Ca2+-permeable AMPA receptors set the threshold for retrieval of drug memories.

Abstract

Frequent relapse prevents the successful treatment of substance use disorders and is triggered in part by retrieval of drug-associated memories. Drug-conditioned behaviours in rodents are reinstated upon drug memory retrieval following re-exposure to cues previously associated with the drug, or the drug itself. Therapies based on mechanistic insights from rodent studies have focused on amnesic procedures of cue-drug associations but with so far limited success. Conversely, more recent studies propose that inhibiting drug memory retrieval offers improved anti-relapse efficacy. However, mechanisms of memory retrieval are poorly understood. Here, we used a conditioned place preference (CPP) procedure in mice to investigate the cellular and molecular underpinnings of drug-induced memory retrieval. After extinction training of CPP, Ca2+-permeable AMPA receptors (CP-AMPARs) accumulated at drug-generated silent synapses of nucleus accumbens (NAc) medium spiny neurons. The NAc CP-AMPARs regulated the retrieval mechanism of drug memories after extinction. Specifically, we used different priming doses of cocaine, fentanyl, or a cue associated with drug exposure to reinstate CPP, providing different memory retrieval conditions. Although both high and low doses of these two drugs induced CPP reinstatement, compromising CP-AMPAR accumulation impaired CPP reinstatement, induced by low doses of each drug or the cue. This threshold effect was mediated by NAc CP-AMPARs as region specific knock-down of PSD-95 prevented low-dose cocaine-induced retrieval selectively. These results demonstrate the NAc as a brain region and CP-AMPARs as key synaptic substrates that govern the threshold for drug-induced retrieval and behavioural expression of drug memories.