Despite intensive medication development efforts, no effective
pharmacotherapy for
cocaine abuse has demonstrated efficacy for long-term use. Given the obvious importance of the
dopamine transporter in the addictive properties of
cocaine, the development and use of compounds that target the
dopamine transporter represents a reasonable approach for the pharmacological treatment of
cocaine abuse. The therapeutic approach of replacement or substitute agonist medication has been successful, as shown with
methadone maintenance for
heroin dependence and
nicotine replacement for tobacco use. A number of preclinical studies with
dopamine transporter inhibitors provide evidence that substitute agonists may be used effectively to reduce
cocaine use. Nonhuman primate models of
drug self-administration provide a rigorous, systematic approach to characterize medication effectiveness in subjects with a documented history of
drug use. Several
cocaine analogs and other
dopamine transporter inhibitors, including analogs of
GBR 12909 and
WIN 35,065-2, have been shown to reduce
cocaine self-administration in nonhuman primates. A possible limitation to the use of selective
dopamine transporter inhibitors as medications is their potential for abuse liability given their demonstrated reinforcing effects in nonhuman primates. However, limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness. Moreover, pharmacokinetic properties that result in slow onset and long duration of action may enhance their effectiveness to reduce
cocaine use while limiting their abuse liability.