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

• Main Authors: Po-JungHuang, 黃柏融
• Other Authors: Po-Wu Gean
• Format: Others
• Language: en_US
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/ur3axg

碩士 === 國立成功大學 === 藥理學研究所 === 107 === 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.