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

导致Wistar京都大鼠应激性酒精滥用的单胺机制

基本信息

批准号：
7126981
负责人：
SHANAZ MOHAMMEDALI TEJANI-BUTT
金额：
$ 20.56万
依托单位：
UNIVERSITY OF THE SCIENCES PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2010-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：临床报告表明酒精与情绪之间有直接的联系，据信抑郁症可以成为酗酒的诱人因素。压力已被确定为抑郁行为的前提，可以在承受压力和饮酒量增加之间达到关系。虽然中唇多巴胺（DA）途径代表了酗酒的重要病理生理靶标，但去甲肾上腺素（NE）系统与抑郁疾病的发病机理和治疗有关。鉴于压力，抑郁症和酗酒之间的关系仍然很少了解，因此有用的策略是在展示所需表型的动物模型中研究这些关系。先前的研究表明，Wistar-Kyoto（WKY）大鼠菌株表明行为抑郁症的易感性。 WKY大鼠表现出更大的敏感性对应激诱发的胃溃疡。慢性应激导致WKY大鼠下丘脑 - 垂体 - 肾上腺轴的失调。与其他大鼠菌株相比，WKY大鼠在基线时的NE和DA谱图表现出显着差异。压力加剧了抑郁行为，并调节WKY大鼠边缘区域的NE转运蛋白（NET）部位。 WKY大鼠消耗更多的酒精，而在特定的中边缘地区DA转运蛋白（DAT）的增加。有趣的是，抗抑郁药阻断净或DAT不仅可以减轻抑郁行为，而且还增加了类似的中溶液区域的DAT位点，如WKY大鼠饮酒后所见。这些结果暗示了DA和NE途径在这两种疾病中的作用，并表明酒精可能有助于减轻WKY大鼠的抑郁症状。鉴于目前尚不清楚DA或NE途径受损或NE途径的病理后果，该提议将检验以下假设：WKY大鼠中存在这些途径的不足，这可能会使它们倾向于抑郁行为，从而导致饮酒量增加。