Role of nucleus accumbens microRNA-181a and MeCP2 in incubation of heroin craving in male rats.

Abstract

Epigenetic regulation has been implicated in the incubation of drug craving (the time-dependent increase in drug seeking after prolonged withdrawal from drug self-administration). There is little information available on the role of microRNAs in incubation of heroin craving. This study aimed to investigate the roles and mechanisms of miR-181a and methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) in incubation of heroin seeking. MiRNA sequencing was used to predict potential miRNAs, and miRNA profiles were performed in the NAc after 1day or 14days after withdrawal from heroin self-administration. Following 14days of heroin self-administration, rats were injected of lentiviral vectors into the NAc and evaluated for the effects of overexpression of miR-181a or knockdown of MeCP2 on non-reinforced heroin seeking after 14 withdrawal days. Lever presses during the heroin-seeking tests were higher after 14 withdrawal days than after 1day (incubation of heroin craving). miR-181a expression in NAc was lower after 14 withdrawal days than after 1day, and meCP2 expression in NAc was higher after 14days than after 1day. Luciferase activity assay showed that the 3'UTR of MeCP2 is directly regulated by miR-181a. Overexpression of miR-181a in NAc decreased heroin seeking after 14 withdrawal days and decreased MeCP2 mRNA and protein expression. Knockdown of MeCP2 expression in NAc by LV-siRNA-MeCP2 also decreased heroin seeking after 14 withdrawal days. Results indicate that incubation of heroin craving is mediated in part by time-dependent decreases in NAc miR181a expression that leads to time-dependent increases in MeCP2 expression. Our data suggest that NAc miR-181a and MeCP2 contribute to incubation of heroin craving.