Studies on the role of GABA in Cocaine Addiction

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DESCRIPTION (provided by applicant): The goal of the proposed research is to investigate the role of the major inhibitory neurotransrnitter gammaaminobutyric acid (GABA) in the reinforcing and discriminative stimulus effects of cocaine. Understanding the neurobiological mechanisms underlying the behavioral effects of cocaine are critical for the development of effective medications for cocaine addiction. The primary mechanism involved in the reinforcing effects of cocaine is activation of the mesolimbic dopamine (DA) system. Recent studies have indicated a modulatory role of GABA on mesolimbic DA activity, and drugs that facilitate GABAergic neurotransmission have been shown to alter some of the behavioral effects of cocaine in both humans and laboratory animals. The proposed studies will evaluate the effects of pharmacoiogical modulation of GABA on self-administration, reinstatement and discrimination of low and high doses of cocaine. GABAergic neurotransmission can be altered by a number of different mechanisms (i.e., activation or blockade of GABAA and GABAB receptors, inhibition of GABA transaminase, inhibition of GABA synthesis and inhibition of GABA reuptake); drugs affecting each of these mechanisms will be evaluated using several procedures to provide a comprehensive assessment of GABAergic influence on the behavioral effects of cocaine which may be relevant to addiction. Drug self-administration and reinstatement of drug-seeking in animals provide valid information on drug reinforcement and relapse, respectively. Drug discrimination procedures in animals provide information analogous to assessment of subjective effects in humans, and provide a highly selective behavioral measure which often corresponds with a drug's activity at a specific neurotransmitter system. One aim is to investigate if GABAergic drugs alter the rate and pattern of ongoing cocaine self-administration. A second aim is to explore if GABAergic drugs alter the motivation to take cocaine as measured by the maximum work output under a progressive ratio schedule of cocaine injection. The specificity of any effect on cocaine-taking will be evaluated in parallel studies with a non-drug reinforcer using the same procedures as for self-administration and progressive ratio. A third aim will determine if GABAergic drugs alter the 'priming' effects of cocaine on reinstatement of self-administration (i.e., drug-seeking). A fourth aim is to evaluate if GABAergic drugs alter the discriminative stimulus effects of cocaine. The results of these studies will increase our understanding of the role of GABA in the behavioral effects of cocaine and may lead to the development of better medications for the treatment of cocaine addiction.