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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）：临床报告表明酒精和情绪之间存在直接联系，并且认为抑郁症可以作为酒精滥用的诱发因素。压力已被确定为抑郁行为的前因，并且可以在暴露于压力和饮酒量增加之间绘制关系。虽然中脑边缘多巴胺（DA）通路是酒精滥用的重要病理生理学靶点，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、抑郁和酗酒之间的关系仍然知之甚少，一个有用的策略是在表现出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）大鼠品系表现出行为抑郁症的易感特征。WKY大鼠对应激诱导的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特征表现出显著差异。应激加重WKY大鼠抑郁行为并调节边缘区NE转运体（NET）位点。WKY大鼠消耗更多的酒精，在特定的中脑边缘区的DA转运体（DAT）网站的增加。有趣的是，阻断NET或DAT的抗抑郁药物不仅减轻了抑郁行为，而且增加了WKY大鼠饮酒后类似的中脑边缘区的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，并表明酒精可能有助于减轻WKY大鼠的抑郁症状。鉴于抑郁行为和酒精滥用中受损的DA或NE通路的病理后果目前尚不清楚，本提案将检验WKY大鼠中存在这些通路缺陷的假设，这可能使它们易患抑郁行为，导致饮酒量增加。