title: 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 (OX(1)R) and orexin-2 (OX(2)R) receptor. While a role for OX(1)R has been established in both ethanol reinforcement and ethanol-seeking behaviour, the role of OX(2)R in these behaviours is relatively less-studied. The aim of this study was to determine the role of central OX(2)R 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 OX(2)R 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 OX(2)R 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 OX(2)R in the NAc in mediating the reinforcing effects of ethanol. This effect appears to be drug-specific as antagonism of central OX(2)R had no impact on sucrose self-administration. Thus, OX(2)R in addition to OX(1)R may represent a potential therapeutic target for the treatment of ethanol-use disorders. However, unlike OX(1)R, no impact of OX(2)R antagonism was observed on cue-induced reinstatement, suggesting a more prominent role for OX(2)R in ethanol self-administration compared to cue-conditioned ethanol-seeking.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia.
authors.forename: Robyn Mary
authors.initials: RM
authors.lastname: Brown
authors.forename: Shaun Yon-Seng
authors.initials: SY
authors.lastname: Khoo
authors.forename: Andrew John
authors.initials: AJ
authors.lastname: Lawrence
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003213:Conditioning, Psychological / Q000187:drug effects*; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D000431:Ethanol / Q000008:administration & dosage*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D012201:Reward; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage
chemical_list: C572065:1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone; C578625:Hcrtr2 protein, rat; D007546:Isoquinolines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D011725:Pyridines; D000431:Ethanol; D013395:Sucrose