sb-334867-a and Alcohol-Related-Disorders

The orexin/hypocretin (ORX) system regulates motivation for natural rewards and drugs of abuse such as alcohol. ORX receptor antagonists, most commonly OX1R antagonists including SB-334867 (SB), decrease alcohol drinking, self-administration and reinstatement in both genetically-bred alcohol-preferring and outbred strains of rats. Importantly, levels of alcohol seeking and drinking in outbred rats are variable, as they are in humans. We have shown that OX1R antagonism selectively decreases homecage alcohol drinking in high-, but not low-alcohol-preferring rats. It is unknown, however, whether this effect is selective to homecage drinking or whether it also applies to alcohol seeking paradigms such as self-administration and reinstatement following extinction, in which motivation is high in the absence of alcohol. Here we trained Sprague Dawley rats to self-administer 20% ethanol paired with a light-tone cue on an FR3 regimen. Rats were then extinguished and subjected to cue-induced reinstatement. Rats were segregated into high- and low-ethanol-responding groups (HR and LR) based on self-administration levels. During self-administration and cue-induced reinstatement, rats were given SB or vehicle prior to ethanol seeking. In both conditions, OX1R antagonism decreased responding selectively in HR, but not LR rats. There were no non-specific effects of SB treatment on arousal or general behavior. These data indicate that ORX signaling at the OX1R receptor specifically regulates high levels of motivation for alcohol, even in the absence of direct alcohol reinforcement. This implicates the ORX system in the pathological motivation underlying alcohol abuse and alcoholism and demonstrates that the OX1R may be an important target for treating alcohol abuse.

Topics: Alcohol Drinking; Alcohol-Related Disorders; Animals; Animals, Outbred Strains; Benzoxazoles; Central Nervous System Depressants; Conditioning, Operant; Cues; Disease Models, Animal; Drug-Seeking Behavior; Ethanol; Male; Motivation; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Rats, Sprague-Dawley; Self Administration; Urea

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.

Topics: Alcohol Deterrents; Alcohol Drinking; Alcohol-Related Disorders; Animals; Benzoxazoles; Choice Behavior; Compulsive Behavior; Dose-Response Relationship, Drug; Isoquinolines; Male; Mice, Inbred C57BL; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Pyridines; Quinine; Urea