lnc15qD3 expression in the NAc shell regulates the reconsolidation of opioid reward memories.

Following memory retrieval, permanent drug memories become unstable and easily disrupted, followed by reconsolidation; this pattern holds promise for treating substance use disorder (SUD). Recent research has demonstrated that epigenetic modifications, including long noncoding RNA (lncRNA) regulation, participate in learning and memory. However, the role of lncRNAs in drug-memory reconsolidation remains unclear. Here, we found that in conditioned place preference (CPP) and self-administration (SA) mouse models of drug abuse, lnc15qD3 expression was substantially upregulated after contextual cue exposure in the nucleus accumbens (NAc) shell but not in the core. Furthermore, after retrieval, viral-mediated knockdown of lnc15qD3 disrupted the reconsolidation of morphine-induced CPP memories in the NAc shell but not in the core. Additionally, the inhibitory effect cannot be reversed by time or morphine priming. Similarly, using a heroin SA protocol, lnc15qD3 knockdown in the NAc shell after retrieval long-term suppressed heroin-seeking behaviors. We further investigated the molecular events downstream of lnc15qD3 mediating the reconsolidation of opioid reward memories in rescue assays and in vitro experiments. Our results indicated that lnc15qD3 binds to endogenous miR-7118-5p/miR-6914-5p, which alters the expression of Notch2 and regulates opioid addictive memory reconsolidation. Consequently, lnc15qD3 may be applied as a target for anti-relapse therapy.