The long range goal of this project is to develop methods of quantifying the dopamine transporter (DAT) site in human brain to provide insight into the neuroscience of addictive behavior in cocaine abuse. Positron emission tomography (PET) imaging studies will be employed to measure the DAT density and occupancy. The first goal will be to develop quantitative measurement of absolute density (B/max) in normal human brain as an improvement over existing measures of B/max/K/D. Two methods will be studied, one with unlabeled mazindol and IV unlabeled WIN 35,428 given prior to the second of two high specific activity [11/C] WIN 35,428 PET scans. Using quantitative model calculations, B/max will be obtained. Validation of these techniques in postmortem baboon brains will be performed. Upon successful development of this procedure, we will apply these methods to obtain B/max in cocaine users immediately after cocaine withdrawal and one month later. The change in B/max will be compared with test-retest of B/max in normal volunteers studied at the same interval. This will allow examination of the brain response variability to long-term cocaine abuse and comparison to control B/max values. A parallel study will also be employed to examine the pharmacokinetics of potential medications for cocaine abuse. The first step will be to test the hypothesis that time to peak drug level in brain is inversely correlated with the behavioral response. Not only will this be tested with plasma levels but specifically with the onset of peak occupancy levels against subjective effects of IV cocaine. Testing of such hypotheses is a fundamental element in the understanding of drug abuse and dopamine. This will be done by monitoring the effects of IV cocaine given at different time intervals on the reduction in binding of cocaine given by programmed infusion. This will allow the relationship of DAT occupancy vs. drug dose injection rate. The next step is to measure the DAT occupancy for varying levels of two putative medications, oral GBR 12909 and IV unlabelled WIN 35,428. By measuring the dose response of DAT occupancy vs. drug dose, a number of steps towards medication development are achieved. These include determination of the drub doses at which percent occupancy is high and most optimal; examination of the subjective effects of these drugs when given orally or by slow infusion, thereby determining their suitability as therapeutic drugs. At the conclusion of this five year project, important neuroscience information concerning measurement of DAT in cocaine withdrawal will be obtained. A fundamental hypothesis of drug abuse and drug delivery will be tested. Furthermore, the DAT occupancy vs. dose relationships will be developed and applied to two putative treatment drugs, as a first step towards rational drug trials. The possible non-competitive nature of GBR 12909 will also be tested in vivo.
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