Weaver W R, Wolf K M, Chiappinelli V A
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Missouri 63104.
Mol Pharmacol. 1994 Nov;46(5):993-1001.
We have examined an excitatory response mediated by nicotinic acetylcholine receptors located on the somata and/or dendrites of chick lateral spiriform neurons. On the basis of pharmacological and anatomical studies, these receptors belong to a subgroup of nicotinic receptors termed high affinity nicotine receptors, because they exhibit a high affinity for nicotinic agonists but little or no sensitivity to alpha- or kappa-bungarotoxin. We now report physiological evidence that high affinity nicotine receptors in the lateral spiriform nucleus are heterogeneous. Intracellular recording in brain slices was used to examine the pharmacological characteristics of nicotinic responses in individual lateral spiriform neurons. Nicotinic responses to brief applications of carbachol were inhibited by trimethaphan, dihydro-beta-erythroidine, or d-tubocurarine. Trimethaphan was unusual, in that a wide range of concentrations (< or = 50 microM to > 500 microM) were required to block this nicotinic response in different neurons. To quantitate the inhibition observed with trimethaphan and dihydro-beta-erythroidine, dose-response curves were generated in superfusion studies using a wide range of concentrations of both agonist (3-3000 microM carbachol in the presence of 1 microM atropine and 0.25 microM tetrodotoxin) and antagonists (10-500 microM trimethaphan or 0.1-3 microM dihydro-beta-erythroidine). The data yielded an EC50 of 25 +/- 5 microM for carbachol, with a Hill coefficient of 1.4 +/- 0.1 (mean +/- standard error; n = 8). In the case of dihydro-beta-erythroidine, a narrow range of Ki values was obtained (0.09-0.16 microM; n = 5). In contrast, Ki values for trimethaphan varied over a 15-fold concentration range (4-66 microM; n = 17), demonstrating that trimethaphan showed selectivity for different receptor subtypes found in the lateral spiriform nucleus. For both antagonists, the data indicate a competitive mode of inhibition.
我们研究了由位于鸡外侧螺旋神经元胞体和/或树突上的烟碱型乙酰胆碱受体介导的兴奋性反应。基于药理学和解剖学研究，这些受体属于烟碱型受体的一个亚组，称为高亲和力尼古丁受体，因为它们对烟碱型激动剂表现出高亲和力，但对α-或κ-银环蛇毒素几乎没有或没有敏感性。我们现在报告生理学证据，表明外侧螺旋核中的高亲和力尼古丁受体是异质性的。使用脑片内记录来检查单个外侧螺旋神经元中烟碱型反应的药理学特征。对短时间应用卡巴胆碱的烟碱型反应可被三甲噻方、二氢β-刺桐碱或d-筒箭毒碱抑制。三甲噻方不同寻常之处在于，在不同神经元中阻断这种烟碱型反应需要很宽的浓度范围（≤50μM至＞500μM）。为了定量观察到的三甲噻方和二氢β-刺桐碱的抑制作用，在灌流研究中使用了宽范围浓度的激动剂（在1μM阿托品和0.25μM河豚毒素存在下的3 - 3000μM卡巴胆碱）和拮抗剂（10 - 500μM三甲噻方或0.1 - 3μM二氢β-刺桐碱）生成剂量反应曲线。数据得出卡巴胆碱的EC50为25±5μM，希尔系数为1.4±0.1（平均值±标准误差；n = 8）。对于二氢β-刺桐碱，获得了较窄的Ki值范围（0.09 - 0.16μM；n = 5）。相比之下，三甲噻方的Ki值在15倍的浓度范围内变化（4 - 66μM；n = 17），表明三甲噻方对在外侧螺旋核中发现的不同受体亚型具有选择性。对于两种拮抗剂，数据均表明为竞争性抑制模式。
