The Role Of PP2A In Morphine Abuse And Relapse

Morphine,the world’s largest amount of analgesics,is an essentia component of opioid drugs,but chronic abuse of morphine will cause serious drug dependence.The addict who has quitted morphine abuse relapse promptly once exposed to the environment of morphine abuse.The hippocampus is actively involved in the process of environmental cue-dependent morphine relapse.The long-term potentiation(LTP)of mouse hippocampus is enhanced by the stimulation of acute morphine,but compromised upon forming environment-dependent morphine preference.Recent studies have shown that the regulation of protein phosphorylation is critical in drug craving behavior of morphine abuse.The protein phosphatase 2A(PP2A)belongs to serine/threonine protein phosphatase,and a key regultor of cell growth,development,formation of microtubule microfilament,synaptic plasticity and so on.Some researchers found that the acetylation of histone increased in morphine addicted mice,resulting in promotion of morphine addiction.Nevertheless,whether PP2A could regulate the behavior of morphine preference by modulating the synaptic plasticity in hippocampushas remains elusiveMethods:In this study,we generated conditional knockout(KO)mice with CAl-specific deletion of PP2A by Cre-loxP system(CAl-Cre;PP2Aflox/flox),combined with behavioral analysis,western blotting and electrophysiological recording,to explore the role of PP2A in the process of morphine abuse and its relapse.Results:We found in morphine CPP test,both PP2Aflox/flox(WT)mice and KO mice were capable of forming morphine preference,and preference behavior could be dissipated after extinction training.In the priming stage,WT mice with low doses of morphine could induce morphine preference behavior,and KO mice could also induce preference behavior,but the effect of priming was significantly lower than that of WT mice.There was no significant difference in the motor ability between the two groups of mice at each stage.This indicated that PP2A molecules in the hippocampal CA1 region were involved in the regulation of morphine preference behavior in priming stage.PP2A and phosphorylated PP2A were detected in 5 different brain(nucleus accumbens,ventral tegmental area,hippocampus,prefrontal cortex and amygdal)regions related to addiction in mice of WT and KO respectively,and we found that the effects of morphine on PP2A and phosphorylation level of PP2A were region-specific.These results suggested that PP2A in the hippocampal CA1 region might affect the transmission of the hippocampus to other brain regions,and the behaviour of morphine preference were coordinated by several different brain regions.Through electrophysiology recording experiments,we found that in the hippocampus of KO mice LTP induction was blocked,while WT mice could generate LTP at priming stage by low dose of morphine.The results showed that PP2A in the hippocampal CAI region could modulate the abuse of morphine by influencing the plasticity in the hippocampus.Surprisingly,WT mice with a certain concentration of sodium butyrate by intraperitoneal injection and increased amount of happiness running at extinction stage displayed simliar behavior and modulation of hippocampal plasticity as KO mice at priming stage.It implied that the relapse rate could be reduced effectively by regular physical exercise during detoxification.Conclusion:PP2A in the hippocampal CAI regulates the behavior of morphine preference by influencing the hippocampal plasticity.And PP2A may even be involved in one of the neural mechanisms underlying drug craving.My study of PP2A may provide reference value and significance to the development of drug treatment and relapse.