Cocaine is believed to work by blocking the dopamine transporter (DAT) and thereby increasing the availability of free dopamine within the brain. Although this concept is central to current cocaine research and to treatment development, a direct relationship between DAT blockade and the subjective effects of cocaine has not been demonstrated in humans. We have used positron emission tomography to determine what level of DAT occupancy is required to produce a subjective 'high' in human volunteers who regularly abuse cocaine. We report here that intravenous cocaine at doses commonly abused by humans (0.3-0.6 mg kg(-1)) blocked between 60 and 77% of DAT sites in these subjects. The magnitude of the self-reported high was correlated with the degree of DAT occupancy, and at least 47% of the transporters had to be blocked for subjects to perceive cocaine's effects. Furthermore, the time course for the high paralleled that of cocaine concentration within the striatum, a brain region implicated in the control of motivation and reward. This is the first demonstration in humans that the doses used by cocaine abusers lead to significant blockade of DAT, and that this blockade is associated with the subjective effects of cocaine. Although these findings provide justification to target the DAT for medication development they suggest that for drugs to be effective in blocking cocaine's effects they would have to be given at doses that achieve almost complete DAT occupancy.
Summary: To assess the stability of different measures of receptor occupancy from [llC]raelopride (a D2 antago nist) studies with positron emission tomography, we an alyze data from five testlretest studies in normal volun teers in terms of individual model parameters from a three-compartment model, the distribution volume (DV) and the ratio of DVs from a receptor-containing region of interest to a non-receptor-containing region. Large vari ations were found in the individual model parameters, limiting their usefulness as an indicator of change in re ceptor systems. The DV ratio showed the smallest vari ation. Individual differences were reflected' in the greater intersubject variation in DV than intrasubject variation. The potential effects of blood flow on these measure ments were addressed both experimentally and by simu lation studies using three models that explicitly incorpo rate blood flow into a compartmental model that also in-The distribution volume (DV) has been used ex tensively to monitor changes in receptor systems probed with reversibly binding radiotracers such as e1C]raclopride (Dewey et aI., 1992(Dewey et aI., , 1993 Volkow et aI., 1994) Abbreviations used: BO, basal ganglia; CB, cerebellum; COV, coefficient of variation; DA, dopamine; DV, distribution vol ume; OABA, -y-aminobutyric acid; NLSQ, nonlinear least squares; PET, positron emission tomography; ROI, region of interest. 995eludes receptor-ligand binding. None of the models showed any variation in the DV with changes in blood flow as long as flow was held constant during the simu lation. Experimentally, blood flow was significantly re duced by hyperventilation in a human subject. The DV was found to be reduced relative to baseline in the hyper ventilation study, but the DV ratio remained unchanged. The effect of elevated and reduced flow was also tested in two baboon experiments in which Pe02 was varied. Some variability in the DV ratio was observed but was not cor related with changes in blood flow. This raises the possi bility that other factors indirectly related to changes in blood flow (or Pe02) may cause changes in DV, and these effects need to be considered when evaluating experimen tal results.
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