Gamma-aminobutyric acid A receptor alpha 4 in the nucleus accumbens mediates cue-induced heroin-seeking behavior in male rats via miR-7b.

OBJECTIVE

This study investigated miR-7b's regulatory role in the nucleus accumbens (NAc) and its interaction with gamma-aminobutyric acid A receptor alpha 4 (GABRA4) during cue-induced heroin-seeking reinstatement.

METHODS

A heroin self-administration model (4 h/day) was established in rats. Cue-induced reinstatement was assessed postextinction. Dual-luciferase reporter assays validated miR-7b/GABRA4 binding. Gain- and loss-of-function approaches via adeno-associated virus (AAV)-mediated miR-7b overexpression (AAV-miR-7b-OE) and GABRA4 knockdown [AAV-small interfering RNA (siRNA)-GABRA4] were applied in the NAc.

RESULTS

Reinstatement correlated with reduced miR-7b (P < 0.05) and elevated GABRA4 expression in the NAc. Luciferase assays confirmed miR-7b's direct regulation of the GABRA4 3'-untranslated region (3'-UTR) (P < 0.01). NAc-targeted AAV-miR-7b-OE significantly increased reinstatement behavior (P < 0.01), concomitant with decreased GABRA4 mRNA. Meanwhile, AAV-siRNA-GABRA4-mediated GABRA4 silencing increased reinstatement responses postextinction (P < 0.05).

CONCLUSION

MiR-7b suppression and GABRA4 upregulation form a feedback loop promoting cue-induced heroin-seeking reinstatement. These findings identify a compensatory miR-7b/GABRA4 axis in the NAc that counteracts relapse vulnerability, proposing novel targets for addiction intervention.