The cocaine epidemic has produced a demand for pharmacologic treatments which may blunt either the dysphoria during pharmacologic """"""""withdrawal"""""""" from cocaine, or the intense craving which often precedes relapse. The search for effective medications has been hampered by a lack of basic knowledge both about the effects of chronic cocaine use on the brain itself, and, in particular, about the neurochemical substrates of cocaine craving. The proposed studies feature the use of two recently available technologies, in vivo imaging of brain neurotransmitter systems and craving induction through cue exposure, to yield initial knowledge about the brain correlates of cocaine craving and withdrawal states in humans. Specifically, the work proposed will image the activity of mesolimbic D2 dopamine receptor systems (thought to mediate several important effects of cocaine) both during pharmacologic withdrawal from cocaine and during induced cocaine craving. In vivo brain imaging will be accomplished with SPECT (Single-Photon Emission Computer Tomography) scans, using IBZM (I123- iodobenzamide), a specific dopaminergic D2 receptor radioligand, as the imaging agent. The maximum uptake of this ligand in a specific brain area, relative to a reference area with few or no D2 receptors, can be used to estimate the relative number of brain dopamine receptors, a feature which may change as a result of chronic cocaine use/withdrawal. The evacuation/competitive displacement of this same ligand can be used to infer an increase in endogenous dopamine activity, hypothesized here to occur during cocaine craving states. Study 1 (Imaging during pharmacologic withdrawal from cocaine) will image cocaine-dependent patients at 1, 2 1/2, and 4 weeks following cessation of chronic cocaine use. A group of age and sex-matched control patients will be imaged at similar intervals. Study 2 (Imaging during induced cocaine craving) uses a within-subjects design, imaging abstinent cocaine patients and control subjects during exposures to both Cocaine cues and Non-drug (""""""""Neutral"""""""") cues. the response to Sexual and Anxiety-producing cues will also be imaged in the same subjects as a control for different types of arousal. SPECT images will be cross-registered with a Magnetic Resonance Image (MRI) to derive anatomical boundaries of the region of interest (ROI). Analyses for both studies will include repeated measures ANOVAs, with planned comparisons of anticipated differences within - subjects, across different conditions or specified time points.
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