INTERACTION OF ALCOHOL AND THE HPT-AXIS

申请人摘要：这份修订后的提案是为了调查 饮酒与下丘脑-垂体-甲状腺的相互作用 (HPT)--大鼠的轴功能。HPT轴功能的衡量标准包括 酗酒者甲状腺激素、TSH和TSH对TRH的反应发生改变 引起这些变化中的某些变化的倾向可以是继承的，并且可以 有助于酒精中毒的发展。在一些使用老鼠的研究中， HPT-轴指标的变化与酗酒者报告的变化相似 是由长期饮酒引起的，甲状腺状况一直是 一些研究表明，这会影响自愿饮酒。然而， 一幅清晰的图景还没有出现，部分原因是之前的许多工作 缺乏对营养、新陈代谢、 条件反射和相关变量。目前，酒精的概念是 滥用改变了HPT轴功能，饮酒行为受到 HPT轴功能未得到充分开发(或测试)和 因此并不能为预防和治疗提供多少帮助 酗酒。 将遵循两个研究策略：1)确定慢性 酒精暴露会改变HPT轴功能，2)以确定 HPT轴改变，如在甲状腺功能减退症中发生，影响自愿 饮酒。具体而言，急性、慢性和非传染性疾病的影响 慢性间歇性酒精，急性和慢性戒断 酒精1)T_3、T_4、rT_3、TSH、TSH对血清TRH的反应，2)T_3， 脑组织中的T4、RT3和TRH；3)脑垂体和脑中的TRH受体 要下定决心。酒精和甲状腺激素的作用 HPT轴功能改变中的代谢将被确定。其影响 中枢和外周给药甲状腺激素和促甲状腺激素释放激素 从抗血清到T_3、T_4和TRH的集中注射Fab片段 自愿饮酒也将被审查。这些临床前研究 研究可能有助于确定人类的HPT-轴状况 发展酒精中毒的易感性，从而确定新的策略 用于预防甚至治疗酒精中毒。

APPLICANT'S ABSTRACT: This revised proposal is to investigate the interactions of alcohol consumption and Hypothalamic-pituitary-thyroid (HPT)-axis function in rats. Measures of HPT-axis function including thyroid hormones, TSH and TSH response to TRH are altered in alcoholics - a tendency to incur certain of these changes may be inherited and may contribute to the development of alcoholism. In some studies using rats, changes in HPT-axis measures similar to those reported in alcoholics have been induced by chronic alcohol ingestion, and thyroid status has been shown in some studies to influence voluntary alcohol consumption. However, a clear picture has not emerged, in part because much of the previous work lacked adequate controls for differences in nutrition, metabolism, conditioning and associated variables. Presently, the concept that alcohol abuse alters HPT-axis function and that drinking behavior is influenced by HPT-axis function have not been adequately developed (or tested) and therefore can offer little insight toward the prevention and treatment of alcoholism. Two research strategies will be followed: 1) to determine how chronic alcohol exposure changes HPT-axis function and 2) to determine how an altered HPT-axis such as occurs in hypothyroidism, affects voluntary alcohol consumption. Specifically, the effects of acute, chronic and chronic intermittent alcohol, and acute and chronic withdrawal from chronic alcohol in 1) T3, T4, rT3, TSH, TSH response to TRH in blood serum, 2) T3, T4, rT3 and TRH in brain and 3) TRH receptors in pituitary and brain, will be determined. The contributing roles of alcohol and thyroid hormones metabolism in altering HPT-axis function will be ascertained. The effects of centrally and peripherally administered thyroid hormones and TRH and centrally administered Fab fragments from antisera to T3, T4 and TRH on voluntary alcohol consumption will also be examined. These preclinical studies may help to identify HPT-axis conditions in man which increase susceptibility to develop alcoholism and thereby identify novel strategies for prevention and even treatment of alcoholism.