Effects of GABA_B receptor compounds in animal models of nicotine dependence

项目3：评估GABA受体化合物在尼古丁依赖动物模型中的作用。 在之前的资助期间进行的临床前研究表明，激活GABA{B}受体可能是治疗尼古丁依赖的有用策略，正向调节剂比激动剂表现出更好的副作用。具体地说，在大鼠中，GABA{B}激动剂或正向调节剂减少了：i)尼古丁对尼古丁依赖的条件性和非条件性增强效应；ii)尼古丁诱导的伏隔核分子效应；iii)尼古丁的奖赏增强效应，假设尼古丁也与尼古丁依赖有关；以及iv)线索诱导的尼古丁寻找增加，推测与人类复发有关。与激动剂相比，GABA{B}正向调节剂的副作用有所改善，这是因为调节剂比激动剂更有可能在不改变对食物反应的剂量下阻止尼古丁诱导的行为。因此，我们的数据为GABA{B}正向调节剂作为尼古丁依赖治疗方法的概念提供了临床前证据。项目3的主要目标是继续提供我们已有的GABA{B}化合物的体内行为表征，以及由项目1产生并在项目2中表征的化合物的GABA{B}特性和选择性，以及它们的代谢和药代动力学特性。具体地说，项目3的具体目标将是评估GABA{B}化合物对以下方面的影响：(1)使用固定和递增比率的强化计划静脉注射尼古丁的强化和激励效果；(2)在颅内自我刺激过程中评估尼古丁的奖励增强效果；(3)线索诱导尼古丁寻求的恢复；以及(4)在尼古丁戒断早期对引发焦虑的情况增加的反应性。行为结果将为项目1和2提供反馈，并为未来的化学工作提供信息。补充性实验将比较对尼古丁相关行为有积极影响的化合物的效果与它们对食物动机行为的影响，为潜在的抗成瘾药物提供一个重要的“副作用”相关的药物筛选方面。总而言之。项目3将提供新型GABA{B}受体化合物的临床前行为特征，作为尼古丁依赖的治疗方法，在经过充分验证的行为大鼠模型中。

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.