Effects of GABA_B receptor compounds in animal models of nicotine dependence

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Abstract 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.