Little is known of the role of regulatory neuropeptides in ethanol consumption and subsequent sensitivity to ethanol's effects. Neuropeptide Y (NPY), a 36-amino acid peptide, is distributed widely throughout the peripheral and central nervous systems, and is implicated in the control of many behaviors. We have investigated NPY-knockout mice and transgenic mice that overexpress NPY, and have found that ethanol consumption and resistance are inversely related to NPY levels. Proposed experiments will assess the hypothesis that ethanol and NPY share certain anxiolytic properties and that these interact to modulate ethanol consumption and ethanol-induced sedation. Specific experiments will address the following questions: (A) Which specific NPY receptors regulate the effects of NPY on ethanol intake and ethanol-induced sedation? To address this, voluntary ethanol consumption and ethanol-induced sedation will be assessed in mutant mice lacking specific central NPY receptors. (B) Where in the brain does NPY modulate voluntary ethanol consumption and the acute intoxicating effects produced by ethanol? This will be assessed by administering NPY into specific brain regions of NPY-knockout mice and assessing subsequent effects on ethanol consumption and sensitivity. (C) Does NPY modulate the rewarding and/or aversive effects of ethanol? To address this question, conditioned place preference learning and conditioned taste aversion learning following ethanol will be assessed in NPY-knockout mice and NPY-overexpressing mice. (D) Are the high ethanol consumption of NPY-knockout mice and the low ethanol consumption of NPY-overexpressing mice secondary to altered basal levels of anxiety? We will address this by manipulating anxiety levels in NPY-knockout and overexpressing mice and assessing subsequent effects on voluntary ethanol consumption. Additionally, we will determine if these mice have altered consumption of anxiolytic drugs other than ethanol. Determining how NPY acts to influence voluntary ethanol consumption and ethanol sensitivity is critical to a complete understanding of the neurobiological mechanisms that determine alcohol use and abuse. Such knowledge will be useful for the development of pharmacological treatments targeted at preventing excessive alcohol intake.
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