Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement

Orexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist. The goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses ethanol withdrawal in rodents. As a comparison, SB-408124, a selective orexin-1 receptor antagonist, was also evaluated. Rats were trained to orally self-administer ethanol (8% v/v) or saccharin (0.1% v/v) under a fixed-ratio 3 schedule of reinforcement. A separate group of rats received a liquid diet of ethanol (8% v/v) and withdrawal signs were evaluated 4 h after ethanol discontinuation. In addition, ethanol-induced increases in extracellular dopamine levels in the nucleus accumbens were tested. In separate experiments, the acquisition, expression, and reinstatement of conditioned place preference (CPP) were evaluated in mice. Our results indicate that JNJ-10397049 (1, 3, and 10 mg/kg, sc) dose-dependently reduced ethanol self-administration without changing saccharin self-administration, dopamine levels, or withdrawal signs in rats. Treatment with JNJ-10397049 (10 mg/kg, sc) attenuated the acquisition, expression, and reinstatement of ethanol CPP and ethanol-induced hyperactivity in mice. Surprisingly, SB-408124 (3, 10 and 30 mg/kg, sc) did not have any effect in these procedures. Collectively, these results indicate, for the first time, that blockade of orexin-2 receptors is effective in reducing the reinforcing effects of ethanol.