Institute for Behavioral Genetics, 447UCB, University of Colorado, Boulder, CO 80309, USA.
Biochem Pharmacol. 2010 Oct 15;80(8):1238-51. doi: 10.1016/j.bcp.2010.06.040. Epub 2010 Jun 30.
The nicotinic acetylcholine receptors (nAChR) assembled from alpha4 and beta2 subunits are the most densely expressed subtype in the brain. Concentration-effect curves for agonist activation of alpha4beta2*-nAChR are biphasic. This biphasic agonist sensitivity is ascribed to differences in subunit stoichiometry. The studies described here evaluated desensitization elicited by low concentrations of epibatidine, nicotine, cytisine or methylcarbachol of brain alpha4beta2-nAChR function measured with acetylcholine-stimulated (86)Rb(+) efflux from mouse thalamic synaptosomes. Each agonist elicited concentration-dependent desensitization. The agonists differed in potency. However, IC(50) values for each agonist for desensitization of (86)Rb(+) efflux both with high (EC(50) approximately 3 microM) and low (EC(50) approximately 150 microM) acetylcholine sensitivity were not significantly different. Concentrations required to elicit desensitization were higher that their respective K(D) values for receptor binding. Even though the two components of alpha4beta2*-nAChR-mediated (86)Rb(+) efflux from mouse brain differ markedly in EC(50) values for agonist activation, they are equally sensitive to desensitization by exposure to low agonist concentrations. Mice were also chronically treated with nicotine by continuous infusion of 0, 0.5 or 4.0mg/kg/h and desensitization induced by nicotine was evaluated. Consistent with previous results, chronic nicotine treatment increased the density of epibatidine binding sites. Acute exposure to nicotine also elicited concentration-dependent desensitization of both high-sensitivity and low-sensitivity acetylcholine-stimulated (86)Rb(+) efflux from cortical and thalamic synaptosomes. Although chronic nicotine treatment reduced maximal (86)Rb(+) efflux from thalamus, IC(50) values in both brain regions were unaffected by chronic nicotine treatment.
烟碱型乙酰胆碱受体（nAChR）由α4 和β2 亚基组成，是大脑中表达最密集的亚型。激动剂激活α4β2*-nAChR 的浓度-效应曲线呈双相。这种双相激动剂敏感性归因于亚基组成的差异。本文研究了用乙酰胆碱刺激（86）Rb（+）从小鼠丘脑突触小体中流出来测量脑α4β2-nAChR 功能时，低浓度烟碱、尼古丁、烟碱和甲基卡巴胆碱引起的脱敏作用。每种激动剂都引起浓度依赖性脱敏。激动剂的效力不同。然而，每种激动剂对（86）Rb（+）流出的脱敏作用的 IC（50）值，无论是对高（EC（50）约 3 μM）还是低（EC（50）约 150 μM）乙酰胆碱敏感性，都没有显著差异。引起脱敏作用的浓度高于其各自受体结合的 K（D）值。尽管脑内α4β2*-nAChR 介导的（86）Rb（+）流出的两个组成部分在激动剂激活的 EC（50）值上有显著差异，但它们对低浓度激动剂暴露引起的脱敏作用同样敏感。小鼠还通过持续输注 0、0.5 或 4.0mg/kg/h 进行慢性尼古丁处理，并评估尼古丁引起的脱敏作用。与以前的结果一致，慢性尼古丁处理增加了烟碱结合位点的密度。急性暴露于尼古丁也引起了皮质和丘脑突触小体中高敏感性和低敏感性乙酰胆碱刺激（86）Rb（+）流出的浓度依赖性脱敏作用。尽管慢性尼古丁处理降低了丘脑的最大（86）Rb（+）流出量，但两个脑区的 IC（50）值均不受慢性尼古丁处理的影响。
