Relations between heterogeneity of dopamine transporter binding and function and the behavioral pharmacology of cocaine

Abstract

Both in vitro binding studies and studies of dopamine uptake have indicated that there is a heterogeneity of action of cocaine and cocaine analogs. 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 have indicated that the high-affinity component appears to be the one most directly involved in the actions of cocaine related to abuse. These conclusions are based on correlations of affinities and psychomotor stimulant effects. In addition, tolerance to the psychomotor stimulant effects of cocaine occurs with a concomitant change in only the high-affinity component for dopamine uptake. Certain dopamine uptake inhibitors may have only actions mediated by the low-affinity component. These drugs bind to the dopamine transporter and inhibit dopamine uptake; however, they do not have behavioral effects like those of cocaine. This finding is a critical point of inquiry for the dopamine hypothesis because, based on the neurochemical data, these drugs should have behavioral 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-affinity site. Recently, some benztropine analogs have been discovered that bind to the dopamine transporter and inhibit dopamine uptake monophasically but have behavioral effects that are dissimilar to those of cocaine. These compounds may prove useful in determining the behavioral significance of heterogeneity of actions at the dopamine transporter. Further, these studies may provide leads to novel therapeutics for the treatment of cocaine abuse.