FUNCTIONAL ACTIVITY OF PRESYNAPTIC NICOTINIC RECEPTORS

突触前烟碱受体的功能活性

• 批准号: 2430023
• 负责人: PETER P ROWELL
• 金额: $ 8.61万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-29 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2430023
• 关键词: behavioral habituation /sensitization; dopamine; dosage; drug tolerance; laboratory rat; neuropharmacologic agent; neurotransmitter transport; nicotine; nicotinic receptors; radiotracer; receptor binding; receptor sensitivity; reinforcer; synaptosomes

The reinforcing properties of nicotine are thought to arise from the ability of the drug to stimulate the release of neurotransmitters from nerve endings of the brain. With prolonged exposure, nicotinic receptors become desensitized with a concomitant loss of functional activity. Long- term desensitization has been suggested as the mechanism responsible for the increase in brain nicotinic receptor density seen in animals administered nicotine and in human cigarette smokers. Interestingly, animals studies have indicated that nicotinic receptor upregulation occurs most effectively when stimulating concentrations of nicotine are achieved, even if only periodical, rather than by low-dose constant infusion. Since the steady-state brain levels of nicotine achieved with low-dose nicotine infusion are sufficient to maintain nicotinic receptors in a constant state of desensitization, this indicates that long-term desensitization may not fully account for receptor upregulation. Studies in our lab and others have indicated that high-level nicotine exposure can produce a long-lasting decreased in receptor function which has been termed receptor inactivation. It is possible that this inactivation process, rather than constant desensitization, is responsible for the increase in central nicotinic receptors seen with chronic nicotine administration. Also, several studies have shown that, although there is an increased number of receptors, there is a decrease in receptor-mediated functional activity, again indicating some form of receptor inactivation may occur. This proposal is designed to characterize the processes of receptor stimulation, desensitization, inactivation and upregulation produced by nicotine and several other potent nicotinic agents using a combination of in vitro superfusion, receptor binding, and in vivo drug administration studies. In addition, correlations between the potency and efficacy of these agents to produce the various activities may provide an indication of the functional consequences of these processes. The results of this study will expand our knowledge of the complex relationship between the concentration, duration and frequency of nicotinic drug exposure and the processes of receptor stimulation, desensitization, inactivation and upregulation. The importance of nicotine as a dependent drug, the current wide-spread use of transdermal nicotine, and the potential possibilities for nicotinic agonists as therapeutic agents in patients with cholinergic deficit all indicate that an understanding of these processes is important.

尼古丁的增强作用被认为源于 药物刺激神经递质释放的能力 大脑的神经末梢。随着时间的延长，尼古丁受体 变得不敏感，并伴随着功能活动的丧失。长- 术语脱敏被认为是导致 动物大脑尼古丁受体密度的增加 服用尼古丁和人类吸烟者。有趣的是， 动物研究表明，尼古丁受体表达上调。 当刺激尼古丁浓度达到最有效时， 即使只是定期输液，也不能通过低剂量的持续输液。自.以来 低剂量尼古丁对大脑稳态尼古丁水平的影响 输液足以使尼古丁受体保持恒定 脱敏状态，这表明长期脱敏 可能不能完全解释受体上调的原因。 我们实验室和其他实验室的研究表明，高水平的尼古丁 暴露会导致受体功能的长期下降， 已被称为受体失活。这是有可能的 负责的是失活过程，而不是持续的脱敏 慢性尼古丁引起的中枢尼古丁受体的增加 行政管理。此外，多项研究表明，尽管有 受体数量增加，受体介导的数量减少 功能活性，再次表明某种形式的受体失活 可能会发生。 这一建议是为了描述受体的过程。 产生的刺激、脱敏、失活和上调 尼古丁和其他几种有效的尼古丁制剂使用 体外灌流、受体结合和体内给药 学习。此外，药效和药效之间的相关性 这些试剂产生的各种活动可能会提供一个适应症 这些过程的功能后果。这样做的结果 研究将扩大我们对两国之间复杂关系的认识 尼古丁药物暴露的浓度、持续时间和频率以及 受体的刺激、脱敏、失活和 上调。尼古丁作为一种依赖药物的重要性，目前 尼古丁透皮吸收的广泛使用及其潜在的可能性 烟碱能激动剂作为胆碱能患者的治疗药物 所有这些缺陷都表明，对这些过程的理解是 很重要。