title: Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models.
abstract: To examine the role of orexin-1 and orexin-2 receptor activity on ethanol self-administration, compounds that differentially target orexin (OX) receptor subtypes were assessed in various self-administration paradigms using high-drinking rodent models. Effects of the OX1 antagonist SB334867, the OX2 antagonist LSN2424100, and the mixed OX1/2 antagonist almorexant (ACT-078573) on home cage ethanol consumption were tested in ethanol-preferring (P) rats using a 2-bottle choice procedure. In separate experiments, effects of SB334867, LSN2424100, and almorexant on operant ethanol self-administration were assessed in P rats maintained on a progressive ratio operant schedule of reinforcement. In a third series of experiments, SB334867, LSN2424100, and almorexant were administered to ethanol-preferring C57BL/6J mice to examine effects of OX receptor blockade on ethanol intake in a binge-like drinking (drinking-in-the-dark) model. In P rats with chronic home cage free-choice ethanol access, SB334867 and almorexant significantly reduced ethanol intake, but almorexant also reduced water intake, suggesting non-specific effects on consummatory behavior. In the progressive ratio operant experiments, LSN2424100 and almorexant reduced breakpoints and ethanol consumption in P rats, whereas the almorexant inactive enantiomer and SB334867 did not significantly affect the motivation to consume ethanol. As expected, vehicle-injected mice exhibited binge-like drinking patterns in the drinking-in-the-dark model. All three OX antagonists reduced both ethanol intake and resulting blood ethanol concentrations relative to vehicle-injected controls, but SB334867 and LSN2424100 also reduced sucrose consumption in a different cohort of mice, suggesting non-specific effects. Collectively, these results contribute to a growing body of evidence indicating that OX1 and OX2 receptor activity influences ethanol self-administration, although the effects may not be selective for ethanol consumption.
authors.affiliation: Medical University of South Carolina Charleston, SC, USA ; Charleston Alcohol Research Center Charleston, SC, USA.
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Anderson
authors.affiliation: Medical University of South Carolina Charleston, SC, USA ; Charleston Alcohol Research Center Charleston, SC, USA ; Ralph H. Johnson VA Medical Center USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Becker
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company Indianapolis, IN, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Adams
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company Indianapolis, IN, USA.
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Jesudason
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company Indianapolis, IN, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rorick-Kehn
keywords: C57BL/6J mouse; P rat; ethanol consumption; hypocretins/orexins; operant progressive ratio