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Negative emotional memory after withdrawal is one of the most important factors that induce relapse.Activation of the GluR2/AMPAR trafficking pathway is thought to play a significant role in maintaining long-term memory.Protein kinase M zeta (PKM-zeta),an autonomously active fragment of atypical PKCs,is involved in GluR2/AMPAR trafficking.It remains unclear whether PKM-zeta and GluR2/AMPAR trafficking participate in the maintenance of negative emotional memory after drug withdrawal.In this study,a conditioned place aversion model,a sensitive model for detection of the motivational aversion of drug withdrawal,was first established by injecting morphine (20 mg/kg,i.p) and naloxone (1 mg/kg,i.p) through conditioning for four times.At 1,7,and 14 days after conditioned place aversion expression,ZIP,an inhibitor of PKM-zeta,was microinjected into bilateral insular cortex to explore the effect of PKM-zeta at different maintenance times on conditioned place aversion.The results showed that ZIP clearly reversed the maintenance of conditioned place aversion.Western blotting showed that the expression of PKM-zeta was significantly increased on days 7 and 14 after conditioned place aversion expression.Moreover,pre-injection of Tat-GluR23Y,an AMPAR endocytosis blocker,into the insular cortex 1 hour before ZIP injection on the 1st day after conditioned place aversion expression reversed the inhibitory effect of ZIP.Our results suggest for the first time that insular cortex is involved in regulating aversive memory after morphine withdrawal.The mechanism may be related to activation of PKM-zeta and the GluR2/AMPAR trafficking pathway and maintenance of the numbers of GluR2/AMPAR in the postsynaptic density.