Orexin-1 receptor antagonism decreases ethanol consumption and preference selectively in high-ethanol–preferring Sprague–Dawley rats

Abstract

Work from our laboratory has shown that orexin (ORX; or hypocretin) neurons in the lateral hypothalamus are involved in preference for morphine, cocaine, and food. Other groups have demonstrated a connection between the ORX system and ethanol-related behaviors. Here, we extended those results to investigate, in outbred Sprague–Dawley rats, the relationship between ethanol preference and the ORX system. In Experiment 1, rats were trained to drink 10% ethanol using the intermittent access (IA) technique. In Experiment 2, different groups of rats were trained to drink 10% ethanol using either IA or the sucrose-fade (SF) technique. Following ethanol-drinking acquisition, ethanol preference was assessed using two-bottle-choice tests. The rats were then tested for changes in preference with additional two-bottle-choice tests following administration of the orexin-1 receptor antagonist SB-334867 (SB; 30 mg/kg, intraperitoneally). Differences in ethanol preference were observed across individuals, with a significantly higher ethanol preference observed in rats trained to drink using IA compared with SF. In both Experiments 1 and 2, SB reduced ethanol preference selectively in rats with high ethanol preference. These results demonstrate a strong, causal relationship between the ORX system and ethanol preference in outbred rats. These findings provide additional evidence that the ORX system provides opportunities to develop novel treatments for alcohol abuse.