Nicotinic Receptor Desensitization to Reduce Drug Self-Administration

尼古丁的摄入是烟草成瘾的主要机制。对烟瘾的适当治疗仍然存在问题。设计有效治疗方法的部分问题在于对尼古丁成瘾的药理学方面的理解不足。除了激活尼古丁乙酰胆碱受体外，尼古丁还会引起明显的受体脱敏。目前还不清楚尼古丁在受体水平上的两种作用——刺激和脱敏——对其特定的行为影响有多大，包括强化和成瘾。沙替丁- a是一种新型化合物，提供有效的脱敏a4B2烟碱受体。我们的初步研究显示了沙替丁- a的前景。我们已经证明，无论是急性还是慢性给药，沙替丁-a都能显著减少尼古丁的自我给药。拟议的神经行为学研究将扩大沙替丁-a的特性，确定在减少长期尼古丁自我给药方面达到最大功效的剂量和时间效应函数，以及看到副作用的剂量。性别差异的反应将在研究的所有阶段确定。沙替丁-a在尼古丁启动、条件提示和压力挑战下减少尼古丁自我给药复发的疗效将被确定。新开发的沙替丁类尼古丁脱敏剂化合物将被筛选用于阻断尼古丁诱导的运动亢进致敏。在这个筛选中有效的化合物和剂量将被测试在显著减少尼古丁自我给药和帮助防止复发方面的功效。本研究的预期有益结果是确定使用尼古丁脱敏剂减少对烟草依赖和促进戒烟的最有效方法。

Nicotine intake constitutes a principal mechanism for tobacco addiction. Adequate treatment of smoking addiction remains problematic. Part of the problem with devising effective treatment is a poor understanding of the pharmacologic aspects of nicotine that underlie addiction. In addition to activating nicotinic acetylcholine receptors, nicotine also causes pronounced receptor desensitization. It is not currently known how much of each of nicotine's two actions at the receptor level - stimulation vs. desensitization, contribute to its particular behavioral effects, including reinforcement and addiction. Sazetidine-A is a novel compound that provides potent desensitization of a4B2 nicotinic receptors. Our preliminary studies have shown the promise of sazetidine-A. We have shown that Sazetidine-A significantly reduces nicotine self-administration both with acute and chronic administration. The proposed neurobehavioral studies will broaden the sazetidine-A characterization, determining the dose and time-effect function at which the maximum efficacy in reducing extended access nicotine self-administration is reached and the doses at which side effects are seen. Sex-differences in response will be determined in all phases of the study. Sazetidine-A efficacy in reducing relapse to nicotine self-administration with challenges of nicotine priming, conditioned cues and stress will be determined. Newly developed compounds in the Sazetidine class of nicotinic desensitizing agents will be screened for blockade of nicotine-induced sensitization of locomotor hyperactivity. Those compounds and doses effective in this screen will be tested for efficacy in significantly reducing nicotine self-administration and helping to prevent relapse. The intended beneficial outcome of this research is to determine the most effective way to use nicotinic desensitizing agents to reduce dependence on tobacco and facilitate cessation.