Relationship between subjective effects of cocaine and dopamine transporter occupancy

Abstract

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.

SPECT imaging of D2 dopamine receptors and endogenous dopamine release in mice

“…The D2R has been implicated in cocaine addiction, as well as cocaine craving, in humans [19][20][21][22]. Therefore, the D2R may provide a target for prevention of relapse after cocaine detoxification, and the study of striatal D2R availability in mouse models of cocaine addiction is important to unravel its role in human cocaine addiction.…”

Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys

“…The relevance of the DAT in the abuse liability of cocaine is supported further by neuroimaging studies. In human cocaine users, a significant correlation was observed between the level of DAT occupancy and the magnitude of the subjective high following administration of cocaine (Volkow et al, 1997) or the behavioral stimulant methylphenidate (Volkow et al, 1999).…”

Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys

“…However, in order to produce equivalent increases in locomotor activity in rodents, selective DAT inhibitors must exhibit greater occupancy of DAT than does the nonselective monoamine transporter inhibitor cocaine (Rothman et al, 1992;Vaugeois et al, 1993). Neuroimaging studies in humans have found a significant correlation between DAT occupancy and the subjective high following administration of cocaine (Volkow et al, 1997) or methylphenidate . However, DAT inhibitors differ in their effectiveness as positive reinforcers.…”