[31] Dopamine transporter mutants, small molecules, and approaches to cocaine antagonist/dopamine transporter disinhibitor development

Dopamine transporters (DAT) terminate dopaminergic neurotransmission by Na+ and Cl− dependent reaccumulation of dopamine into presynaptic neurons. A number of substantial lines of evidence have suggested that the actions of cocaine in inducing its rewarding and reinforcing properties are largely because of its inhibition of the DAT, especially the transporter expressed on terminals of mesolimbic-mesocortical dopaminergic neurons whose cell bodies lie in the ventral tegmental area (VTA) of the basal midbrain. Reduction in psychostimulant reward after lesions of these VTA neurons, the ability of psychostimulants to enhance dopamine spillover from their terminal areas in nucleus accumbens, the good correlations between the relative potencies of cocaine analogs in tests of behavioral reward and their potencies at the dopamine transporter, and results in transgenic animals in which dopamine transporter is overexpressed in catecholaminergic neurons or deleted—have been interpreted as fitting with the idea that the role of cocaine in reward largely depend on its action at the dopamine transporter. Thus, the chapter explains dopamine transporter mutants, small molecules, and approaches to cocaine antagonist and dopamine transporter disinhibitor development.