GABA regulation of dopamine release in the nucleus accumbens is sexually dimorphic and changed by cocaine exposure

Rationale Dopamine release in the nucleus accumbens (NAc) core is shaped by local inhibitory microcircuits, yet whether this regulation differs between sexes remains unknown. Objectives Here, we investigated sex differences in GABA-A and GABA-B receptor regulation of dopamine release in the NAc core and determined whether these mechanisms are altered by repeated cocaine exposure. Methods Using ex vivo fast-scan cyclic voltammetry, we measured dopamine release in the NAc core of male and female mice following pharmacological manipulation of GABA-A and GABA-B receptors. Single-nucleus RNA sequencing data were analyzed to assess sex differences in GABA receptor subunit expression. Finally, mice received repeated cocaine injections (10 mg/kg, i.p., five consecutive days), and dopamine release regulation by GABA receptors was assessed 24 hours after the final injection. Results GABA-A and GABA-B receptors exerted distinct, sexually dimorphic control over dopamine release. GABA-B receptor antagonism increased dopamine release in males but not females; GABA-A receptor antagonism produced stronger enhancement of dopamine release in females. These differences were not explained by broad differences in receptor expression or responsiveness to receptor activation, suggesting sex differences in the engagement of local GABAergic circuits. Interestingly, GABA-B regulation occurs indirectly through cholinergic interneurons, whereas GABA-A regulation was independent of cholinergic input, potentially suggesting a more direct mechanism at dopamine axon terminals. Repeated cocaine exposure selectively attenuated GABA-A–dependent modulation in females. Conclusions Together, these findings identify divergent GABAergic pathways that tune dopamine output across sexes and reveal how cocaine reshapes these microcircuits, offering a mechanistic basis for sex differences in addiction vulnerability.