Cruz S L, Mirshahi T, Thomas B, Balster R L, Woodward J J
Department of Pharmacology and Toxicology, Medical College, Virginia Commonwealth University, Richmond, USA.
J Pharmacol Exp Ther. 1998 Jul;286(1):334-40.
Previous studies have shown that toluene, which is commonly abused, depresses neuronal activity and causes behavioral effects in both animals and man similar to those observed for ethanol. In this study, the oocyte expression system was used to test the hypothesis that toluene, like ethanol, inhibits the function of ionotropic glutamate receptors. Oocytes were injected with mRNA for specific N-methyl-D-aspartate (NMDA) or non-NMDA subunits and currents were recorded using conventional two-electrode voltage clamp. To enhance the low water solubility of toluene, drug solutions were prepared by mixing toluene with alkamuls (ethoxylated castor oil) at a 1:1 ratio (v:v) and diluting this mixture to the appropriate concentration with barium-containing normal frog Ringer solution. Alkamuls, up to 0.1%, had no significant effects on membrane leak currents or on NMDA-induced currents. Toluene, up to approximately 9 mM, had only minor effects on membrane leak currents but dose-dependently inhibited NMDA-mediated currents in oocytes. The inhibition of NMDA receptor currents by toluene was rapid, reversible and the potency for toluene's effects was subunit dependent. The NR1/2B subunit combination was the most sensitive with an IC50 value for toluene-induced inhibition of 0.17 mM. The NR1/2A and NR1/2C receptors were 6- and 12-fold less sensitive with IC50 values of 1.4 and 2.1 mM, respectively. In contrast, toluene up to approximately 9 mM did not inhibit kainate-induced currents in oocytes expressing GluR1, GluR1(+)R2 or GluR6 subunits. These results suggest that some of the effects of toluene on neuronal activity and behavior may be mediated by inhibition of NMDA receptors.
以往的研究表明，常见的滥用药物甲苯会抑制神经元活动，并在动物和人类中产生与乙醇类似的行为效应。在本研究中，利用卵母细胞表达系统来检验甲苯与乙醇一样会抑制离子型谷氨酸受体功能这一假设。向卵母细胞注射特定N-甲基-D-天冬氨酸（NMDA）或非NMDA亚基的信使核糖核酸（mRNA），并使用传统的双电极电压钳记录电流。为提高甲苯的低水溶性，将甲苯与聚氧乙烯蓖麻油（alkamuls）按1:1比例（体积比）混合，并用含钡的正常青蛙任氏液将该混合物稀释至适当浓度来制备药物溶液。浓度高达0.1%的聚氧乙烯蓖麻油对膜漏电流或NMDA诱导的电流无显著影响。浓度高达约9 mM的甲苯对膜漏电流仅有轻微影响，但能剂量依赖性地抑制卵母细胞中NMDA介导的电流。甲苯对NMDA受体电流的抑制作用迅速、可逆，且其效应的效力具有亚基依赖性。NR1/2B亚基组合最为敏感，甲苯诱导抑制的半数抑制浓度（IC5）值为0.17 mM。NR1/2A和NR1/2C受体的敏感性分别低6倍和12倍，IC5值分别为1.4 mM和2.1 mM。相比之下，浓度高达约9 mM的甲苯不会抑制表达GluR1、GluR1(+)R2或GluR6亚基的卵母细胞中由红藻氨酸诱导的电流。这些结果表明，甲苯对神经元活动和行为的某些影响可能是由NMDA受体的抑制介导的。
