Disentangling the molecular mechanisms underlying the retrieval and extinction of morphine withdrawal-associated memories in the basolateral amygdala and dentate gyrus

Abstract

Despite their indisputable efficacy for pain management, opiates prescription remains highly controversial due to their elevated addictive potential. Relapse in drug use is one of the principal problems for addiction treatment, being drug-associated memories among its main triggers. Consequently, the extinction of these memories has been proposed as a useful therapeutic tool. Hence, by using the conditioned place aversion (CPA) paradigm in rats we investigated some of the molecular mechanisms that occurred during the retrieval and extinction of morphine withdrawal memories in the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which control emotional and episodic memories, respectively. The retrieval of aversive memories associated with the abstinence syndrome paralleled with decreased mTOR activity and increased Arc and GluN1 expressions in the DG. Additionally, Arc mRNA levels in this nucleus very strongly correlated with the CPA score exhibited by the opiate-treated rats. On the other hand, despite the unaltered mTOR phosphorylation Arc augmented in the BLA. After the extinction test, Arc and GluN1 expressions raised in both the DG and BLA of control and morphine-treated animals. Remarkably, Homer1 expression in both areas correlated almost perfectly with the extinction showed by morphine-dependent animals. Also, Arc expression in the DG correlated strongly with the extinction of the CPA manifested by the group treated with the opiate. Finally, our results support coordinated activity of some of these neuroplastic proteins for the extinction of morphine activity in a regional-dependent manner. Present data provide evidence of differential expression and activity of synaptic molecules during the retrieval and extinction of aversive memories of opiate withdrawal in amygdalar and hippocampal regions that will likely permit the development of therapeutic strategies able to minimize relapses induced by drug-associated aversive memories.

Differential role of dopamine D3 receptor through balanced modulation of Akt/mTOR and ERK1/2 activity in the reactivation of cocaine rewarding memories evoked by psychological versus physiological stress

“…Classically, the activity of ERK1/2 and Akt/mTOR pathways, for their role in synaptoplasticity, had been considered vital for hippocampal declarative memory retrieval [32]. Nonetheless, ours and others' studies recently reported diminished mTOR and/or Akt phosphorylation after the recall of drug-associated aversive and rewarding memories in the NAcc, hippocampus and BLA [7,8,33,34]. The present investigation uncovers a different pattern of activation of these kinases in the BLA and DG determined by the kind of stressor that triggered the recall of cocaine-associated memories.…”

Male and female rats show opiate withdrawal-induced place aversion and extinction in a Y-maze paradigm

“…Also, the persistence of the CPA behavioral response may also depend upon the extinction procedure [26]. Indeed, extinction through reconditioning may occur more rapidly in a classical two-compartments CPA paradigm [31,32,36].…”