Project 3: Assessment of the effects of GABA{B} receptor compounds in animal models of nicotine dependence. Preclinical work conducted during the previous funding period suggests that activation of GABA{B} receptors may be a useful therapeutic strategy for nicotine dependence, with positive modulators exhibiting a better side-effect profile than agonists. Specifically, in rats GABA{B} agonists or positive modulators decreased: i) conditioned and unconditioned reinforcing effects of nicotine that contribute to nicotine dependence;ii) nicotine-induced molecular effects in the nucleus accumbens;iii) the reward enhancing effects of nicotine hypothesized to also contribute to nicotine dependence;and iv) cue-induced increases in nicotine-seeking with putative relevance to relapse in humans. The improved side-effect profile of GABA{B} positive modulators compared to agonists is suggested by the fact that modulators were more likely than agonists to block nicotine-induced behaviors at doses that did not alter responding for food. Thus, our data provide preclinical proof of concept for GABA{B} positive modulators as treatments for nicotine dependence. The main aim of Project 3 is to continue to provide in vivo behavioral characterization of GABA{B} compounds already available to us, and compounds generated by Project 1 and characterized in Project 2 for their GABA{B} properties and selectivity, and their metabolic and pharmacokinetic properties. Specifically, the Specific Aims of Project 3 will be the assessment of the effects of GABA{B} compounds on the: (1) reinforcing and motivational effects of intravenously self-administering nicotine, using fixed- and progressive-ratio schedules of reinforcement;(2) reward enhancing effects of nicotine assessed in the intracranial self-stimulation procedure;(3) cue-induced reinstatement of nicotine-seeking;and (4) increased reactivity to an anxiogenic situation during early nicotine withdrawal. Behavioral results will provide feedback to Projects 1 and 2, and inform future chemistry efforts. Complementary experiments will compare the effects of compounds that have positive effects on nicotine-related behaviors with their effects on food motivated behaviors, providing an important "side-effect"-related aspect of drug screening for potential anti-addiction medications. In summary. Project 3 will provide the behavioral preclinical characterization of novel GABA{B} receptor compounds as treatments for nicotine dependence in well validated behavioral rat models.

Public Health Relevance

Tobacco smoking, attributed to the addictive properties of nicotine, is a worldwide health problem. This project will assess in well validated rat models of nicotine dependence the putative therapeutic efficacy of newly synthesized GABA{B} receptor compounds. Preclinical proof of concept in these animal models may lead to the clinical development of compounds for the therapeutic indication of nicotine dependence.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZMH1-ERB-C)
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University of California San Diego
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