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.
Highlights
Orexins A and B are neuropeptides synthesized in neurons originating in the lateral hypothalamus (LH) that project throughout the brain and bind to two widely expressed G-protein coupled receptors, orexin-1 (OX1) and orexin-2 (OX2)
Data from the present series of experiments provide evidence that blockade of OX1 and OX2 receptors reduces ethanol selfadministration in a variety of high-drinking rodent paradigms, observed effects were dependent on the specific procedures used to evaluate ethanol-seeking behavior
The OX1 receptor antagonist reduced home cage ethanol drinking in rats and binge-like drinking in mice, without influencing progressive ratio operant responding in rats
Summary
Orexins A and B are neuropeptides synthesized in neurons originating in the lateral hypothalamus (LH) that project throughout the brain and bind to two widely expressed G-protein coupled receptors, orexin-1 (OX1) and orexin-2 (OX2). OX1 receptors selectively bind orexin A, whereas OX2 receptors bind orexin A and B with equal affinity (Sakurai et al, 1998) This neuropeptide system plays an established role in numerous behavioral and regulatory functions including sleep, arousal, and feeding behavior (Willie et al, 2001; Sakurai, 2002). While orexin neurons in the dorsomedial hypothalamus are believed to regulate arousal and stress responses, orexin neurons within the LH are hypothesized to play a role in regulating reward processing for natural rewards as well as drugs of abuse (Harris and Aston-Jones, 2006) This has led to the suggestion that the orexin system is involved in addiction (for review, see Sharf et al, 2010; Mahler et al, 2012). Evidence previously supported functional differences between the two receptors, with OX2 receptor activity more closely related to arousal and OX1 receptor activity more closely associated with reward (Aston-Jones et al, 2010), more recent research has revealed a role for OX2 receptors in reward processes as well (Shoblock et al, 2011; Brown et al, 2013)
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