Reconsolidation of a cocaine associated memory requires DNA methyltransferase activity in the basolateral amygdala

Abstract

Drug addiction is considered an aberrant form of learning, and drug-associated memories evoked by the presence of associated stimuli (drug context or drug-related cues) contribute to recurrent craving and reinstatement. Epigenetic changes mediated by DNA methyltransferase (DNMT) have been implicated in the reconsolidation of fear memory. Here, we investigated the role of DNMT activity in the reconsolidation of cocaine-associated memories. Rats were trained over 10 days to intravenously self-administer cocaine by nosepokes. Each injection was paired with a light/tone conditioned stimulus (CS). After acquisition of stable self-administration behaviour, rats underwent nosepoke extinction (10 d) followed by cue-induced reactivation and subsequent cue-induced and cocaine-priming + cue-induced reinstatement tests or subsequently tested to assess the strength of the cocaine-associated cue as a conditioned reinforcer to drive cocaine seeking behaviour. Bilateral intra-basolateral amygdala (BLA) infusion of the DNMT inhibitor5-azacytidine (5-AZA, 1 μg per side) immediately following reactivation decreased subsequent reinstatement induced by cues or cocaine priming as well as cue-maintained cocaine-seeking behaviour. In contrast, delayed intra-BLA infusion of 5-AZA 6 h after reactivation or 5-AZA infusion without reactivation had no effect on subsequent cue-induced reinstatement. These findings indicate that memory reconsolidation for a cocaine-paired stimulus depends critically on DNMT activity in the BLA.

DNMT3a in the hippocampal CA1 is crucial in the acquisition of morphine self‐administration in rats

“…Additionally, we found that the reconsolidation of morphine withdrawal memory was impaired by injection of a DNMT inhibitor into the agranular insular cortex or basolateral amygdala . Similarly, intra–basolateral amygdala infusion of the DNMTs inhibitor 5‐azacytidine hindered the reconsolidation of cocaine associated memory and then decreased subsequent reinstatement induced by cues or drug priming . All these evidence suggests that DNA methylation in different brain regions are involved in different aspects and/or stages of drug addiction.…”

Cocaine-mediated downregulation of microglial miR-124 expression involves promoter DNA methylation

“…Previous reports have demonstrated that cocaine can modulate the levels of targeted genes by epigenetic mechanisms (promoter DNA methylation). 31,32 DNMTs including, DNMT1, 3a, and 3b, are the proteins responsible for regulating and maintaining promoter DNA methylation levels. 33 To investigate whether DNMTs are associated with cocaine-mediated miR-124 downregulation, we examined the protein levels of DNMT1 and 3a in those cocaine-treated BV-2 cells.…”

The Naturally Occurring Compound Garcinia Indica Selectively Impairs the Reconsolidation of a Cocaine-Associated Memory

“…Recent work in rodents has been aimed at targeting the reconsolidation process and interfering with drug-associated memories to reduce craving and prolong abstinence (cf., Taylor et al, 2009;Sorg 2012;Torregrossa and Taylor, 2013;Everitt, 2014;Taylor and Torregrossa, 2015;Torregrossa and Taylor, 2016). Indeed, it has been demonstrated that specifically manipulating cocaine-cue memories following memory retrieval using pharmacological agents can block the reconsolidation of these memories and reduce drug-seeking behavior in rats (Lee et al, 2005(Lee et al, , 2006Sanchez et al, 2010;Wan et al, 2014;Shi et al, 2015;Merlo et al, 2015). However, most of these studies to date have used intracranial drug infusions.…”