Activation of Epac in the BLA disrupts reconsolidation and attenuates heroin‐seeking behaviour

Abstract

AbstractThe susceptibility to drug cravings evoked by stimuli poses a formidable hurdle in the treatment of addiction and the prevention of relapse. Pharmacological interventions targeting drug‐associated memories hold promise for curbing relapse by impeding the process of memory reconsolidation, predominantly governed by cAMP signalling. Exchange Protein Activated by cAMP (Epac) serves as a distinctive mediator of cAMP signalling, which has been implicated in reinforcing the effects of cocaine and facilitating the acquisition. Nonetheless, the role of Epac in heroin‐related memory and the subsequent seeking behaviour remains enigmatic. In this study, we explored the impact of Epac activation on the reconsolidation process of drug‐related memories associated with heroin self‐administration. Over the course of 10 consecutive days, rats underwent training, wherein they acquired the behaviour of nose poking to obtain heroin accompanied by a tone + light cue. This nose‐poking behaviour was subsequently extinguished when heroin infusion and cue presentation were discontinued. Subsequently, we administered 8‐pCPT‐cAMP (8‐CPT), an Epac‐specific activator, into the basolateral amygdala at various time points, either in the presence or absence of a conditioned stimulus. Our findings demonstrate that administering 8‐CPT immediately after memory retrieval effectively reduces cue‐ and heroin‐induced reinstatement, with the observed effects persisting significantly for a minimum of 28 days. However, infusion of 8‐CPT for a duration of 6 h following the memory retrieval trial, or without it altogether, had no discernible impact. Thus, these findings strongly suggest that Epac activation can disrupt the reconsolidation of heroin‐associated memory, thereby diminishing the reinstatement of heroin‐seeking behaviour.