Effects of GABA_B receptor compounds in animal models of nicotine dependence

摘要项目3：评估GABA{B}受体化合物在尼古丁依赖动物模型中的作用。 在上一个资助期内进行的临床前工作表明，GABA{B}受体的激活可能是尼古丁依赖的一种有用的治疗策略，阳性调节剂表现出比激动剂更好的副作用。具体来说，在大鼠中，GABA{B}激动剂或正调节剂减少了：i）尼古丁的条件和非条件强化作用，导致尼古丁依赖; ii）尼古丁在伏核中诱导的分子效应; iii）尼古丁的奖励增强作用假设也有助于尼古丁依赖;和iv）线索诱导的尼古丁寻求增加，推测与人类复发相关。与激动剂相比，GABA{B}阳性调节剂的副作用特征得到改善，这是因为在不改变对食物的反应的剂量下，调节剂比激动剂更可能阻断尼古丁诱导的行为。因此，我们的数据为GABA{B}阳性调节剂作为尼古丁依赖的治疗提供了临床前概念证明。 项目3的主要目的是继续提供我们已经获得的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中表征其GABA{B}性质和选择性及其代谢和药代动力学性质的化合物。具体而言，项目3的具体目标是评估GABA{B}化合物对以下方面的影响：（1）使用固定和渐进比例强化方案，静脉内自我给予尼古丁的强化和激励作用;（2）在颅内自我刺激程序中评估尼古丁的奖赏增强作用;（3）线索诱导的尼古丁寻求恢复;和（4）在早期尼古丁戒断期间对焦虑状态的反应性增加。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。补充实验将比较对尼古丁相关行为具有积极影响的化合物的效果与其对食物动机行为的影响，为潜在的抗成瘾药物的药物筛选提供重要的“副作用”相关方面。总之。项目3将提供新型GABA{B}受体化合物在经过充分验证的行为大鼠模型中作为尼古丁依赖治疗的行为临床前表征。

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.