The Effect And Mechanism Of Y-QA31 In Methamphetamine Addiction

Drug addiction,also known as drug dependence,is a type of brain disease caused by repeated ingestion of addictive substances over a long period of time.It is characterized by tolerance and recurrence,and manifests as uncontrollable and compulsive drug-seeking and drug-taking behavior,as well as a long-lasting and intense craving for drugs.Drug addiction not only seriously damages the physical and mental health of addicts,but also accelerates the spread of infectious diseases such as AIDS and Hepatitis C,it has become one of the most serious medical and social problems that threaten the family and society.Methamphetamine(METH),belongs to amphetamine-type stimulants(ATS).It is one of the most widely abused new synthetic drugs in the world since the beginning of this century.The chemical structure of methamphetamine has high fat solubility,making it easily through the blood-brain barrier in the central nervous system(CNS),promote brain reward system to secrete more dopamine(DA),resulting in obvious euphoria and mental stimulation,long-time methamphetamine abuse can also lead to brain function damage.Since the etiology and mechanism of drug addiction have not been completely elucidated because of the complex and complicated mechanism of drug addiction.To date,no effective drugs have been developed for methamphetamine addiction and relapse.Therefore,the development of effective anti-methamphetamine drug and study of its mechanism is of great significance for the prevention and treatment of drug addiction.DA is the most important neurotransmitter in drug addiction rewards.Among the five DA receptor subtypes,D3 receptor(D3R)has the strongest binding to endogenous DA,and D3 R distribution is specific,it is highly expressed in the ventral tegmental area(VTA)and nucleus accumbens(NAc),which is closely related to addiction,and is involved in the regulation of DA synthesis and release.Previous studies have also shown that highly selective D3 R ligands are of great significance for the treatment of drug addiction.Y-QA31 is a dopamine D3 R antagonist,it has high affinity and selectivity for D3 R,and also has high affinity for 5-HT1 AR.There is no report of Y-QA31 anti-methamphetamine addiction study.Objective Different behavioral experimental models were used to evaluate the effect of Y-QA31 on anti-methamphetamine addiction,and study its mechanism of action to provide experimental theoretical basis for further development of new drugs.Methods Locomotion test was used to observe the effect of Y-QA31 on spontaneous activities and behavioral sensitization induced by methamphetamine;Conditioned place preference(CPP)test was used to observe the effect of Y-QA31 on METH-induced CPP acquisition,expression,reinstatement and whether Y-QA31 can induce CPP or not.Locomotion test and behavioral sensitization were represented by distance of spontaneous activity;CPP tests were represented by CPP scores.After the test of behavioral sensitization,all rats were decapitated,the materials of striatum(Str),hippocampus(Hip),prefrontal cortex(PFC)were harvested from rats’ brain,and the DAT,5-HTT and 5-HT1 AR levels were measured by western blot.Result(1)Methamphetamine(0.5 mg/kg,i.p.)could significantly increase spontaneous activity in rats,Y-QA31(6.25 、 12.5 、 25 、 50mg/kg,i.p.)could dose-dependently reduced acute spontaneous methamphetamine induced activity in rats,with a statistically significant difference in dose of 50 mg/kg.(2)Y-QA31(12.5,25,50mg/kg,i.p.)had no significant effect on spontaneous activity in rats.(3)Y-QA31(12.5,25,50 mg/kg,i.p.)can significantly reduce the extent of METH-induced behavioral sensitization in rats.(4)Y-QA31 had a reduced effect on the expression of METH-induced behavioral sensitization in rats,but there was no significant difference.(5)Repetitive injection of YQA31(6.25,12.5,25,50 mg/kg,i.p.)did not alter the acquisition of METH-induced CPP.(6)A single injection of YQA31(prior to CPP test)dose-dependently attenuated the expression of METH-induced CPP,with a statistically significant difference in dose of 50 mg/kg.(7)A single injection of YQA31(25,50mg/kg,i.p.)decreased the reinstatement of METH-induced CPP.(8)Y-QA31(12.5,25,50 mg/kg,ip)did not induce CPP,suggesting that Y-QA31 is not addictive.(9)In the animals’ model of behavioral sensitization,methamphetamine could decrease the expressions of DAT,5-HTT and 5-HT1 AR in Str,Hip and PFC brain regions of rats,with a statistically significant difference of DAT,5-HTT in Str,Y-QA31 had a different degree of up-regulation.Conclusion In summary,dopamine D3 receptor antagonist Y-QA31 had varying degrees of therapeutic effects on methamphetamine addiction and inhibit its relapse behavior,and Y-QA31 itself has no addictive potential;Y-QA31 may take effect in related brain regions,such as Str,Hip and PFC,which are closely related to addiction,the possible mechanism is to up-regulate the expression of DAT and 5-HTT in the brain,and reduce intracerebral DA content.