title: Orexin-1 receptor blockade suppresses compulsive-like alcohol drinking in mice.
abstract: Addiction is promoted by pathological motivation for addictive substances, and, despite extensive efforts, alcohol use disorders (AUDs) continue to extract a very high social, physical, and economic toll. Compulsive drinking of alcohol, where consumption persists even when alcohol is paired with negative consequences, is considered a particular obstacle for treating AUDs. Aversion-resistant alcohol intake in rodents, e.g. where rodents drink even when alcohol is paired with the bitter tastant quinine, has been considered to model some compulsive aspects of human alcohol consumption. However, the critical mechanisms that drive compulsive-like drinking are only beginning to be identified. The neuropeptide orexin has been linked to high motivation for cocaine, preferred foods, and alcohol. Thus, we investigated the role of orexin receptors in compulsive-like alcohol drinking, where C57BL/6 mice had 2-hr daily access to 15% alcohol with or without quinine (100 μM). We found that systemic administration of the widely used selective orexin-1 receptor (OX1R) blocker, SB-334867 (SB), significantly reduced compulsive-like consumption at doses lower than those reported to reduce quinine-free alcohol intake. The dose of 3-mg/kg SB, in particular, suppressed only compulsive-like drinking. Furthermore, SB did not reduce concurrent water intake during the alcohol drinking sessions, and did not alter saccharin + quinine consumption. In addition, the OX2R antagonist TCS-OX2-29 (3 or 10 mg/kg) did not alter intake of alcohol with or without quinine. Together, our results suggest that OX1R signaling is particularly important for promoting compulsive-like alcohol drinking, and that OX1Rs might represent a novel therapy to counteract compulsive aspects of human AUDs.
authors: Alcohol Center for Translational Genetics, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors: Kelly
authors: K
authors: Lei
authors: Alcohol Center for Translational Genetics, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors: Scott A
authors: SA
authors: Wegner
authors: Alcohol Center for Translational Genetics, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors: Ji-Hwan
authors: JH
authors: Yu
authors: Alcohol Center for Translational Genetics, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA. Electronic address: Frederic.Hopf@ucsf.edu.
authors: F Woodward
authors: FW
authors: Hopf
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000188:drug therapy / Q000378:metabolism; D019973:Alcohol-Related Disorders / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D003192:Compulsive Behavior / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011803:Quinine; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; C572065:1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone; D000427:Alcohol Deterrents; D001583:Benzoxazoles; D007546:Isoquinolines; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D011725:Pyridines; D014508:Urea; D011803:Quinine
keywords: Alcohol; Compulsive; Orexin; SB-334867