There is no effective pharmacotherapy for cocaine abuse and dependence despite extensive testing of potential medications. The clinical data suggest that the search for direct-acting dopaminergic agents effective in treating cocaine abuse is unlikely to be productive, and investigations of other agents which perturb the noradrenergic and serotonergic systems have been equally disappointing. Recent data suggest that both NMDA and GABA may provide new avenues for pharmacological intervention in the treatment of cocaine abuse. We propose to continue our laboratory investigation into novel potential medications for the treatment of cocaine abusers by evaluating the NMDA antagonist, dextromethorphan, and the GABAergic agents, vigabatrin and gabapentin. We will include measures of cocaine self-administration under a modified progressive ratio procedure, a cocaine discrimination procedure and measures of subjective effects, including cocaine craving. This expanded profile of the ways in which these potential treatment medications interact with cocaine use and the consequences of that use, will allow us to make more informed decisions in designing specific pharmacological interventions to treat cocaine abusers. All participants will be tested under double blind conditions with placebo and active medication maintenance and with multiple doses of smoked cocaine. This use of a medication-maintenance model mimics the treatment situation and increases our ability to detect the effects of active medications, even those with slow onset of therapeutic effects. Laboratory research with human participants provides the necessary bridge from laboratory to clinic, and allows a relatively short, well controlled and safe alternative to the initial testing of a medication in an open label or even small controlled clinical trial. Combining the data from sensitive drug self-administration, drug discrimination and subjective effects measures will allow us to understand more fully the interaction between NMDA antagonism or GABAergic effects and cocaine's effects, and consequently to inform cocaine medication development endeavors. Such data will provide important information about the underlying neural mechanisms of single and repeated dose cocaine use in humans. The overall strength of this protocol lies in our utilization of a controlled laboratory setting to examine the interactive effects of an NMDA antagonist (dextromethorphan), a GABA transaminase inhibitor (vigabatrin), and a GABA analog which potentiates GABA (gabapentin), with cocaine use, cocaine """"""""craving,"""""""" and the subjective, physiological and discriminative stimulus effects of cocaine.
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