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.
