Using a multidisciplinary approach we plan to measure the effects of cocaine using several different indices of CNS function and behavior in men and women. Concurrent measures of l) hydrolysis of phosphatidylcholine using proton magnetic resonance spectroscopy (1H MRS) of the basal ganglia; 2) cerebral blood volume (CBV) using dynamic susceptibility contrast magnetic resonance imaging (DSC MRI); 3) regional spontaneous electroencephalographic (EEG) activity; 4) plasma cocaine and benzoylecgonine levels and 5) mood state via continuously available joystick device and periodic visual analog scales will be integrated. Healthy men and women who have a negative family history of alcoholism and use cocaine on an occasional basis will participate. In EXPERIMENT 1 (years 1-3), each subject will serve as their own control in a double- blind administration of i.v. cocaine or placebo. Each subject will receive three doses of cocaine (0.1, 0.2 and 0.4 mg/kg) and placebo. A total of 20 men and 40 women will be studied. Half of the women will be studied during the mid-follicular phase and the other half will be studied during the mid-luteal phase of their menstrual cycle. Baseline measures will include spontaneous EEG activity, a 1H MRS evaluation of basal ganglia metabolites, a determination of regional CBV by DSC MRI. Following the injection of either placebo or cocaine (T = 0), 1H MRS of the basal ganglia will be repeated at T = 15 and 48 minutes and DSC MRI will be performed at T = 5 and 25 minutes. EEG activity will be collected in between these procedures. Selection of these time points for measurement of regional CBV is based upon anticipated peak plasma cocaine levels following i.v. cocaine administration and subsequent decrement of plasma cocaine levels and associated waning of peak drug effects on mood states and behavior. Since the half-life of cocaine is relatively short, measurement of regional CBV will be possible during important temporal intervals associated with cocaine reinforcement. In EXPERIMENT 2 (year 4), the above indices will be measured in a group of 10 male and 20 female subjects who have been pretreated with a 5-day regimen of various doses of sertraline (25, 50 or 75 mg/day, p.o.) to determine if cocaine-induced changes in brain function are altered by a serotonin uptake inhibitor. There is mounting evidence that measures of CBV, brain biochemistry and brain electrical activity can provide new and important information regarding alterations in spontaneous cocaine-induced changes in behavioral states. In addition, findings that an increased amount and distribution of EEG alpha activity is associated with drug-induced euphoria illustrate the importance of obtaining precisely timed, topographic evaluations of brain electrical activity. By combining all three measures of brain function into a single study design, the proposed research plan offers a unique opportunity to gain new insight into the basic mechanisms of cocaine reinforcement--information that will be valuable in designing the next generation of pharmacotherapies.
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