Central orexin (hypocretin) 2 receptor antagonism reduces ethanol self-administration, but not cue-conditioned ethanol-seeking, in ethanol-preferring rats

Abstract

Orexins are hypothalamic neuropeptides which bind to two G-protein-coupled receptors, orexin-1 (OX₁R) and orexin-2 (OX₂R) receptor. While a role for OX₁R has been established in both ethanol reinforcement and ethanol-seeking behaviour, the role of OX₂R in these behaviours is relatively less-studied. The aim of this study was to determine the role of central OX₂R in ethanol-taking and ethanol-seeking behaviour. Indiana ethanol-preferring rats were trained to self-administer ethanol (10% w/v) or sucrose (0.7–1% w/v) in the presence of reward-associated cues before being implanted with indwelling guide cannulae. The selective OX₂R antagonist TCS-OX2-29 was administered i.c.v. to assess its effect on operant self-administration and cue-induced reinstatement following extinction. Following i.c.v. injection TCS-OX2-29 reduced self-administration of ethanol, but not sucrose. Despite reducing ethanol self-administration, TCS-OX2-29 had no impact on cue-induced reinstatement of ethanol seeking. To determine where in the brain OX₂R were acting to modulate ethanol self-administration, TCS-OX2-29 was microinjected into either the shell or core of the nucleus accumbens (NAc). Intra-NAc core, but not shell, infusions of TCS-OX2-29 decreased responding for ethanol. Importantly, the doses of TCS-OX2-029 used were non-sedating. Collectively, these findings implicate OX₂R in the NAc in mediating the reinforcing effects of ethanol. This effect appears to be drug-specific as antagonism of central OX₂R had no impact on sucrose self-administration. Thus, OX₂R in addition to OX₁R may represent a potential therapeutic target for the treatment of ethanol-use disorders. However, unlike OX₁R, no impact of OX₂R antagonism was observed on cue-induced reinstatement, suggesting a more prominent role for OX₂R in ethanol self-administration compared to cue-conditioned ethanol-seeking.