In vivo microdialysis reveals that blockade of accumbal orexin OX 2 but not OX 1 receptors enhances dopamine efflux in the nucleus accumbens of freely moving rats.

The nucleus accumbens contain orexinergic neural inputs and orexin OX 1 - and OX 2 -receptors. Behavioural studies suggest that accumbal orexin receptors modulate accumbal dopaminergic activity-dependent locomotion in rats. We studied the effects of intra-accumbal injection of orexin receptor ligands on accumbal extracellular dopamine levels in freely moving rats, using in vivo microdialysis and analysed the roles of OX 1 - and OX 2 -receptors in the regulation of basal accumbal dopamine efflux. The orexin receptor ligands were applied intra-accumbally though a microinjection needle attached with a dialysis probe. Neither the nonselective OX 1 - and OX 2 -receptor agonist orexin-A nor the preferential OX 2 -receptor agonist orexin-B (500.0 pg and 5.0 ng) altered accumbal dopamine levels. The nonselective OX 1 - and OX 2 -receptor antagonist MK-4305 (suvorexant, 500.0 pg, 2.5 and 5.0 ng) enhanced dopamine efflux. A 2-h tetrodotoxin infusion into nucleus accumbens through the probe or co-administration of orexin-A (500.0 pg) strongly inhibited MK-4305 (5.0 ng)-induced accumbal dopamine efflux. The selective OX 2 -receptor antagonist EMPA (90.0 and 900.0 pg, 9.0 ng) increased dopamine efflux. Intra-accumbal infusion of tetrodotoxin abolished EMPA (9.0 ng)-induced dopamine efflux. The selective OX 1 -receptor antagonist SB-334867 (10.0 and 20.0 ng) failed to alter dopamine efflux. Co-administration of orexin-B (500.0 pg) inhibited both EMPA (9.0 ng)- and MK-4305 (5.0 ng)-induced dopamine efflux. Intraperitoneal injection of MK-4305 (10.0 mg/kg) did not affect accumbal dopamine efflux. The present study provides in vivo neuropharmacological evidence that accumbal OX 2 - but not OX 1 -receptors exert inhibitory regulation of basal accumbal dopamine efflux and that blockade of accumbal OX 2 -receptors enhances dopamine efflux in nucleus accumbens of freely moving rats.