There is now strong evidence that individual differences in the physiological and behavioral effects of drugs or stress may be traceable, at least in part, to differences in prior exposure to as little as a single stressful episode. One process that may account for such effects has been termed, by us, time-dependent sensitization (TDS). TDS refers to the ability of drugs or nonpharmacological stressors administered once or intermittently, to trigger effects in laboratory rats which then grow, up to a point, with the passage of time. Once triggered, TDS can last for months following a single exposure to the inducing agent. For example, a single exposure to either physical restraint of amphetamine (AM) can augment an animal's behavioral response to subsequent AM given one month later. TDS is also widespread, cutting across drug categorizations, transmitters, and bodily systems. Since stress appears to be the key element in inducing TDS, any further investigation of its mechanisms and health implications should concentrate on a physiological system that shows TDS and is causally related to the effects of stress on a wide range of behavioral and physiological processes. The system that most closely fulfills these criteria is the hypothalamic-pituitary- adrenocortical system (HPA axis). There are three parts to this application. Experimental Series I proposes to continue our characterization of TDS of the HPA function. Experimental Series II directly tests the hypothesis that activation of the HPA axis is a key factor in the molecular events leading to TDS. Measurements will include Type II hippocampal glucocorticoid receptors and corticotropin releasing factor in addition to ACTH and CORT and attempts will be made to block TDS by pharmacologically blocking HPA activation at several levels. Experimental Series III asks whether TDS has physio-logical/adaptive significance for the organism, as reflected by TDS-induced changes in carbohydrate metabolism, and in the impact of stress-induced immunosuppression in an animal model of rheumatoid arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH024114-16
Application #
2244101
Study Section
Special Emphasis Panel (SRCM (01))
Project Start
1988-01-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1995-06-30
Support Year
16
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Antelman, S M; Caggiula, A R; Kocan, D et al. (1991) One experience with 'lower' or 'higher' intensity stressors, respectively enhances or diminishes responsiveness to haloperidol weeks later: implications for understanding drug variability. Brain Res 566:276-83
Antelman, S M; Cunnick, J E; Lysle, D T et al. (1990) Immobilization 12 days (but not one hour) earlier enhanced 2-deoxy-D-glucose-induced immunosuppression: evidence for stressor-induced time-dependent sensitization of the immune system. Prog Neuropsychopharmacol Biol Psychiatry 14:579-90

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