The effects of chronic administration of cocaine will be measured with respect to 1) changes in GABA-related neurochemical parameters in the nigrostriatal system, 2) changes in stereotyped hyperactivity produced by cocaine, apomorphine and other psychomotor stimulants, and 3) changes in the ability of cocaine and apomorphine to antagonize neurochemical and behavioral responses induced by dopamine-receptor antagonists. The neurochemical mechanisms responsible for the development of these changes, and the persistence of these changes following drug withdrawal will be examined. Pharmacological (dopamine agonist and antagonists, GABA agonists) and surgical (lesions of neural pathways containing dopamine, serotoin) manipulations will be evaluated for their ability to prevent the changes induced by chronic cocaine treatment. In the process we will determine whether the neurochemical mechanisms involved in a) the development of sensitization to cocaine and/or b) the development of tolerance to apomorphine, are similar to those mechanisms responsible for the changes in GABA synthesis and receptor function following chronic exposure to cocaine. These studies will help to a) determine how GABAergic dopaminergic, and possibly serotonergic pathways interact in the basal ganglia, b) identify the neural circuits which are involved in the psychomotor stimulant actions of drugs such as cocaine, and c) determine how these neural circuits can be altered by repeated, prolong exposure to psychomotor stimulants. The results will contribute to an understanding of the neurochemical basis for some of the toxic and pathological snydromes induced by chronic abuse of psychomotor stimulants. At the same time, this information may aid in the design and development of effective antidotes and therapy for disorders associated with stimulant abuse.
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