Effects And Mechanisms Of Sigma-1 Receptor Allosteric Modulator SOMCL-668 On Methamphetamine Induced Addiction In Mice

Aim:Drug abuse is one of the most serious medical and societal issues,but there are currently no viable effective treatment options.It’s a type of chronic mental disorder and psychological disease state brought on by the use of addictive drugs.Methamphetamine(METH)is one of the most extensively abused new synthetic drugs in the world,with a substantial market share,due to its easy molecular composition and manufacturing processes.SOMCL-668 is a previously found allosteric modulator of sigma-1 receptor in our laboratory.The significance of sigma-1 receptors in the incidence and progression of drug misuse has received increasing attention in recent years.We evaluated and confirmed the effect of SOMCL-668 on methamphetamine-induced addictive behavior in mice using several behavioral research models,and we investigated its potential mechanisms,providing a theoretical foundation for the future development of medications to treat addiction.Methods:The effect of SOMCL-668 on the formation of addictive memory and the extraction process was observed by conditional place preference test,and its effect on the formation and expression of behavioral sensitization was observed using behavioral sensitization model.Mice pretreated with the specific antagonist BD1063 and knockout of the sigma-1 receptor verified the target of SOMCL-668.The role of sigma-1 receptor and SOMCL-668 in maintaining dendritic spinous homeostasis and regulating transcription factors ΔFosB and CREB by methods of golgi staining and western blotting.Results:(1)In the methamphetamine-induced conditioned place preference model in mice,SOMCL-668 alone did not induce preference behavior in mice,indicating that SOMCL-668 has no central addiction potential;SOMCL-668 had no obvious influence on the formation,extinction and priming of conditioned place preference;(2)SOMCL-668 inhibited the high spontaneous activity of mice induced by acute methamphetamine;(3)In methamphetamine-induced behavioral sensitization model,SOMCL-668 significantly inhibited the formation and expression of behavioral sensitization in mice,and at the same time improved the depression and anxiety-like behaviors induced by methamphetamine in mice during withdrawal period;(4)The sigma-1 receptor antagonist BD1063 can significantly block the effect of SOMCL-668 on the inhibition of methamphetamine-induced high spontaneous activity and behavioral sensitization;(5)Sigma-1 receptor knockout mice were more susceptible to methamphetamine-induced behavioral sensitization;(6)SOMCL668 can significantly improve methamphetamine-induced increase in the density of dendritic spines in the hippocampus of mice;(7)Sigma-1 receptor deletion significantly reduces dendritic spine density in hippocampus and prefrontal cortex;(8)SOMCL-668 significantly down-regulated methamphetamine-induced increases in ΔFosB and p-CREB expressions.Conclusions:The anti-methamphetamine addiction effect of Sigma-1 receptor allosteric modulator SOMCL-668 mainly occurs in the process of behavioral sensitization and has a good alleviation effect on depression and anxiety-like behavior in mice during withdrawal,and its possible mechanism of action is to reverse the synaptic plasticity caused by methamphetamine and the change of transcription factor expression.Our results show that SOMCL-668 is a potential therapeutic agent for intervening in methamphetamine addiction,providing new ideas for finding new targets for the treatment of drug addiction.