Inhibition of neuronal nicotinic acetylcholine receptors by the abused solvent, toluene
Inhibition of neuronal nicotinic acetylcholine receptors by the abused solvent, toluene
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DOI：
10.1038/sj.bjp.0704874
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发表时间：
2002-10-01
影响因子：
7.3
通讯作者：
Woodward, JJ
中科院分区：
文献类型：
--
作者：
Bale, AS;Smothers, CT;Woodward, JJ
1甲苯是一类工业溶剂的代表性例子，可作为滥用药物自愿吸入。来自该实验室和其他实验室的先前数据表明，甲苯在不影响非NMDA受体的浓度下调节N-甲基-D-天冬氨酸（NMDA）、γ-氨基丁酸（GABA）和甘氨酸受体的功能。2我们利用双电极电压钳和全细胞膜片钳技术评估甲苯对卵母细胞和培养的海马神经元中表达的神经元烟碱乙酰胆碱受体的影响。甲苯（50 μ m至10 mM）产生了可逆的，浓度依赖性抑制乙酰胆碱诱导的电流在非洲爪蟾卵母细胞表达各种烟碱受体亚型。α 4 β 2和α 3 β 2亚基组合对甲苯抑制的敏感性显著高于α 4 β 4、α 3 β 4和α 7受体。3由α 4和β 2（V253 F）亚基组成的受体显示出α 4 β 4样甲苯敏感性，而含有α 4和β 4（F255 V）亚基的受体显示出α 4 β 2样甲苯敏感性。4在海马神经元中，甲苯（50 μ m至10 mM）剂量依赖性抑制乙酰胆碱介导的反应，IC 50为1.1 mM。两者合计，这些结果表明，烟碱受体，如NMDA受体，表现出亚基依赖性的敏感性甲苯，并可能代表一个重要的网站的行动甲苯的一些神经行为的影响。
1 Toluene is a representative example of a class of industrial solvents that are voluntarily inhaled as drugs of abuse. Previous data from this lab and others has shown that toluene modulates the function of N-methyl-D-aspartate (NMDA), gamma-aminobutyric acid (GABA) and glycine receptors at concentrations that do not affect non-NMDA receptors.2 We utilized two-electrode voltage-clamp and whole cell patch-clamp techniques to assess the effects of toluene on neuronal nicotinic acetylcholine receptors expressed in oocytes and cultured hippocampal neurons. Toluene (50 mum to 10 mM) produced a reversible, concentration-dependent inhibition of acetylcholine-induced current in Xenopus oocytes expressing various nicotinic receptor subtypes. The alpha4beta2 and alpha3beta2 subunit combinations were significantly more sensitive to toluene inhibition than the alpha4beta4, alpha3beta4 and alpha7 receptors.3 Receptors composed of alpha4 and beta2(V253F) subunits showed alpha4beta4-like toluene sensitivity while those containing alpha4 and beta4(F255V) subunits showed alpha4beta2-like sensitivity.4 In hippocampal neurons, toluene (50 mum to 10 mM) dose-dependently inhibited ACh-mediated responses with an IC50 of 1.1 mM. Taken together, these results suggest that nicotinic receptors, like NMDA receptors, show a subunit-dependent sensitivity to toluene and may represent an important site of action for some of the neurobehavioural effects of toluene.