The direct examination of dopamine activity in the human brain is now feasible with PET and appropriate radiotracers. The purpose of this proposal is to investigate the nature of the changes in the dopaminergic system that occur with chronic cocaine use. These studies are specifically planned in human cocaine abusers because these individuals are representative of patients seeking medical help for treatment of cocaine dependence. The strategy for studying the dopaminergic changes, during cocaine dependence involves: assessment of postsynaptic receptor (D2) availability using 18F N-methylspiroperidol; assessment of presynaptic dopamine transporter using 11 C-cocaine; assessment of brain metabolism using 18F-fluorodeoxyglucose in areas of the brain which receive afferents from the dopamine system. Indirect measurements of dopaminergic function will also be made using endocrinological tests. PET studies will be carded out at different times during the detoxification period to examine the changes in dopamine activity that occur during the withdrawal period. The working hypotheses are: (1) During cocaine abuse and/or shortly after detoxification, there is a decrease in postsynaptic dopamine receptors and an increase in dopamine transporter sites to compensate for dopamine overstimulation from chronic use of cocaine. (2) Dopamine activity in the brain of cocaine abusers is not static, but changes during the detoxification period. (3) This dynamic nature of changes in dopamine activity may explain the changing nature of the psychiatric symptomatology observed in the cocaine abuser during detoxification. Recent results of PET studies in chronic cocaine abusers support the working hypotheses. This approach represents a unique opportunity to examine the temporal response of the dopaminergic system to chronic cocaine abuse, to correlate this with behavioral changes that occur during the withdrawal period and to test the """"""""dopamine depletion hypothesis"""""""" for cocaine dependence and its implications in pharmacological treatment.
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