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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007809-03
Application #
2044138
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1990-01-01
Project End
1993-12-31
Budget Start
1992-01-01
Budget End
1993-12-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Rezvani, A H; Garbutt, J C; Overstreet, D H et al. (1997) Thyrotropin releasing hormone analog TA-0910 suppresses alcohol intake in alcohol drinking African green monkeys. Alcohol Clin Exp Res 21:261-6
Mason, G A; Rezvani, A H; Overstreet, D H et al. (1997) Involvement of dopamine D2 receptors in the suppressive effect of the thyrotropin-releasing hormone analog TA-0910 on alcohol intake in alcohol-preferring rats. Alcohol Clin Exp Res 21:1623-9
Mason, G A; Rezvani, A H; Overstreet, D H et al. (1996) Thyrotropin-releasing hormone analog TA-0910 reduces voluntary alcohol intake of P rats subchronically in a limited scheduled access paradigm. Alcohol Clin Exp Res 20:1000-3
Mason, G A; Rezvani, A H; Grady, D R et al. (1994) The subchronic effects of the TRH analog TA-0910 and bromocriptine on alcohol preference in alcohol-preferring rats: development of tolerance and cross-tolerance. Alcohol Clin Exp Res 18:1196-201
Noonan, L R; Walker, C H; Li, L et al. (1993) Effects of thyroid state on preference for and sensitivity to ethanol in Fischer-344 rats. Prog Neuropsychopharmacol Biol Psychiatry 17:475-86
Mason, G A; Noonan, L R; Garbutt, J C et al. (1992) Effects of ethanol and control liquid diets on the hypothalamic-pituitary-thyroid axis of male Fischer-344 rats. Alcohol Clin Exp Res 16:1130-7
Rezvani, A H; Garbutt, J C; Shimoda, K et al. (1992) Attenuation of alcohol preference in alcohol-preferring rats by a novel TRH analogue, TA-0910. Alcohol Clin Exp Res 16:326-30
Shimoda, K; Mason, G A; Walker, C H et al. (1991) Administration of chlordiazepoxide affects [3H][3-MeHis2]thyrotropin-releasing hormone binding in rat brain. Peptides 12:199-202