EVALUATION OF NOVEL TREATMENTS FOR STIMULANT DEPENDENCE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cocaine abuse continues to pose a significant public health problem in the U.S. with no broadly effective treatment available. Cocaine exerts a broad array of pharmacological effects, but several decades of multidisciplinary research have led to the accepted theory that the mesolimbic-cortical dopamine system plays a critical role in mediating the reinforcing effects of cocaine related to its abuse. Moreover, documented neural perturbations in dopamine systems result from chronic cocaine use and are hypothesized to underlie the persistent craving and withdrawal symptoms that occur during abstinence. Clinical studies evaluating dopamine agents have, however, failed to demonstrate efficacy against cocaine use; these results are attributable, in part, to the adverse effects associated with the clinically available dopamine agonists and traditional dopamine antagonists. More recently, it has been theorized that compounds with partial agonist/antagonist properties at dopamine receptor sites may provide an effective pharmacological strategy with a decreased risk of intolerable side effects. Aripiprazole is the newest atypical antipsychotic marketed in the United States. Its neuropharmacological profile distinguishes it from all other atypical antipsychotics. Aripiprazole exhibits high affinity for the D2 receptor where it behaves as a partial agonist, in contrast to the antagonist actions of other atypical antipsychotics. Aripiprazole also acts as a partial agonist at the 5-HT1a and as an antagonist at 5-HT2 receptors. These receptor systems are recognized as playing an important role in mood regulation, and activity at these sites has been shown to modify the effects of cocaine in a variety of paradigms. The combined receptor actions coupled with its intermediate intrinsic efficacy have led to the characterization of aripiprazole as a new class of agent, a dopamine-serotonin stabilizer. We hypothesize that aripiprazole may be effective against cocaine use by direct blockade of its acute effects and through restoration of neural homeostasis of systems dysregulated by chronic cocaine use. Aripiprazole may also have therapeutic efficacy against cigarette smoking. Clinical studies suggest that D2 receptor activity can modify smoking behavior in normal smokers. Moreover, studies in schizophrenics who smoke suggest that atypical antipsychotic agents may significantly reduce cigarette smoking in comparison to baseline rates when patients are maintained on traditional antipsychotics. Together, these intriguing data suggest that atypical antipsychotic medications, with their combined dopamine and serotonin activities, may be a useful strategy for reducing cigarette smoking. The present inpatient study, whose principal aim is to evaluate the efficacy of aripiprazole against cocaine, provides a unique opportunity to explore the effects on smoking as a secondary aim. The primary aims of this project are to: 1) evaluate the safety and tolerability of aripiprazole over a range of doses in individuals who are cocaine and tobacco dependent, 2) evaluate the ability of aripiprazole to attenuate the positive subjective effects of cocaine related to its abuse liability in comparison to placebo, and 3) evaluate directly the efficacy of aripiprazole to reduce the reinforcing efficacy of cocaine by employing validated laboratory procedures of cocaine self-administration. The secondary aims of this project are to: 1) evaluate the efficacy of aripiprazole over a range of doses to reduce cigarette smoking using controlled laboratory methodology of smoking topography, and 2) evaluate the effect of aripiprazole on ad lib smoking in a controlled inpatient laboratory environment. This project will enroll healthy, cocaine-dependent volunteers who are cigarette smokers. They will reside as inpatients under careful medication supervision for the study duration. The study will employ a double-blind, randomized, parallel group, multi-dose design to explore the effect of aripiprazole on cocaine and cigarette smoking outcomes. The methods planned for use have been developed and successfully employed in our laboratory. We hypothesize that aripiprazole treatment will significantly reduce the positive subjective response to cocaine and will significantly reduce cocaine self-administration in comparison to placebo. We also hypothesize that significant reductions in smoking behavior will occur in response to aripiprazole treatment in comparison to placebo. This project will provide important new information on the relative safety and efficacy of aripiprazole for the treatment of cocaine dependence and tobacco dependence, while producing the requisite safety interaction data needed for the launch of an outpatient clinical trial to evaluate aripiprazole in outpatient cocaine dependent individuals.