RELATIONSHIP BETWEEN SUBJECTIVE EFFECTS OF COCAINE AND DOPAMINE TRANSPORTER OCCUPANCY

Cocaine is believed to work by blocking the dopamine transporter (DAT) and thereby increasing the availability of free dopamine within the b rain(1-4). Although this concept is central to current cocaine researc h and to treatment development, a direct relationship between DAT bloc kade and the subjective effects of cocaine has not been demonstrated i n humans. We have used positron emission tomography to determine what level of DAT occupancy is required to produce a subjective 'high' in h uman volunteers who regularly abuse cocaine. We report here that intra venous 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 magnitu de of the self-reported high was correlated with the degree of DAT occ upancy, and at least 47% of the transporters had to be blocked for sub jects 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. Th is is the first demonstration in humans that the doses used by cocaine abusers lead to significant blockade of DAT, and that this blockade i s associated with the subjective effects of cocaine. Although these fi ndings provide justification to target the DAT for medication developm ent they suggest that for drugs to be effective in blocking cocaine's effects they would have to be given at doses that achieve almost compl ete DAT occupancy.