CHARACTERIZATION OF NICOTINE RECEPTORS

尽管尼古丁在中枢产生不同的药理作用 神经系统，对尼古丁的亚型知之甚少 负责调节尼古丁不同行为的受体。 这项提议的主要目标是了解神经元的功能。 烟碱受体和确定各种烟碱受体的作用 尼古丁在中枢神经系统中药理作用的亚基 体内和体外方法。我们建议继续我们的架构- 活动关系研究提供了耐人寻味的结果和 扩展我们当前的类比系列，并继续进行几个新的 首创精神。类似物将在几个活体中进行评估 (小鼠的抗伤害性和运动能力低下以及大鼠的药物辨别) 和体外(3(H)-尼古丁和125I-α-BGTX结合)检测 尼古丁样效应。有趣的类比将在青蛙身上进行评估 表达不同烟碱受体亚基的卵母细胞在 体内和体外的研究结果。这种方法应该为我们提供新的 具有更高选择性和独特轮廓的化合物将用于 区分受体亚型负责调节不同的 尼古丁的作用。我们计划测试脊髓型尼古丁 受体与神经节和脑中的受体不同，通过研究 鞘内烟碱受体激活(I.T.)和静脉注射。 行政管理。此外，我们还将确定以下措施的有效性 选择性尼古丁拮抗剂在I.T.后阻断这些激动剂。和 I.C.V.行政管理。此外，我们将确定一些 两者在体外脱敏和耐受机制的研究 在活体内接近。体外受体的比较 脱敏和体内观察到的“脱敏”过程将是 已执行。脱敏的速度和程度与 不同烟碱激动剂对神经元型烟碱型乙酰胆碱受体的影响 非洲爪哇卵母细胞中表达的亚基组合将被比较 不同烟碱在体内的脱敏作用 在动物身上使用的激动剂。最后，我们将调查 烟碱受体的内在活性在生产中的重要性 慢性输注几种药物对抗伤害作用的耐受性 对[(3)H]-尼古丁具有广谱亲和力的尼古丁激动剂 结合部位。这些研究将有助于理解 神经元型烟碱受体与多种烟碱作用的确立 尼古丁药理作用中的受体亚基。

Although nicotine produces diverse pharmacological effects in the central nervous system, relatively little is known regarding subtypes of nicotinic receptors responsible for mediating the different actions of nicotine. The broad goal of this proposal is to understand the function of neuronal nicotinic receptors and establish the role of various nicotinic receptors subunits in the pharmacological effects of nicotine in the CNS using both in vivo and in vitro approaches. We propose to continue our structure- activity relationship studies which are providing intriguing results and expand our current series of analogs as well as proceed with several new initiatives. Analogs will be evaluated in several in vivo (antinociception and hypomotility in mice and drug discrimination in rats) and in vitro (3(H)-nicotine and 125I-alpha-BGTX binding) assays for nicotine-like effects. Interesting analogs will be evaluated in frog oocytes expressing different nicotinic receptor subunits to corroborate in vivo and in vitro findings. This approach should provide us with novel compounds with greater selectivity and unique profiles to be used for distinguishing receptor subtypes responsible for mediating the different actions of nicotine. We plan to test the hypothesis that spinal nicotinic receptors differ from those in ganglia and brain by studying the SAR for nicotinic receptor activation after intrathecal (i.t.) and i.c.v. administration. In addition, we will determine the effectiveness of selective nicotinic antagonists to block these agonists after i.t. and i.c.v. administration. Furthermore, we will determine some of the mechanisms underlying desensitization and tolerance using both in vitro and in vivo approaches. A comparison between in vitro receptor desensitization and the 'desensitization' process observed in vivo will be performed. The rate and extent of desensitization associated with different nicotinic agonists on neuronal nicotinic acetylcholine receptor subunit combinations expressed in Xenopus laevis oocytes will be compared with the in vivo "desensitization" obtained with different nicotinic agonists administered in animals. Finally, we will investigate the importance of intrinsic activity of nicotinic receptors in producing tolerance to the antinociceptive effect after chronic infusion of several nicotinic agonists with a wide spectrum of affinity for [(3)H]-nicotine binding sites. These studies will help to understand the function of neuronal nicotinic receptors and establish the role of various nicotinic receptors subunits in the pharmacological effects of nicotine.