kg imatinib mesylate significantly attenuated the conditional site preference and was not ignited and was dose-dependent; in the case of non-dosed rats, a conditioned place preference still exists. With the group of 0.75g/kg alcohol or training CPP, no significant effect was seen at 1, 5, 10mg/kg imatinib mesylate after administration, 15, 20, 30mg/kg imatinib mesylate significantly attenuated the conditioned place preference and was not ignited and dose-dependent; in the case of non-dosed rats, a conditioned place preference still exists. The ratio of the imatinib mesylate to the alcohol is more than or equal to 1:50, so that the drug seeking behavior after addiction can be blocked, the psychological craving can be inhibited, and the recrudescence can be prevented and treated.

Example 7: effects of imatinib mesylate administration after unconditional stimulation (combination, compound), environmental clue stimulation and direct administration on drug seeking behavior of rats after morphine addiction and drug relapse after withdrawal

The effects of direct 30mg/kg imatinib mesylate administration, administration after unconditional stimulation (combination, compound), and environmental cue-induced administration on morphine-dependent post-foraging behavior and relapse after withdrawal were studied by establishing a morphine Conditional Place Preference (CPP) model.

Materials (I) and (II)

Medicine preparation: morphine (Qinghai pharmaceutical factory), imatinib mesylate (Novartis Pharmastein AG).

Experimental animals: SPF grade SD male rats weighing 180-220 g. Provided by lakan slyka laboratory animals ltd, the animal certification number is No.420110200001750, and the production license number: SCXK (Xiang) 2017-. Rat feed purchased from the laboratory animal center of Wuhan university.

An experimental instrument: the same as in example 1.

Second, Experimental methods

(1) Establishment of morphine CPP model

And (3) testing a basic value: on day 1, the three-compartment tunnel was opened, the CPP program on the computer was started, the rat was placed from the middle compartment and allowed to move freely in the three compartments for 15 minutes, and the computer synchronously recorded the residence time in each compartment.

After the baseline was tested, rats were divided into 24 groups (n-10) according to CPP score:

conditional location preference training: and closing the channel between the three boxes on days 2 to 9. On days 2, 4, 6, and 8, the administration group was subcutaneously injected with morphine (10mg/kg) and placed on the concomitant drug side for 45 minutes: the control group was injected subcutaneously with physiological saline (1mL/kg) and placed on the non-concomitant side for 45 minutes. On days 3, 5, 7, and 9, the rats in the administration group and the control group were injected with physiological saline (1mL/kg), and the administration group was placed on the non-concomitant drug side and the control group was placed on the concomitant drug side for 45 minutes. The concomitant side of each rat was fixed. Each group of rats was then returned to the home cage.

Morphine CPP test: the same as in example 1.

(2) Detection of effect of imatinib mesylate on foraging behavior

On day 11 of the experiment, for rats induced by substance cues, the combination group was injected 30 minutes earlier with morphine (2, 3, 4mg/kg, s.c.) or physiological saline (1mL/kg, s.c.), followed by 30mg/kg of imatinib mesylate intraperitoneally, and the combination group was administered with 30mg/kg of imatinib mesylate or a mixture of morphine (2, 3, 4mg/kg, i.p.) or physiological saline (1 mL/kg). The rats induced by environmental clues are placed back to the drug accompanying side for 15 minutes, and then 30mg/kg of imatinib mesylate or 1mL/kg of physiological saline is injected into the abdominal cavity; the non-induced rats were directly administered imatinib mesylate (30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.), and then the rats were returned to the rearing cage and subjected to the test of conditional site preference behavior after 24 hours.

(3) Morphine CPP retest

The rats were tested for their preference for the concomitant medication box on day 1, day 12, and day 7, day 18 after imatinib mesylate administration for 15 minutes, similar to the basal test period. On day 19, the ignition was carried out with a small dose of morphine (3mg/kg, s.c.). After morphine injection, rats were placed in the middle box and CPP value testing was initiated for 15 minutes. Rats were not treated during the non-detection period.

Third, experimental results

The results are shown in FIG. 10, and the difference between the administered group and the control group is significant. 10. 20 and 30mg/kg imatinib mesylate administration significantly attenuated the conditioned place preference for all administration groups; in the case of non-dosed rats, a conditioned place preference still exists. The result shows that the administration of imatinib mesylate and morphine in a ratio of 2:1 can block the foraging behavior after addiction and inhibit psychological craving. After the stimulation with small dose of morphine, the unconditional stimulation induction comprises the combination of the drug and the compound preparation, when the morphine dose for induction is 3mg/kg, rats (including combination and compound) with 10, 20 and 30mg/kg dose are not ignited; environmental induction was not ignited only with the 20, 30mg/kg imatinib mesylate group; whereas the group administered imatinib directly, all were ignited. The fact that the drug administration (combination and compound) can prevent the relapse after the unconditional stimulation is carried out is shown, and only when the ratio of the dose of the imatinib mesylate to the dose of the morphine used in the training is more than or equal to 2:1, and the ratio of the dose of the morphine used in the unconditional stimulation to the dose of the morphine used in the training is less than or equal to 1:3, all the doses can inhibit the drug-seeking behavior and can not be ignited, so that the relapse is well prevented and treated; the drug administration (combination and compound) after being stimulated by environmental clues can only partially stop the drug-seeking behavior and has weak effect of preventing reburning; the imatinib mesylate is directly administrated, the effect of stopping foraging behavior can be achieved only when the dosage of the imatinib mesylate reaches 30mg/kg, and the effect of preventing reburning is weak.

Example 8: influence of imatinib mesylate after unconditional stimulation (combination and compound), environmental clue stimulation and direct administration on drug seeking behavior of cocaine addict in rats and drug recovery after withdrawal

Referring to example 7, similar results were obtained by exchanging the addictive drug morphine for cocaine (fig. 11).

Example 9: influence of imatinib mesylate after unconditional stimulation (combination and compound), environmental clue stimulation and direct administration on drug seeking behavior after alcohol addiction and drug relapse after withdrawal of rats

Grouping:

the alcohol dose used during CPP training was 0.75g/kg, and the alcohol dose used during the 19 th day challenge was 0.3 g/kg. The rest of the procedure was identical to example 5.

The results are shown in FIG. 12, and the difference between the administered group and the control group is significant. 15. The 30mg/kg imatinib mesylate administration significantly attenuated the conditioned place preference for all administration groups; in the case of non-dosed rats, a conditioned place preference still exists. Shows that the imatinib mesylate and the alcohol are dosed according to the proportion of 1:50, so that the drug seeking behavior after addiction can be blocked, and the psychological craving can be inhibited. After the stimulation with a small amount of alcohol, the induction of substance clues comprises the combination administration of the drug and the compound preparation group, and when the induction dose of the alcohol is 0.25g/kg, rats (comprising the combination and the compound) in the groups of 15 and 30mg/kg are not ignited; whereas the environmentally induced group, only the group using 30mg/kg imatinib mesylate, was not ignited; whereas the group directly dosed with imatinib mesylate, all ignited. It is shown that re-absorption can be prevented when the drug is administered (combination and combination) after unconditional stimulation, and that the effect is only obtained when the dose of imatinib mesylate used is 1:50 or more to the dose of alcohol used during training and the dose of alcohol used during unconditional stimulation is 1:3 or less to the dose of alcohol used during training; the mode of drug delivery (combination and compound) after environmental stimulation can only prevent the drug foraging behavior but cannot prevent the relapse; the imatinib mesylate is directly administrated, and the effect of stopping the foraging behavior can be achieved only when the dosage of the imatinib mesylate reaches 30mg/kg, and the relapse cannot be prevented.

Example 10: effect of imatinib mesylate on withdrawal symptoms after mouse morphine CPP formation

Materials (I) and (II)

Medicine preparation: morphine (Qinghai pharmaceutical factory), imatinib mesylate (Selleck Chemicals).

Experimental animals: SPF grade SD male mice, weighing 32-36 g. Provided by lakan slyka laboratory animals ltd, the animal certification number is No.42010200001574, and the production license number: SCXK (Xiang) 2016-. Rat feed purchased from the laboratory animal center of Wuhan university.

An experimental instrument: 5 l transparent beaker, stopwatch.

Second, Experimental methods

(1) Morphine training CPP

And measuring a baseline value.

Animal grouping and treatment: after baseline measurements, mice were divided into 12 groups (n-10) with the following values:

the rest of the procedure was similar to example 5.

(2) Observation of withdrawal symptoms

On the day of the experiment, different doses of imatinib mesylate (1.5, 7.5, 15, 30, 45mg/kg, i.p.) were administered to the administration groups for the combined administration group, mice in the control group were injected with physiological saline (1mL/kg, i.p.) and all mice were injected with morphine (5mg/kg, s.c.) at a small dose after 0.5h and with naloxone (2mg/kg, s.c.) after 1h, and then half-hour withdrawal symptoms were observed, and the observation indexes were the number of jumps and the amount of weight change; for the combination preparation administration group, different doses of imatinib mesylate (1.5, 7.5, 15, 30, 45mg/kg) or a mixed agent of physiological saline (1mL/kg) and morphine (5mg/kg) were subcutaneously administered to the administration group, naloxone (2mg/kg, s.c.) was administered after 1h, and then withdrawal symptoms were observed for half an hour with the observation indexes of the number of jumps and the amount of change in body weight.

Third, experimental results

The results are shown in fig. 13, and compared with the control group, the imatinib mesylate at 15, 30 and 45mg/kg can relieve the withdrawal symptoms of the mice regardless of the combined administration or the compound administration.

Example 11: effect of imatinib mesylate on withdrawal symptoms after cocaine CPP formation in mice

Materials (I) and (II)

Medicine preparation: cocaine (Qinghai pharmaceutical Co., Ltd.), imatinib mesylate (Selleck Chemicals).

An experimental instrument: conditional position preference instrument and elevated cross maze

II, an experimental method:

(1) cocaine training CPP

Baseline measurements were taken and after baseline measurements, the rats were divided into 12 groups (n-10) with:

the dose of cocaine used for training was 10mg/kg, and the procedure was identical to that of cocaine CPP trained in example 5.

(2) Elevated cross maze

After CPP formation, drug withdrawal was carried out for 72 hours, followed by the elevated plus maze experiment.

The mice were intraperitoneally injected with 1.5, 7.5, 15, 30, 45mg/kg imatinib mesylate or 1mL/kg physiological saline, and after 1 hour, the mice were placed in the center of the elevated maze, and the number of times the mice entered the closed arms and the time spent in the closed arms were counted.

Third, test results

The results are shown in fig. 14, compared with the control group, the administration group has obvious difference, the time of the rats which are administered 30mg/kg staying in the closed arms and the times of entering the closed arms are both obviously lower than other groups, which shows that the withdrawal symptoms after cocaine addiction can be inhibited when the cocaine dose of imatinib mesylate and cocaine CPP training is more than or equal to 2: 1.

Example 12: effect of imatinib mesylate on withdrawal symptoms after alcohol CPP formation in mice

Firstly, a laboratory instrument: a conditional position preference instrument and an elevated cross maze.

Second, Experimental methods

(1) Alcohol CPP formation

Baseline, after baseline measurement, rats were assigned, 14 groups:

the alcohol dosage for CPP formation is 0.75 g/kg. The rest of the procedure was the same as in example 6.

(2) Elevated cross maze

After CPP formation, drug withdrawal was carried out for 72 hours, followed by the elevated plus maze experiment.

The mice were intraperitoneally injected with 1.5, 7.5, 15, 30, 45mg/kg imatinib mesylate or 1mL/kg physiological saline, and after 1 hour, the mice were placed in the center of the elevated maze, and the number of times the mice entered the closed arms and the time spent in the closed arms were counted.

Third, experimental results

The results are shown in fig. 15, and compared with the control group, the imatinib mesylate at 15, 30 and 45mg/kg can relieve the withdrawal symptoms of the mice regardless of the combined administration or the compound administration.

Example 13: dose effect of imatinib mesylate on formation and expression of morphine sensitization in rats

The results of examples 1, 4 and 7 show that imatinib mesylate and its dose ratio with opioid can inhibit opioid addiction and relapse after withdrawal in rats. In the experiment, a rat morphine sensitization model is established, the improvement effect of the proportion of the imatinib mesylate and the opioid in the rat hypergenic spontaneous activity caused by morphine is discussed, and the drug with definite curative effect and low toxicity for resisting the hypergenic spontaneous activity of morphine addiction is selected.

Materials (I) and (II)

Medicine preparation: morphine (Qinghai pharmaceutical factory), imatinib mesylate (Selleck Chemicals).

Experimental animals: SPF grade SD male rats weighing 180-220 g. Provided by lakan slyka laboratory animals ltd, the animal certification number is No.4201200001721, and the production license number: SCXK (Xiang) 2017-. Rat feed purchased from the laboratory animal center of Wuhan university.

An experimental instrument: spontaneous activity test box (developed by the institute of medicine make internal disorder or usurp of Chinese academy of medical sciences): the experiment is automatically controlled by a computer. The device comprises four spontaneous activity observation boxes, a video synthesizer, a video pattern sampling card, analysis software and the like. The system carries out video tracking on the movement of the rat and automatically records the movement track and the movement times of the rat. The evaluation index of spontaneous activity is the total number of activities of the rat within a certain period of time (e.g. 60 minutes), i.e. the increase of the total number shows the increase of spontaneous activity.

Second, Experimental methods

Animal molding: the day before the experiment (day 0), the experimental rats were subjected to baseline measurement of activity and were randomly divided into 14 groups (n ═ 10) according to the measurement results:

effect on formation: on days 1 to 5 of the experiment, physiological saline (1mL/kg) or imatinib mesylate (1, 5, 10, 20, 30mg/kg) was administered intraperitoneally 30 minutes prior to the subcutaneous injection of morphine (10 mg/kg); or subcutaneously administering imatinib mesylate or a mixture of normal saline and morphine. The experiment was repeated for 5 days.

Effect on expression: the experiment was repeated for 5 days, on days 1 to 5, with morphine (10mg/kg) or physiological saline (1mL/kg) injected subcutaneously. Then, the patient was weaned for 5 days, and on experiment day 11, imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.) was injected first, and then a small dose of morphine (5mg/kg) was injected subcutaneously to stimulate, and the spontaneous activity of each group was examined for 60 minutes, and the change in the spontaneous activity was observed.

Thirdly, experimental results:

the results are shown in FIG. 16, for the effect on formation: after 5 days of continuous morphine administration to rats, rats given 30mg/kg dose of imatinib mesylate had a significant difference compared to rats subjected to physiological saline intervention, and were able to inhibit the formation of morphine sensitization in rats.

Effect on expression: after subcutaneous morphine injection on day 11, it was observed that rats administered with 30mg/kg dose of imatinib mesylate had a significant difference compared to rats administered with saline intervention, inhibiting morphine-sensitized expression in rats.

Example 14: dose effect of imatinib mesylate on formation and expression of sensitization of cocaine in rats

Referring to example 13, similar results were obtained by exchanging the addictive drug morphine for cocaine (fig. 17).

Example 15: dose effect of imatinib mesylate on the formation and expression of alcohol sensitization in rats

The dosage of the alcohol used in the molding process is 0.75g/kg, and the dosage of the imatinib mesylate is 1, 5, 10, 15, 20 and 30 mg/kg.

The rest of the procedure was in accordance with example 13.

The results are shown in FIG. 18, for the effect on formation: after 5 days of continuous morphine administration to rats, rats given 15, 20 and 30mg/kg dose of imatinib mesylate have significant difference compared with rats subjected to physiological saline intervention, and can inhibit the formation of morphine sensitization in rats.

Effect on expression: after subcutaneous morphine injection on day 11, it was observed that rats given a medium 15, 20, 30mg/kg dose of imatinib mesylate had significant differences compared to rats that had been administered saline intervention, inhibiting morphine-sensitized expression in rats.

Example 16: dose effect of imatinib mesylate on the development of food addiction in rats

Materials (I) and (II)

Drugs and reagents: self-made high-sugar and high-fat food (10% of sucrose content and 30% of lipid content); imatinib mesylate (Novartis Pharmastein AG).

Experimental animals: SPF grade SD male rats weighing 220-. The animal qualification number is NO.42010200001670 provided by the experimental animal research center of Hubei province, and the production license number is: SCXK (Hubei) 2017-. Rat feed purchased from the laboratory animal center of Wuhan university.

An experimental instrument: the same as in example 1.

Second, Experimental methods

Establishment of high-sugar high-fat food CPP model

And (3) testing a basic value: on day 1, the three-compartment tunnel was opened, the CPP program on the computer was started, the rat was placed from the middle compartment and allowed to move freely in the three compartments for 15 minutes, and the computer synchronously recorded the residence time in each compartment.

Grouping experimental animals: based on the measured basis, the rats were divided into 12 groups (n-8):

conditional location preference training: and closing the channel between the three boxes on days 2 to 9. On days 2, 4, 6 and 8, the experimental group was injected with different doses of imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) 30 minutes in advance, then fed freely and placed on the concomitant side for 45 min; the control group was injected with normal saline (1mL/kg, i.p.) at the corresponding time point, then fed freely, and placed 45min on the non-concomitant side. On days 3, 5, 7 and 9, the rats in the experimental group and the control group are injected with normal saline and given with clear water, the administration group is placed on the non-concomitant drug side, and the control group is placed on the concomitant drug side for 45 min. The concomitant side of each rat was fixed. After the experiment, each group of rats was returned to the rearing cage.

CPP test: the same as in example 1.

Detection indexes are as follows: after the rats are trained, a condition position preference box is adopted to detect the addiction condition of high-sugar and high-fat food, a condition position preference Score (CPP Score) reflects the formation condition of the addiction behaviors of the rats, the CPP Score is increased, and the addiction behaviors are formed.

Third, experimental results

The results are shown in fig. 19, and the effect of imatinib mesylate on the development of high-sugar, high-fat food addiction is dose-effect; 1.5 and 10mg/kg of imatinib mesylate has no significant influence on addiction to high-sugar and high-fat foods, and 20 and 30mg/kg of imatinib mesylate can obviously inhibit the formation of addiction to high-sugar and high-fat foods in rats.

Example 17: dose effect of imatinib mesylate on the effects of reintegration after formation of high-sugar and high-fat food addiction and relapse after withdrawal

Materials (I) and (II)

Drugs and reagents: self-made high-sugar and high-fat food (10% of sucrose content and 30% of lipid content); imatinib mesylate (Novartis Pharmastein AG).

Experimental animals: SPF grade SD male rats weighing 220-. The animal qualification number is NO.42010200001673 provided by the experimental animal research center of Hubei province, and the production license number is: SCXK (Hubei) 2017-. Rat feed purchased from the laboratory animal center of Wuhan university.

An experimental instrument: the same as in example 1.

Second, Experimental methods

(1) Establishment of high-sugar high-fat food CPP model

And (3) testing a basic value: on day 1, the three-compartment tunnel was opened, the CPP program on the computer was started, the rat was placed from the middle compartment and allowed to move freely in the three compartments for 15 minutes, and the computer synchronously recorded the residence time in each compartment.

Based on baseline test results, rats were divided into 18 groups (n-8):

conditional location preference training: and closing the channel between the three boxes on days 2 to 9. On days 2, 4, 6, and 8, the experimental group had free access to high-sugar and high-fat foods and placed on the concomitant drug side for 45 minutes; the control group was given clear water and placed on the non-concomitant side for 45 minutes. On days 3, 5, 7 and 9, the rats in the experimental group and the rats in the control group are both given clear water, the experimental group is placed on the non-concomitant drug side, and the rats in the control group are placed on the concomitant drug side for 45 minutes. The concomitant side of each rat was fixed. Each group of rats was then returned to the home cage.

CPP test: CPP testing was performed on day 10, similar to the baseline testing phase. The three-compartment tunnel was opened, without any treatment, the CPP program on the computer was started, the rat was placed from the middle compartment and allowed to move freely in the three compartments for 15 minutes, and the computer synchronously recorded the residence time in each compartment. The preference score (CPP score) is defined as the difference between the time spent in the concomitant medication chamber and the time spent in the non-concomitant medication chamber. The post-CPP measurement of the rats in the concomitant kit was compared with the anterolateral measurement to determine whether the rats developed CPP. And according to the CPP post-measurement value, rats which do not form the CPP are removed, and the animals are matched and grouped.

(2) Establishment of model for inducing drug-seeking behavior after environmental clues or unconditional re-exposure

On day 11 of the experiment, for the substance cue-induced rats, different doses of imatinib mesylate (1, 5, 10, 20, 30mg/kg) were injected after administration of a small amount of high-sugar, high-fat diet; rats induced by environmental cues were injected with imatinib mesylate (1, 5, 10, 20, 30mg/kg) 15min after exposure to the dosing chamber; for rats dosed directly, different doses of imatinib (1, 5, 10, 20, 30mg/kg) were dosed directly without any induction; all rats were then returned to the home cage.

(3) CPP retesting

The rats were tested for their preference for concomitant medication on days 1 and 7 after imatinib mesylate administration, i.e., days 12 and 18 of the experiment, for 15 minutes, similar to the basal test period. Rats were not treated anywhere from day 13 to day 17; on day 19, a small amount of high-sugar, high-fat food was given to light and the conditioned place preference was tested.

Detection indexes are as follows: after the rats are trained, a condition position preference box is adopted to detect the addiction condition of high-sugar and high-fat food, a condition position preference Score (CPP Score) reflects the formation condition of the addiction behaviors of the rats, the CPP Score is increased, and the addiction behaviors are formed.

Third, experimental results

The results are shown in FIG. 20, for rats induced by physical and environmental cues and directly dosed without induction, the non-dosed rats still had a conditional site preference; the foraging behavior can be inhibited after the treatment of 10, 20 and 30mg/kg of imatinib mesylate; however, after 1 week, only 30mg/kg of imatinib mesylate was not ignited in the environmentally induced rats, and none was ignited in the substance induced rats using 10, 20, 30mg/kg doses of imatinib mesylate; however, rats administered directly were challenged with imatinib mesylate at whatever dose was used. It is shown that the substance thread induction followed by imatinib mesylate administration is more effective than the environmental induction followed by administration or administration directly.

Example 19: dose effect of imatinib mesylate on rat gambling behaviour under rat gambling task conditions

Materials (I) and (II)

Experimental animals: SPF grade SD male rats weighing 275-300 g. The animal qualification number is NO.42010200001574 provided by the experimental animal research center of Hubei province, and the production license number is: SCXK (Hubei) 2017-. Rat feed purchased from the laboratory animal center of Wuhan university.

An experimental instrument: five-hole operator compartments, each enclosed in a ventilated sound reduction cabinet. 5 arrayed response holes are arranged 2 cm above the bottom of each operating room, a stimulation lamp is arranged behind each hole, and the nasal-stab reactions of the small holes can be detected by using horizontal infrared beams. The opposite wall had a food warehouse in the middle, also an infrared beam and a tray light, into which 45mg of sucrose pellets could be fed through an external pellet dispenser. The room can be illuminated with room lighting and controlled by software written by the Med PC for CAW running on an IBM compatible computer.

II, an experimental method:

grouping experimental animals: total 6 groups (n ═ 10), i.e. saline group, total 6 groups of imatinib mesylate 1, 5, 10, 20, 30 mg/kg.

Establishing a rat gambling behavior model: animals were first acclimated to the operating room twice daily for 30 minutes, during which time sucrose particles were placed in the reaction wells and food banks. After the adaptation was completed, the animals were trained to stick their nose in a lighted reaction well within 10 seconds to obtain a reward, the spatial location of the stimulating light appearing in different wells of 1, 2, 4 and 5 in different experiments. Each phase consisted of 100 trials lasting approximately 30 minutes. The animals were then trained for 7 forced selection of rGT (or rGT variants of the control group) and then on a complete free selection task. This ensures that all animals have the same experience under the four fortification conditions and is intended to prevent a simple prejudice against a particular hole. The percentage of trials in which animals selected a particular option was calculated according to the formula in the reference: the number of choices/total choices for a particular choice is 100(Di C P, Manvich D F, Pushparaj A, et al. effects of discrete on choice behavior in a cadent gambling task: association with hydrocarbon levels [ J ]. Psychopharmacology,2018,235(1):23-35), each experiment lasting 30 minutes, subjects responding with a nasal stamp on the illuminated food library, which reaction extinguished the tray light and triggered the start of the 5 second test interval (ITI). At the end of the ITI, wells 1, 2, 4, and 5 were illuminated for 10 seconds (only one well was illuminated in the forced selection version of the task used in training). If the animal does not respond within 10 seconds, the test is recorded as missing, the tray light is re-illuminated and the animal can begin a new test.

Option 1	Option 2	Option 3	Option 4
				1 granule of cane sugar, p is 0.9	2 granules of sucrose, p ═ 0.8	3 granules of cane sugar, p ═ 0.5	4 granules of cane sugar, p ═ 0.4
Penalty time of 5s, p is 0.1	Penalty time of 10s, p is 0.2	Penalty time of 30s, p is 0.5	Penalty time of 40s, p is 0.6

Explanation of the table above: the four wells in the laboratory were set with different reward and penalty probabilities, and corresponding reward sucrose amounts and penalty times, with no food reward during the penalty times, indicating that within 30 minutes, the best benefit would be obtained if only option 2 was selected after a series of selections were completed.

Training until the baseline of the rats stabilized, and the rGT group of rats consistently appeared biased towards the two sucrose selection, the best revenue selection; the overall trend is P2 > P4 > P1 > P3, but in fact the best choice is ranked as P2 > P1 > P3 > P4.

After training, rats were dosed with drugs, the first day after baseline stabilization, rats induced by environmental cues, placed in the experimental setup as during the acclimation period, but without starting the experiment, then dosed with imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.), the rats dosed directly, i.e. without being placed in the experimental setup, were dosed with imatinib mesylate (1, 5, 10, 20, 30mg/kg, i.p.) or physiological saline (1mL/kg, i.p.), then all rats were returned to the cages, and behavioral testing was performed on day 1 after dosing. On day 7 post-dose, behavioral testing was again performed.

Third, experimental results

The results are shown in FIG. 21: for rats exposed to the environment, after the administration of imatinib mesylate, 10, 20, 30mg/kg of imatinib mesylate significantly increased the optimal choice of rGT, i.e., P2, and decreased the choice of P4, compared to the control group; however, for the rats directly dosed, no significant effect was produced by any dose of imatinib mesylate. The results demonstrate that for the gambling task in rats, after baseline stabilization, the animals are given environmental cues prior to administration to induce enhanced improvement compared to direct administration.

And (4) conclusion: the results of the above examples show that addictive substances specifically activate nucleus accumbens and not other neuronal c-kit receptors in brain regions and post-receptor ERK, AKT, PKMzeta signaling pathways; the imatinib mesylate inhibits psychological craving behaviors by blocking c-kit receptors and signal paths thereof, thereby achieving the effects of preventing addictive substances and addictive behaviors and preventing and treating relapse. Similarly, imatinib and its derivatives can be used in combination with addictive substances or related clues of addictive behaviors or compound preparations for preventing and treating addiction and relapse after withdrawal.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (5)

1. The application of imatinib or a derivative thereof and an addictive substance in preparing a medicament is characterized in that: the medicine comprises drugs for addiction prevention, treatment and relapse prevention; the addictive substance comprises morphine, cocaine and alcohol; the imatinib derivative is imatinib mesylate;

the use mode of the medicine is that the imatinib or the derivative thereof and the addictive substance are used together or in a compound way;

when the addictive substance is morphine or cocaine, the dosage ratio of the imatinib or the derivative thereof to the addictive substance is greater than or equal to 2: 1; when the addictive substance is alcohol, the dosage ratio of the imatinib or the derivative thereof to the addictive substance is more than or equal to 1: 50;

the dosage of the addictive substance in the prevention, treatment and relapse treatment and the dosage of the addictive substance in the addiction treatment need to be less than or equal to 1: 3.

2. The application of imatinib or a derivative thereof and addictive foods in preparing medicines is characterized in that: the medicine comprises medicines for preventing and treating food addiction and preventing relapse; the addictive food comprises high fat food, sweet food and chocolate; the imatinib derivative is imatinib mesylate;

the use mode of the drug is that the imatinib or the derivative thereof is used together with or compounded with addiction food in proportion.

3. The application of imatinib or a derivative thereof in preparing a medicament is characterized in that: the medicine comprises a medicine for preventing and treating addiction behaviors and preventing relapse; the addictive behavior is gambling addiction; the imatinib derivative is imatinib mesylate;

the medicament is administered in a manner such that imatinib or a derivative thereof is administered after induction of addictive behavior cues.

4. Use according to any one of claims 1 to 3, characterized in that: the dose of imatinib or the derivative thereof is 100-400 mg/day.

5. Use according to any one of claims 1 to 3, characterized in that: the medicament is suitable for being prepared into one of the following dosage forms or specifications: injection, infusion solution, pill, tablet, powder, granule, capsule, powder, oral liquid, sustained release preparation, tincture, suppository, and patch.

Images