In vivo microdialysis reveals that blockade of accumbal orexin OX2 but not OX1 receptors enhances dopamine efflux in the nucleus accumbens of freely moving rats.

Abstract

The nucleus accumbens contain orexinergic neural inputs and orexin OX1 - and OX2 -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 OX1 - and OX2 -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 OX1 - and OX2 -receptor agonist orexin-A nor the preferential OX2 -receptor agonist orexin-B (500.0pg and 5.0ng) altered accumbal dopamine levels. The nonselective OX1 - and OX2 -receptor antagonist MK-4305 (suvorexant, 500.0pg, 2.5 and 5.0ng) enhanced dopamine efflux. A 2-h tetrodotoxin infusion into nucleus accumbens through the probe or co-administration of orexin-A (500.0pg) strongly inhibited MK-4305 (5.0ng)-induced accumbal dopamine efflux. The selective OX2 -receptor antagonist EMPA (90.0 and 900.0pg, 9.0ng) increased dopamine efflux. Intra-accumbal infusion of tetrodotoxin abolished EMPA (9.0ng)-induced dopamine efflux. The selective OX1 -receptor antagonist SB-334867 (10.0 and 20.0ng) failed to alter dopamine efflux. Co-administration of orexin-B (500.0pg) inhibited both EMPA (9.0ng)- and MK-4305 (5.0ng)-induced dopamine efflux. Intraperitoneal injection of MK-4305 (10.0mg/kg) did not affect accumbal dopamine efflux. The present study provides in vivo neuropharmacological evidence that accumbal OX2 - but not OX1 -receptors exert inhibitory regulation of basal accumbal dopamine efflux and that blockade of accumbal OX2 -receptors enhances dopamine efflux in nucleus accumbens of freely moving rats.