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.