INTERACTION OF ALCOHOL AND THE HPT-AXIS

申请人摘要：本修订提案旨在调查 饮酒与下丘脑-垂体-甲状腺的相互作用 大鼠的 (HPT) 轴功能。 HPT 轴功能的测量包括 酗酒者的甲状腺激素、TSH 和 TSH 对 TRH 的反应发生了改变 - 发生某些这些变化的倾向可能是遗传的，并且可能 助长酗酒的发展。 在一些使用老鼠的研究中， HPT 轴测量值的变化与酗酒者中报告的类似 是由长期饮酒引起的，甲状腺状态已 一些研究表明它会影响自愿饮酒。 然而， 清晰的图景尚未出现，部分原因是之前的大部分工作 缺乏对营养、代谢差异的充分控制， 调节和相关变量。 目前，酒精的概念 滥用会改变 HPT 轴功能，饮酒行为受以下因素影响 HPT 轴功能尚未得到充分开发（或测试）并且 因此，对预防和治疗这种疾病几乎无法提供任何见解。 酗酒。 将遵循两种研究策略：1）确定慢性 酒精暴露会改变 HPT 轴功能，并 2) 确定如何 HPT 轴改变（如甲状腺功能减退症中发生的情况），影响自主意识 饮酒量。 具体来说，急性、慢性和 慢性间歇性饮酒，以及急性和慢性戒断慢性酒精 1) T3、T4、rT3、TSH、TSH 对血清中 TRH 的反应，2) T3、 大脑中的 T4、rT3 和 TRH 以及 3) 垂体和大脑中的 TRH 受体将 被确定。 酒精和甲状腺激素的贡献作用 将确定改变 HPT 轴功能的代谢。 效果 中央和外周施用的甲状腺激素和 TRH 以及 集中施用来自 T3、T4 和 TRH 抗血清的 Fab 片段 自愿饮酒量也将受到检查。 这些临床前 研究可能有助于确定人类的 HPT 轴状况，这些状况会增加 酗酒的易感性，从而确定新的策略 用于预防甚至治疗酗酒。

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.