Background: Neuropeptide Y (NPY) is a neuropeptide that has been demonstrated to produce anxiolytic effects when administered centrally. To examine the hypothesis that NPY might play a role in alcohol‐seeking behavior, this study took advantage of the genetic differences of the alcohol‐preferring (P) rats and alcohol‐nonpreferring (NP) rats, as well as the high alcohol‐drinking (HAD) rats and low alcohol‐drinking (LAD) rats, in voluntary alcohol consumption to examine if NPY neurons in the brains differ between these selected lines.

Method: The NPY immunoreactivity (NPY‐I) was measured using an established radioimmunohisto‐chemical assay in discrete brain structures including the paraventricular hypothalamic nucleus (PVN), arcuate nucleus (ARC), and central nucleus of the amygdala (CeA).

Result: The quantitative data indicated that there was more NPY‐I in the PVN and ARC of P rats than NP rats, whereas there was less NPY‐I in the PVN and ARC of HAD rats than LAD rats. However, the NPY‐I in the CeA was less in both the P and HAD rats than in the NP and LAD rats, respectively. Therefore, the data indicate that there are innate differences in the NPY‐I in the brain between selectively bred rats with high and low alcohol preference.

Because both P rats and HAD rats have high alcohol preference, the disparate finding between these two lines of rats suggests that the hypothalamic NPY neurons are probably not associated with alcohol preference. In contrast, consistent findings in the CeA of both P rats and HAD rats suggest that NPY in the CeA of P and HAD rats may contribute to the regulation of alcohol consumption. This is substantiated by a recent report showing that NPY‐knockout mice drink significantly more ethanol, and transgenic mice that overexpress the NPY gene drink less alcohol, than wild‐type mice. Together, the findings support the notion that NPY agonists that would enhance NPY function in the amygdala might be useful for the treatment of anxiety and alcoholism.