RELATIONS BETWEEN HETEROGENEITY OF DOPAMINE TRANSPORTER BINDING AND FUNCTION AND THE BEHAVIORAL PHARMACOLOGY OF COCAINE

Both in vitro binding studies and studies of dopamine uptake have indi cated that there is a heterogeneity of action of cocaine and cocaine a nalogs. Both high- and low-affinity binding sites have been identified . Some drugs that bind to the dopamine transporter show both high- and low-affinity components whereas others do not. Behavioral studies hav e indicated that the high-affinity component appears to be the one mos t directly involved in the actions of cocaine related to abuse, These conclusions are based on correlations of affinities and psychomotor st imulant effects. In addition, tolerance to the psychomotor stimulant e ffects of cocaine occurs with a concomitant change in only the high-af finity component for dopamine uptake. Certain dopamine uptake inhibito rs may have only actions mediated by the low-affinity component. These drugs bind to the dopamine transporter and inhibit dopamine uptake; h owever, they do not have behavioral effects like those of cocaine. Thi s finding is a critical point of inquiry for the dopamine hypothesis b ecause, based on the neurochemical data, these drugs should have behav ioral actions like those of cocaine, In contrast, some of these drugs antagonize the behavioral effects of cocaine, suggesting that the low- affinity site somehow modulates the actions mediated by the high-affin ity site. Recently, some benztropine analogs have been discovered that bind to the dopamine transporter and inhibit dopamine uptake monophas ically but have behavioral effects that are dissimilar to those of coc aine. These compounds may prove useful in determining the behavioral s ignificance of heterogeneity of actions at the dopamine transporter, F urther, these studies may provide leads to novel therapeutics for the treatment of cocaine abuse. (C) 1997 Elsevier Science Inc.