Monoamine mechanisms leading to stress induced alcohol abuse in Wistar Kyoto rats

描述（由申请人提供）：临床报告表明酒精和情绪之间有直接联系，人们认为抑郁可能是酒精滥用的一个诱发因素。压力已被确定为抑郁行为的先决条件，并且可以在压力暴露与饮酒增加之间建立关系。虽然中脑边缘多巴胺（DA）通路是酒精滥用的重要病理生理靶点，但去甲肾上腺素（NE）系统与抑郁症的发病机制和治疗有关。鉴于压力、抑郁和酒精滥用之间的关系仍然知之甚少，一个有用的策略是在动物模型中研究这些关系，显示出期望的表型。先前的研究表明，Wistar-Kyoto （WKY）大鼠品系表现出行为抑郁的易感性特征。WKY大鼠对应激性胃溃疡表现出更大的易感性。慢性应激导致WKY大鼠下丘脑-垂体-肾上腺轴的失调。与其他大鼠品系相比，WKY大鼠在基线时的NE和DA谱有显著差异。应激可加重WKY大鼠的抑郁行为并调节脑边缘区的NE转运蛋白（NET）位点。WKY大鼠消耗更多的酒精，特定中脑边缘区域的DA转运蛋白（DAT）位点增加。有趣的是，阻断NET或DAT的抗抑郁药物不仅减轻了抑郁行为，而且还增加了WKY大鼠饮酒后类似中脑边缘区域的DAT位点。这些结果暗示了DA和NE通路在这两种疾病中的作用，并提示酒精可能有助于缓解WKY大鼠的抑郁症状。鉴于抑郁行为和酒精滥用中DA或NE通路受损的病理后果目前尚不清楚，本研究将验证WKY大鼠中存在这些通路缺陷的假设，这可能使它们倾向于抑郁行为，导致酒精消耗增加。

DESCRIPTION (provided by applicant): 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.