RISK FOR ALCHOLISM

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。啮齿类动物的研究表明，压力、中脑边缘多巴胺的产生和滥用药物的异常强化之间存在联系。据推测，压力增加中脑边缘多巴胺产生的能力导致奖励途径对滥用药物的敏感化。事实上，大鼠在应激后会消耗更多的酒精和其他药物，而应激后饮酒会因肾上腺切除术而减弱。在上一个资助期间，我们确定了酗酒风险增加的人（例如，酗酒者的后代）对纳洛酮更敏感，改变了HPA轴动力学和改变了下丘脑阿片样物质活性，这可以在大量饮酒开始之前识别。此外，我们已经表明，长期大量饮酒会导致下丘脑-垂体-肾上腺轴动力学更显着的紊乱，影响情绪，并可能增加戒断后复发的机会。最后，我们发现长期服用纳洛酮可以减弱酒精诱导的HPA轴的激活，也可以减弱主观上对酒精的“喜欢”。“我们假设，由酒精中毒或酒精中毒家族史引起的高皮质醇血症改变了中脑边缘多巴胺的产生，导致异常强化。本申请中概述的实验“独立”。“首先，我们将扩展我们以前的研究结果，并确定高危受试者是否有一个更不稳定的HPA轴来应对心理压力。其次，我们将确定对纳洛酮有高皮质醇反应的人是否也会对“真实的生活”压力有高皮质醇反应。第三，我们将确定是否1）酗酒家族史，2）个性措施或3）焦虑措施相互作用，改变HPA轴动力学。第四，使用PET成像，我们将确定高风险的非酗酒者是否比低风险的受试者产生更多的多巴胺。我们将测试的假设，高皮质醇分泌也是高多巴胺释放的啮齿类动物的文献预测。最后，5 amp; 10年的随访研究将确定高皮质醇产生或高多巴胺释放是否是酒精中毒的独立危险因素。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rodent studies suggest a link between stress, mesolimbic dopamine generation and abnormal reinforcement from drugs of abuse. It has been posited that the ability of stress to increase mesolimbic dopamine production results in sensitization of the reward pathway to drugs of abuse. Indeed, rats will consume more alcohol and other drugs following stress and post-stress alcohol drinking is attenuated by adrenalectomy. During the last funding period, we established that persons at increased risk for alcoholism (e.g., offspring of alcoholics) are more sensitive to Naloxone, have altered HPA axis dynamics and altered hypothalamic opioid activity, which can be identified before the onset of heavy drinking. Moreover, we had shown that chronic heavy drinking induces even more dramatic derangement in HPA axis dynamics, affecting mood and perhaps increasing the chances of relapse following withdrawal. Lastly, we showed that chronic Naltrexone administration blunted alcohol-induced activation of the HPA axis as well as blunting subjective "Liking" of alcohol "high." We hypothesize that hypercortisolemia induced by alcoholism or family history of alcholism alters mesolimbic dopmamine production leading to abnormal reinforcement. The experiments outlined in this application "stand alone." First, we will extend our previous findings and determine if high-risk subjects have a more labile HPA axis in response to a psychological stress. Second, we will ascertain whether high cortisol responders to Naloxone will also be high cortisol responders to "real life" stress. Third, we will determine whether 1) family history of alcoholism, 2) personality measures or 3) anxiety measures interact to alter HPA axis dynamics. Fourth, using PET imaging, we will determine if high-risk nonalcoholics make more dopamine compared to low risk subjects. We will test the hypothesis that high cortisol secretors are also high dopamine releasers as the rodent literature predicts. Finally, 5 amp; 10-year follow-up studies will determine if high cortisol production or high dopamine release is independent risk factors fo ralcoholism.