The repeated use of psychomotor stimulant drugs, such as amphetamine (AMPH), results in both transient and persistent changes in behavior, affect and cognitive function following the sudden discontinuation of drug use. In humans behavioral changes include (1) transient post-AMPH withdrawal depression, (2) a persistent hypersensitivity to environmental stimuli associated with AMPH use, leading to drug craving, and (3) a persistent sensitization to the psychotogenic effects of AMPH. It is hypothesized that these behavioral manifestations of AMPH withdrawal are due, at least in part, to neurochemical adaptations in brain catecholamine (CA) systems produced by repeated drug exposure. Very little is known, however, about the nature of these neurochemical adaptations, their relation to behavior, how they change as a function of time following withdrawal, or how they are altered by putative pharmacotherapies. These questions are very difficult to address in humans. The overall aim of this proposal, therefore, is to use an animal model to characterize the changes in CA neurotransmission associated with different aspects of the AMPH withdrawal syndrome. Changes in CA neurotransmission will be assessed in a number of brain regions by use of on-line automated intracerebral microdialysis in freely moving rats. This technique will allow us to relate changes in the extracellular concentration of dopamine (DA) and norepinephrine (NE) to ongoing behavior across the entire day-night cycle. Specific experiments are designed to characterize the relationship between changes in CA neurotransmission and (1) post-AMPH withdrawal behavioral depression (nocturnal hypoactivity), (2) the behavioral hypersensitivity to environment cues associated with AMPH treatment (conditioned incentive stimuli), and (3) the behavioral hypersensitivity to a subsequent AMPH challenge (behavioral sensitization) -- all as a function of time following the discontinuation of treatment with escalating doses of AMPH. Finally, a variety of pharmacotherapies have been proposed for stimulant drug abuse, but nothing is known about how the neural adaptations produced by repeated exposure to AMPH influence the action of these agents, or vice versa. Therefore, experiments are proposed to determine the interaction between potential pharmacotherapeutic agents and both transient behavioral depression and persistent behavioral sensitization, and their related changes in CA neurotransmission. Furthermore, there is reason to suspect that some agents that are effective in alleviating transient depressive symptoms may later exacerbate stimulant craving or sensitization, and such interactions also will be studied. In conclusion, the experiments proposed here will be important for understanding the long-term effects of chronic stimulant drug use on brain CA systems, and in developing an animal model to test the ability of putative pharmacotherapeutic agents to 'normalize' brain CA systems and behavior during stimulant withdrawal.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004294-06
Application #
3209746
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1988-04-01
Project End
1996-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Arts and Sciences
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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