Neuropeptide Y (NPY) has largely been investigated for the peptide's orexogenic properties and its role in the regulation of body weight. Anxiolytic effects of NPY have also been examined. There is recent interest in the possibility that NPY also may be involved in alcohol-seeking behavior. For example, selectively bred P and NP rats and high alcohol drinking HAD and low alcohol drinking LAD rats differ in NPY levels in brain regions that are involved in the regulation of the orexogenic and anxiolytic effects of NPY . Alcohol intake of NPY knock-out mice is higher than that of controls and alcohol intake of mice over expressing NPY is lower than controls. Recent studies carried out in our laboratory have shown that intracerebral ventricular (ICV) administration of NPY reduces limited-access oral alcohol intake in P and HAD rats. Together, the studies with NPY knockout and over expressing mice and with selectively-bred rats suggest that there may be an inverse relationship between NPY activity and alcohol intake. The proposed research will explore this relationship and examine possible mechanisms for the observed NPY-produced reductions in alcohol self-administration. To determine CNS site(s) of action for this effect, NPY will be administered directly into specific brain areas involved in the orexogenic, anxiolytic and reinforcing effects of NPY. Two hypotheses that may account for NPY-produced reductions in alcohol drinking will be examined: 1) that the effect may be related to NPY-produced alterations in dopaminergic activity in the nucleus accumbens, located in the mesolimbic reward pathway and 2) that the effect may be related to actions of NPY in the amygdala, a structure, located in the mesolimbic reward pathway, which mediates the anxiolytic effects of the peptide. To determine the behavioral significance of previously observed line-differences in NPY levels, P and NP and HAD and LAD rats will be compared. The effects of NPY on alcohol self-administration, behavioral tests of anxiety and on dopamine release in the nucleus accumbens will be measured. The main hypothesis to be tested is that NPY is a factor that can affect alcohol-seeking behavior. The research will expand our understanding of the neurobiology of alcohol abuse and alcoholism and may suggest effective pharmacological treatment interventions.
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