Rationale-Orphanin FQ (OFQ; also known as nociceptin), the endogenous ligand of the opioid receptor-like receptor, injected intracerebroventricularly (i.c.v.) decreases basal motor activity and basal extracellular levels of dopamine (DA) in the nucleus accumbens (Nuc Acc) in rats.Objective-The present study was designed to determine if OFQ similarly attenuates cocaineinduced motor stimulation and to determine if this effect is dependent on attenuation of the increase in extracellular DA.Methods-After a 1-h adaptation period, rats were injected with either artificial cerebrospinal fluid or OFQ (3−30 nmol, i.c.v.) 5 min prior to cocaine (10 mg/kg, i.p.) or apomorphine (3 mg/kg, i.p.) administration and the total distance traveled was measured for a further 1 h. In a separate experiment, changes in extracellular DA were monitored by microdialysis following cocaine and OFQ treatment in anesthetized rats.Results-OFQ dose-dependently attenuated both basal and cocaine-induced motor stimulation. OFQ (30 nmol, i.c.v.) also attenuated both the basal and the cocaine-induced increase in extracellular DA in the Nuc Acc. OFQ, at the highest dose, also decreased the motor stimulation induced by apomorphine.Conclusions-Our results suggest that the modulatory effect of OFQ on locomotor activity is not solely due to its inhibitory action on extracellular DA in the Nuc Acc.

Binge drinking is short-term drinking that achieves blood alcohol levels of 0.08 g/dl or above. It exhibits well-established sex differences in GABAergic inhibitory neurotransmission, including extrasynaptic δ subunit-containing GABA A receptors (δ-GABA A Rs) that mediate tonic inhibition, or synaptic γ2-containing GABA A Rs which underlie fast, synaptic, phasic inhibition have been implicated in sex differences in binge drinking. Ovarian hormones regulate δ-GABA A Rs, further implicating these receptors in potential sex differences. Here, we explored the contribution of extrasynaptic δ-GABA A Rs to male and female binge-like drinking in a critical area of mesolimbic circuitry—the ventral tegmental area (VTA). Quantitative PCR revealed higher Gabrd transcript levels and larger tonic currents in the VTA of females compared to males. In contrast, male and female Gabrg 2 transcript levels and measures of phasic inhibition were equivalent. Intra-VTA infusion of AAV-Cre-GFP in floxed Gabrd mice downregulated δ-GABA A Rs and decreased binge-like drinking in females. There was no significant difference in either male or female mice after GABA A R γ2 subunit reduction in the VTA following AAV-Cre-GFP infusion in floxed Gabrg2 mice. Collectively, these findings suggest sex differences and GABA A R subunit specificity in alcohol intake.