Background: Neuropeptide Y (NPY) is widely expressed in the brain and is known to affect consummatory behaviors including drinking alcohol as well as to play a role in seizures. We investigated the effects of a 4 day binge ethanol treatment model that is known to induce physical dependence and withdrawal seizures to determine the effects of ethanol dependence and withdrawal on NPY expression.

Methods: Male Sprague Dawley® rats were treated with ethanol or control nutritionally complete diets by intragastric treatment three times per day for 2 or 4 days with an average daily dose of approximately 8 g/kg ethanol per day. Ethanol‐fed rats treated for 4 days and then withdrawn for 24, 72, and 168 hr also were studied. Brains were perfused and sectioned for immunohistochemistry for NPY, phospho‐cyclic adenosine monophosphate responsive element binding (pCREB), and other proteins.

Results: NPY immunoreactivity (NPY‐IR) was found in several brain regions, with the hippocampus and cerebral cortex showing the most pronounced changes. NPY‐IR was reduced by ethanol treatment in hippocampus and cortex, although at 72 hr of withdrawal there was a dramatic increase in NPY‐IR in the hilus of the dentate gyrus and in CA3 and CA2 fields of hippocampus. Ethanol withdrawal seizures occurred around 12 to 24 hr of withdrawal, preceding the changes in NPY‐IR at 72 hr. pCREB immunoreactivity (pCREB‐IR) tended to decrease during ethanol treatment but showed a dramatic increase in dentate gyrus at 72 hr of withdrawal. Parvalbumin immunoreactivity indicated that some of the pCREB‐IR and NPY‐IR were within inhibitory interneuron basket cells of the hippocampal hilus. NPY‐IR returned to control levels by 168 hr of withdrawal.

Conclusions: These studies suggest that hippocampal NPY is reduced during the development of ethanol dependence. Ethanol withdrawal seizures precede a dramatic increase in hippocampal NPY‐IR. Previous studies have suggested that NPY in the hippocampus reduces seizure activity and that NPY is induced by seizure activity. Thus, the increase in NPY‐IR at 72 hr of withdrawal after binge ethanol treatment may be protective against prolonged withdrawal seizure activity.