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

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.