Del Re Angelo M, Dopico Alejandro M, Woodward John J
Department of Neurosciences and Center for Drug and Alcohol Programs, Medical University of South Carolina, 173 Ashley Avenue, Suite 403, Charleston, 29425, USA.
Brain Res. 2006 May 4;1087(1):75-82. doi: 10.1016/j.brainres.2006.03.031. Epub 2006 Apr 13.
Toluene (methylbenzene) is representative of a class of industrial solvents that are voluntarily inhaled as drugs of abuse. Previous data from this laboratory and others have shown that these compounds alter the function of a variety of ion channels including ligand-gated channels activated by ATP, acetylcholine, GABA, glutamate and serotonin, as well as voltage-dependent sodium and calcium channels. It is less clear what effects toluene may have on potassium channels that act to reduce the excitability of most cells. Previous studies have shown that ethanol potentiates the function of both the large conductance, calcium-activated potassium channel (BK) and specific members of the G-protein-coupled inwardly rectifying potassium channels (GirKs). Since toluene and other abused inhalants share many behavioral effects with ethanol, it was hypothesized that toluene would also enhance the function of these channels. This hypothesis was tested using two-electrode voltage-clamp electrophysiology to measure the activity of BK and GirK potassium channel currents expressed in Xenopus laevis oocytes. As reported previously, ethanol potentiated currents in oocytes expressing either BK or GirK2 channels. In contrast, toluene caused a concentration-dependent inhibition of BK channel currents with 3 mM producing approximately 50% inhibition of control currents. Currents in oocytes injected with GirK2 mRNA were also inhibited by toluene while those expressing GirK1/2 and 1/4 channels were minimally affected. In oocytes co-injected with mRNA for GirK2 and the mGluR1a metabotropic receptor, exposure to glutamate potentiated currents evoked by a high-potassium solution. Toluene inhibited these glutamate-activated currents to approximately the same degree as those induced under basal conditions. The results of these studies show that toluene has effects on BK and GirK channels that are opposite to those of ethanol, suggesting that these channels are unlikely to underlie behaviors that these two drugs of abuse share.
甲苯（甲基苯）是一类被滥用的工业溶剂的代表。本实验室及其他机构先前的数据表明，这些化合物会改变多种离子通道的功能，包括由三磷酸腺苷（ATP）、乙酰胆碱、γ-氨基丁酸（GABA）、谷氨酸和5-羟色胺激活的配体门控通道，以及电压依赖性钠通道和钙通道。目前尚不清楚甲苯对多数细胞起降低兴奋性作用的钾通道会有什么影响。先前的研究表明，乙醇可增强大电导钙激活钾通道（BK）和G蛋白偶联内向整流钾通道（GirK）特定成员的功能。由于甲苯和其他滥用吸入剂与乙醇有许多行为效应相同，因此推测甲苯也会增强这些通道的功能。本研究采用双电极电压钳电生理学方法，测量非洲爪蟾卵母细胞中表达的BK和GirK钾通道电流活性，对这一假说进行了验证。如先前报道，乙醇可增强表达BK或GirK2通道的卵母细胞中的电流。相比之下，甲苯对BK通道电流产生浓度依赖性抑制，3 mM的甲苯可使对照电流产生约50%的抑制。注射GirK2信使核糖核酸（mRNA）的卵母细胞中的电流也受到甲苯抑制，而表达GirK1/2和1/4通道的卵母细胞中的电流受影响极小。在共注射GirK2 mRNA和代谢型谷氨酸受体1a（mGluR1a）的卵母细胞中，暴露于谷氨酸会增强高钾溶液诱发的电流。甲苯对这些谷氨酸激活电流的抑制程度与基础条件下诱导的电流抑制程度大致相同。这些研究结果表明，甲苯对BK和GirK通道的作用与乙醇相反，这表明这些通道不太可能是这两种滥用药物共有行为的基础。
