Nicotinic Receptor Desensitization to Reduce Drug Self-Administration

尼古丁的摄入构成了烟草成瘾的主要机制。对烟瘾的适当治疗仍然是个问题。设计有效的治疗方法的部分问题是对尼古丁的药理学方面缺乏了解，尼古丁是成瘾的基础。除了激活烟碱型乙酰胆碱受体外，尼古丁还会引起明显的受体脱敏。目前尚不清楚尼古丁在受体水平上的两种作用-刺激和脱敏-在多大程度上对其特定的行为效应做出了贡献，包括强化和成瘾。沙氮替丁-A是一种新型化合物，可有效地脱敏A4B2尼古丁受体。我们的初步研究表明，沙泽替丁-A是有希望的。我们已经证明，沙氮替丁-A在急性和长期给药时都显著减少了尼古丁的自我给药。拟议的神经行为研究将扩大sazetidine-A的特征，确定在减少长期接触尼古丁自我给药方面达到最大效果的剂量和时间-效应函数，以及出现副作用的剂量。性别差异的反应将在研究的所有阶段确定。沙氮替丁-在尼古丁刺激、条件性提示和压力的挑战下，减少尼古丁自我给药复发的有效性将得到确定。将筛选新开发的尼古丁类尼古丁脱敏剂化合物，以阻断尼古丁诱导的运动多动敏化。在这项筛查中有效的化合物和剂量将被测试显著减少尼古丁自我给药和帮助防止复发的有效性。这项研究的预期有益结果是确定使用尼古丁脱敏剂来减少对烟草的依赖并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.