Recent evidence indicates that neuropeptide Y modulates neurobiologic responses to ethanol and ethanol consumption. Resistance to the sedative effects of ethanol, voluntary ethanol consumption, or both was found to be inversely related to neuropeptide Y levels in genetically manipulated rat and mouse models. More recently, intracerebroventricular infusion of neuropeptide Y reduced ethanol drinking in rats selectively bred for high ethanol preference, but not in low-ethanol-preferring or in outbred Wistar rats. In the current study, we determined whether intracerebroventricular infusion of neuropeptide Y would reduce voluntary ethanol consumption in high-ethanol-preferring, C57BL/6 mice. We also studied ethanol-induced sedation after intracerebroventricular infusion of neuropeptide Y. Pretreatment with doses of neuropeptide Y, ranging from 3.0 to 10.0 microg, significantly augmented ethanol-induced sedation without altering locomotor activity or plasma ethanol levels. However, neither a 5.0- nor a 10.0-microg dose of neuropeptide Y altered 2-h drinking of a 10% [volume/volume (vol./vol.)] ethanol solution. Consistent with genetic evidence, the results of current pharmacologic studies provide support that neuropeptide Y modulates ethanol-induced sedation.