The roles of protein phosphatase and protein kinase in the destabilization of methamphetamine-related memory in amygdala

Abstract

Drug addiction is a compulsive drug-seeking behavior characterized by chronically relapsing disorders Repeated methamphetamine (MeAM) administration can develop an intense associative memory between MeAM-paired cues and the rewarding effects of MeAM Reconsolidation of memory involves retrieval-induced destabilization and restabilization processes in order to update as new memory Reactivated memory is destabilized and then restabilized through gene expression-dependent reconsolidation Retrieval-induced destabilization renders memories susceptible to disruption The conditioned place preference (CPP) paradigm is a standard preclinical behavioral model of drug addiction which involves addiction and addiction-related memory The CPP procedure is paired a particular environment with addiction drugs followed by pairing different environments with the absence of the reward drug and induces positive reinforcing effects Previous studies revealed that NR2B-containing NMDAR activation leading to Ca2+ influx that activated calcineurin (CaN) and protein phosphatase 1 (PP1) resulting in dephosphorylation of p-GluR1-Ser845 and subsequently AMPA receptors (AMPARs) endocytosis involves the mechanism of memory destabilization Previous study showed that stimulation of glutamate NMDAR promotes dephosphorylation and activation of striatal-enriched protein tyrosine phosphatase (STEP) via a calcineurin/PP1 pathway Activation of STEP induced endocytosis of NR2B containing-NMDARs and GluR2 containing-AMPARs However these phenomena still need to be investigated in destabilization of MeAM-related memory Moreover We have showed that MeAM-induce CPP memory retrieval stimulates calcineurin activity resulting in the dephosphorylation and activation of STEP Our hypothesis is that MeAM memory retrieval induces STEP activated leading to p-GluR1-Ser845 dephosphorylated subsequently synaptic AMPARs endocytosis and then the destabilization of drug memory in the basolateral amygdala (BLA) Anisomycin (ANI) treatment after the MeAM-associated memory retrieval test disrupted reconsolidation and then disrupted drug-associated memory We found ANI induced MeAM-related CPP memory loss was blocked by STEP inhibitor TC-2153 in a dose-dependent manner To determine the site of action ANI-mediated disruption of MeAM memory was also blocked by microinjecting STEP inhibitor TC-2153 in the BLA Furthermore we also found that STEP inhibitor reverses ANI-induced decrease phosphorylation of GluR1-Ser845 and the number of dendritic spines These phenomena indicated that activation of STEP dephosphorylate p-GluR1-Ser845 to elict APMPARs endocytosis and destabilization of MeAM-related memory

Date of Award	2019
Original language	English
Supervisor	Po-Wu Gean (Supervisor)