BRAIN DAT/5-HTT DYSREGULATION IN COCAINE USERS

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Cocaine binding sites likely located on the dopamine transporter (DAT) are increased throughout the striatum of human cocaine users, suggesting that cocaine increases DAT synthesis. Compensatory upregulation of DAT uptake might contribute to cocaine-associated symptoms such as binging, withdrawal depression, and craving. These results also highlight the utility (and feasibility) of post mortem studies as preliminary step in focusing correlative, treatment-oriented, and mechanistic research. Other anatomical regions (and other monoaminergic neurons) may also be involved in the large range of cocaine-induced clinical phenomena. Recent experiments performed by the applicant in post mortem human brain have proven the feasibility of detecting and quantitating DAT binding sites in limbic regions. SPECIFIC AIM #1 is to test the hypothesis that chronic cocaine exposure increases cocaine binding sites on the DAT in hippocampus, amygdala, and temporal cortex of human users. Saturation and competition binding studies are proposed on striatal and limbic sections taken at autopsy from clinically characterized cocaine users and matched control subjects using quantitative autoradiography. Preliminary experiments will compare DAT binding and uptake characteristics in these regions to those in the striatum, and map the topography of DAT binding in human hippocampus, amygdala, and temporal cortex. Detection of cocaine binding site increases in animals has varied depending on the radioligand used, suggesting that cryptic DAT or even non-DAT sites might be the substrate for increased binding. SPECIFIC AIM #2 is to determine if midbrain DAT mRNA levels are increased in human cocaine users. Cocaine also binds to the serotonin transporter (5-HTT) and potently blocks 5-HT uptake, but little information exists about the effects of chronic cocaine exposure on 5-HTT function. SPECIFIC AIM #3 is to test the hypothesis that 5-HTT binding sites are also increased in cocaine-exposed subjects. Preparatory experiments will determine 5-HTT binding characteristics in hippocampus, amygdala, and temporal cortex, evaluate the overlap of 5-HTT and DAT binding topography in these regions, and determine the selectivity of 5-HTT and DAT uptake processes in regions of overlapping innervation. Dopaminergic neurons exposed to chronic cocaine may also adapt by altering autoreceptor sensitivity. SPECIFIC AIM #14 is to test the hypothesis that dopamine autoreceptor binding in hippocampus, amygdala, and temporal cortex is altered by chronic cocaine use in humans. D2 receptor binding will be compared in these regions of cocaine users and controls. By emphasizing human studies, correlative symptomatology and species differences can be delineated, and relevant neurochemical foci determined for animal modeling.