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.

Blockade of Orexin Receptors in the Posterior Paraventricular Nucleus of the Thalamus Prevents Stress-Induced Reinstatement of Reward-Seeking Behavior in Rats With a History of Ethanol Dependence

“…SB334867 also decreased EtOH drinking and preference to a greater extent in rats with a high preference for EtOH but only weakly in rats with a low preference for EtOH (Moorman and Aston-Jones, 2009 ; Moorman et al, 2017 ). The blockade of OrxR1 selectively decreased the escalation of drinking in EtOH-dependent mice, without altering lower levels of EtOH intake in non-dependent mice (Lopez et al, 2016 ) and was more effective in reducing compulsive-like EtOH drinking in quinine-resistant mice (Lei et al, 2016a , b ). Finally, the dual OrxR antagonist almorexant decreased the breakpoint for EtOH seeking in a progressive-ratio schedule in rats that were genetically predisposed to EtOH preference (Anderson et al, 2014 ).…”

“…Pharmacological manipulations of the Orx system affect EtOH intake and seeking. For example, the OrxR1 antagonist SB334867 decreased voluntary home-cage EtOH drinking (Moorman and Aston-Jones, 2009 ; Anderson et al, 2014 ), operant EtOH self-administration (Lawrence et al, 2006 ; Richards et al, 2008 ; Jupp et al, 2011a ; Lei et al, 2016a ; Moorman et al, 2017 ), and the reinstatement of EtOH seeking that is induced by EtOH-associated stimuli (Lawrence et al, 2006 ; Jupp et al, 2011b ; Martin-Fardon and Weiss, 2014 ; Brown et al, 2016 ; Moorman et al, 2017 ) or stress (Richards et al, 2008 ). SB334867 treatment disrupted EtOH-induced conditioned place preference (CPP) and EtOH-induced locomotor sensitization (Voorhees and Cunningham, 2011 ; Macedo et al, 2013 ).…”

Role of Lateral Hypothalamic Orexin (Hypocretin) Neurons in Alcohol Use and Abuse: Recent Advances

“…However, in the same study, SB-334867 (3 mg/kg i.p.) was sufficient to reduce compulsive-like alcohol responding, in which aversively tasting quinine (100 μM) was added [38]. This provides further evidence that OX receptor antagonism is more effective in rodent models of excessive consumption and high motivation [39] and therefore may provide a useful intervention target for disorders such as addiction, including AUDs, where drug/alcohol motivation is strongly elevated and compulsive-like behaviors are observed.…”

Contribution of Dynorphin and Orexin Neuropeptide Systems to the Motivational Effects of Alcohol

“…Further, OX1R antagonism, using either SB or another selective antagonist (GSK1059865), selectively decreased escalated drinking in dependent (CIE-exposed) mice without altering more moderate levels of alcohol intake in nondependent mice (Lopez et al 2016). Finally, OX1R antagonism was found to be more effective in reducing compulsive-like alcohol drinking in quinine-resistant (but not quininesensitive) mice (Lei et al 2016a). Collectively, these findings may have important clinical implications, as the ORX system may be a particularly attractive target for treatment of individuals that have transitioned to heavy, compulsive-like alcohol drinking.…”

“…Decreased alcohol consumption following OX1R antagonism has also been shown in mouse models of heavy drinking, such as binge-like consumption and escalated alcohol intake resulting from repeated cycles of chronic intermittent ethanol (CIE) vapor exposure (Carvajal et al 2015;Olney et al 2015;Lopez et al 2016). In a model of compulsive-like alcohol drinking (C57BL/6J mice exhibiting aversion resistance to quinineadulterated alcohol), OX1R antagonism (SB), but not OX2R antagonism (TSC-OX2-29) reduced intake of alcohol presented alone or in combination with quinine (Lei et al 2016a).…”