Clinical reports suggest a direct connection between alcohol and mood and it is believed that depression can serve as a predisposing factor for alcohol abuse. Stress has been identified as an antecedent to depressive behavior and a relationship can be drawn between exposure to stress and an increase in alcohol consumption. While the mesolimbic dopamine (DA) pathway represents an important pathophysiological target for alcohol abuse, the norepinephrine (NE) system is implicated in the pathogenesis and treatment of depressive illness. Given that the relationship between stress, depression and alcohol abuse remains poorly understood, a useful strategy would be to study these relationships in an animal model that exhibits the desired phenotypes. Previous studies have revealed that the Wistar-Kyoto (WKY) rat strain demonstrates the predisposed characteristics of behavioral depression. WKY rats show greater susceptibility to stress induced gastric ulcers. Chronic stress leads to dysregulation of the hypothalamic-pituitary-adrenal axis in WKY rats. WKY rats exhibit significant differences in their NE and DA profiles at baseline compared to other rat strains. Stress exacerbates depressive behavior and modulates the NE transporter (NET) site in limbic areas in WKY rats. WKY rats consume greater amounts of alcohol, with increases in DA transporter (DAT) sites in specific mesolimbic areas. Interestingly, antidepressant drugs that block NET or DAT not only alleviated depressive behavior but also increased DAT sites in similar mesolimbic areas as was seen following alcohol consumption in WKY rats. These results implicate a role for DA and NE pathways in both of these disorders and suggest that alcohol may be serving to alleviate depressive symptoms in the WKY rats. Given that the pathological consequences of an impaired DA or NE pathway in depressive behavior and alcohol abuse are presently unknown, this proposal will test the hypothesis that a deficit in these pathways exists in WKY rats, which may predispose them to depressive behavior leading to increased alcohol consumption. ? ? ?
