Extensive Extinction-Elicited Inhibition of Methamphetamine-Primed Drug Memory Is Mediated by the Metabotropic Glutamate 5 Receptor

Abstract

Addiction is a chronic disorder which can be regarded as a disorder of abnormal learning and memory formation Extinction can cover original drug memory but easily relapses Facilitated extinction would diminish the propensity to relapse AMPA receptors (AMPARs) are involved in memory processes Recent researches have demonstrated that GluR2 one of AMPARs subunits expression was increased in NAcore after extinction Lacking-GluR2 AMPARs are calcium-permeable AMPARs (CP-AMPARs) However the role of CP-AMPARs in the memory impairment is still unclear Moreover in previous studies activation of metabotropic glutamate receptors 5 (mGluR5) induced long-term depression attributable to the endocytosis of postsynaptic AMPARs in fear conditioning Therefore the role of mGluR5 in the memory impairment remains to be clarified Here we used a conditioned place preference (CPP) protocol to seek a more effective extinction methodology of methamphetamine (MeAM) memory and delineate its underlying mechanism Conditioning MeAM for 3 days in mice markedly increased the time spent in the MeAM-paired compartment indicating that MeAM induced a significant rewarding effect The mice were then conditioned with saline for 6 or 10 days to extinction MeAM memory We found that prolongation of extinction duration from 6 to 10 days (extensive extinction) prevented MeAM priming effect Then we used electrophysiology to confirm the synaptic insertion of AMPARs reduced in EE but not in extinction The percentage of CP-AMPARs decreased in EE but not in extinction Additionally we found that extinction with mGluR5 activation had similar results to EE: reduced relapse after extinction decreased synaptic AMPARs and the percentage of CP-AMPARs Moreover we used western blot to investigate the surface level of GluR2 subunit of AMPARs and the results showed EE and extinction with mGluR5 activation down regulated the surface of GluR2 On the contrary EE with mGluR5 inhibition suppressed the results of EE It had similar results to extinction These data indicated that EE training-elicited inhibition of MeAM-primed reinstatement is mediated by the metabotropic glutamate 5 receptor and CP-AMPARs play an important role in these processes

Date of Award	2016 Aug 17
Original language	English
Supervisor	Po-Wu Gean (Supervisor)