Cocaine abuse continues to represent a significant public-health concern, and will likely remain a concern for the foreseeable future. Because of the public-health concerns associated with its abuse, identifying an effective pharmacotherapy for the treatment o cocaine abuse has been a priority with the N.I.D.A. for the last decade. Despite the intense efforts of several investigative teams, an effective pharmacotherapy for cocaine abuse has not yet been identified. Cocaine probably exerts its reinforcing effects by increasing synaptic dopamine levels by blocking the dopamine transporter. Gamma-Aminobutyric-acid (GABA) systems inhibit dopamine systems. Increasing GABA activity may result in greater inhibition of dopamine systems and thus attenuate the behavioral effects of cocaine. Preclinical laboratory experiments have demonstrated that GABA agonists attenuate the effects of cocaine under a variety of behavioral arrangements. These findings suggest that GABA systems might be targeted for the development of medications for the treatment of cocaine abuse.
The specific aim of the proposed research is to determine if GABA agonists attenuate the acute reinforcing and subjective effects of intranasally administered cocaine in humans. To accomplish this aim, we will conduct 3 laboratory experiments with volunteers with recent histories of cocaine use. These experiments will determine the acute reinforcing and subjective effects of cocaine following pretreatment with tiagabine (a nipecotic acid derivative), baclofen (a GABA analog), and triazolam (a benzodiazepine) (Experiments 1-3, respectively). The reinforcing effects of cocaine will be assessed with a progressive-ratio schedule similar to those used with nonhuman laboratory animals. Tiagabine is a GABA uptake blocker that increases extracellular GABA levels. Baclofen is a GABA, agonist. Triazolam is an agonist at the GABAA receptor complex that binds non-selectively to BZ, and BZ2 benzodiazepine receptor subtypes. Follow-up experiments will be conducted as needed to determine the effects of the pretreatment agent (i.e., tiagabine, baclofen or triazolam) on responding for a non-drug reinforcer (i.e., money). These studies will provide important information concerning the specificity of the effects of the pretreatment agents. The proposed research will provide important clinical information regarding the potential usefulness of GABA agonists as putative pharmacotherapies for the treatment of cocaine abuse. The proposed research will also provide important basic-science information. First, the inclusion of drug-reinforcement and subjective-effect measures will provide information concerning the relationship between the reinforcing and subjective effects of cocaine. Second, albeit indirectly, the proposed research will determine the extent to which preclinical findings generalize to humans. Finally, the proposed research will allow us to conduct retrospective analyses to determine the influence of individual differences (e.g., gender, other drug use) on the reinforcing and subjective effects of cocaine.
