L-152804 is a nonpeptide, potent, selective and orally available antagonist of a neuropeptide-Y Y5 receptor (NPY Y5). L-152,804 may attenuate drug-induced behavioral effects in vivo. L-152,804 prominently decreased nose-poking for the peak dose of cocaine and shifted the dose-response curve for cocaine downward in self-administration animal model of cocaine addiction-related behavior. Cocaine failed to increase c-fos expression in the nucleus accumbens and striatum of L-152,804-treated mice, indicating that the Y5 antagonist could act by influencing neural activity in these regions. Accordingly, the cocaine-induced increase in accumbal extracellular dopamine was attenuated by L- 152,804 and in Y5-KO mice, suggesting that Y5 antagonism influences cocaine-induced behavior by regulating dopamine. L-152,804 significantly reduced both the dosage of self-administered ethanol and the total number of ethanol-reinforced responses in a rodent genetic animal model of alcoholism. The most likely mechanism by which L-152,804 might have decreased g/kg ethanol intake in both behavioral models is by attenuation of its reinforcing properties. This was evidenced by reduced ethanol-reinforced responding in the absence of changes in response onset, which suggests that the NPY Y5 antagonist did not alter neurobiological processes that control the onset of ethanol responding but inhibited responding once it was initiated.