DNA methyltransferase activity in the basolateral amygdala is critical for reconsolidation of a heroin reward memory

Abstract

The persistence of drug memory contributes to relapse to drug seeking. The association between repeated drug exposure and drug-related cues leads to cravings triggered by drug-paired cues. The erasure of drug memories has been considered a promising way to inhibit cravings and prevent relapse. The re-exposure to drug-related cues destabilizes well-consolidated drug memories, during which a de novo protein synthesis-dependent process termed “reconsolidation” occurs to restabilize the reactivated drug memory. Disrupting reconsolidation of drug memories leads to the attenuation of drug-seeking behavior in both animal models and people with addictions. Additionally, epigenetic mechanisms regulated by DNA methyltransferase (DNMT) are involved in the reconsolidation of fear and cocaine reward memory. In the present study, we investigated the role of DNMT in the reconsolidation of heroin reward memory. In the heroin self-administration model in rats, we tested the effects of DNMT inhibition during the reconsolidation process on cue-induced reinstatement, heroin-priming-induced reinstatement, and spontaneous recovery of heroin-seeking behavior. We found that the bilateral infusion of 5-azacytidine (5-AZA) inhibiting DNMT into the basolateral amygdala (BLA) immediately after heroin reward memory retrieval, but not delayed 6 h after retrieval or without retrieval, decreased subsequent cue-induced and heroin-priming-induced reinstatement of heroin-seeking behavior. These findings demonstrate that inhibiting the activity of DNMT in BLA during the reconsolidation of heroin reward memory attenuates heroin-seeking behavior, which may provide a potential strategy for the therapeutic of heroin addiction.

The Cdk5 inhibitor β‐butyrolactone impairs reconsolidation of heroin‐associated memory in the rat basolateral amygdala

“…The re‐emergence of drug use following a period of abstinence, referred to as relapse caused by heroin‐associated memory, poses a significant challenge for addiction treatment. Studies in rodents and humans have been aimed at targeting the reconsolidation process and inferring with the heroin‐associated memory to reduce craving and sustain abstinence 30–32 . More and more research demonstrated that manipulating heroin‐associated memory after reactivation significantly prevents relapse and reduces drug‐seeking behaviour 33,34 .…”

“…Studies in rodents and humans have been aimed at targeting the reconsolidation process and inferring with the heroin-associated memory to reduce craving and sustain abstinence. [30][31][32] More and more research demonstrated that manipulating heroin-associated memory after reactivation significantly prevents relapse and reduces drug-seeking behaviour. 33,34 These studies indicate that pharmacological approaches combined with reconsolidation may be a promising avenue for identifying potential substances to reduce craving in preclinical rat models.…”

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

“…The Epac‐specific agonist, 8‐(4‐chlorophenylthio)‐2′‐O‐methyladenosine‐3′,5′‐cyclic monophosphate (8‐CPT), was obtained from Sigma‐Aldrich (St. Louis, MO, United States). The infusion volume of 8‐CPT in the BLA (dorsoventral: −8.5 mm, mediolateral: ±5.0 mm and rostrocaudal: −2.8 mm) was 10 nmol per side, following the parameters established in previous studies 21 . Hamilton syringes were connected to 30‐gauge injectors (Plastics One) to facilitate the administration of the drug, which was delivered to a depth of 1 mm below the guide cannula within a duration of 1 min.…”

“…The infusion volume of 8-CPT in the BLA (dorsoventral: À8.5 mm, mediolateral: ±5.0 mm and rostrocaudal: À2.8 mm) was 10 nmol per side, following the parameters established in previous studies. 21 Hamilton syringes were connected to 30-gauge injectors (Plastics One) to facilitate the administration of the drug, which was delivered to a depth of 1 mm below the guide cannula within a duration of 1 min. The drug was allowed to diffuse for an additional 1 min without removing the injection needles.…”

“…19,20 Pharmacological interventions targeting the BLA during memory reactivation or immediately thereafter have shown promising results in preventing the reinstatement of drug-seeking behaviour. These interventions include the use of DNA methyltransferase inhibitors (such as 5-AZA), 21,22 histone deacetylase inhibitors (such as TSA), 23 NMDA receptor antagonists (such as MK801 and D-APV), 24,25 β-adrenergic receptor antagonists (such as propranolol) 26,27 and extracellular signal-regulated kinase inhibitors (such as U0126). 28,29 These findings underscore the pivotal involvement of the BLA in the reconsolidation of memories associated with drug use.…”