Nicotinic Receptor Desensitization to Reduce Drug Self-Administration

烟碱受体脱敏以减少药物自我给药

• 批准号: 8124477
• 负责人: EDWARD D LEVIN
• 金额: $ 14.2万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124477
• 关键词: Acute; Adverse effects; Affect; Alcohols; Americas; Animal Model; Animals; Attenuated; Behavioral; Characteristics; Chronic; Cocaine; Cues; Dependence; Desire for food; Dose; Drug Addiction; Effectiveness; Food; Goals; Health Care Costs; Hyperactive behavior; Intake; Motor Activity; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nociception; Outcomes Research; Pharmaceutical Preparations; Phase; Psychological reinforcement; Public Health; Regulation; Relapse; Self Administration; Self-Administered; Sex Characteristics; Smoking; Stress; Temperature; Testing; Time; Tobacco; Tobacco Dependence; Tobacco use; Withdrawal; addiction; cognitive function; desensitization; drug of abuse; effective therapy; efficacy testing; neurobehavioral; novel; prevent; prototype; receptor; response; sex; smoking cessation

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.

尼古丁的摄入构成了烟草成瘾的主要机制。烟瘾的充分治疗仍然存在问题。设计有效治疗方法的部分问题是对导致成瘾的尼古丁药理学方面了解甚少。除了激活烟碱乙酰胆碱受体外，尼古丁还会导致明显的受体脱敏。目前尚不清楚尼古丁在受体水平上的两种作用（刺激与脱敏）对其特定行为效应（包括强化和成瘾）的贡献有多大。 Sazetidine-A 是一种新型化合物，可为 a4B2 烟碱受体提供有效的脱敏作用。我们的初步研究显示了 sazetidine-A 的前景。我们已经证明，Sazetidine-A 在急性和慢性给药时都能显着减少尼古丁的自我给药。拟议的神经行为研究将扩大 sazetidine-A 的表征，确定达到减少长期尼古丁自我给药的最大功效的剂量和时间效应函数，以及出现副作用的剂量。反应的性别差异将在研究的所有阶段进行确定。将确定 Sazetidine-A 在减少尼古丁自我给药复发以及尼古丁启动、条件暗示和压力挑战方面的功效。将筛选新开发的 Sazetidine 类烟碱脱敏剂化合物，以阻断尼古丁诱导的运动亢进过敏。将测试在该筛选中有效的那些化合物和剂量在显着减少尼古丁自我施用和帮助预防复发方面的功效。这项研究的预期有益结果是确定使用烟碱脱敏剂来减少对烟草的依赖并促进戒烟的最有效方法。