Chebabo S R, Santos M D, Albuquerque E X
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201, USA.
Neurotoxicology. 1999 Dec;20(6):871-82.
In the present study, the whole-cell mode of the patch-clamp technique was applied to neurons of the CA1 pyramidal layer of rat hippocampal slices to investigate the effects of the organophosphate (OP) sarin on field stimulation-evoked and on tetrodotoxin (TTX)-insensitive postsynaptic currents (PSCs) mediated by activation of type A gamma-aminobutyric acid (GABA) receptors or AMPA-type glutamate receptors. At 0.3-1 nM, sarin reduced the amplitude of GABA-mediated PSCs and had no effect on the amplitude of glutamatergic PSCs evoked by field stimulation of neurons synaptically connected to the neuron under study. The effect of sarin on evoked GABAergic PSCs was unrelated to cholinesterase inhibition, was partially reversed upon washing of the neurons with sarin-free external solution, and was mediated by a direct interaction of the OP with muscarinic acetylcholine receptors present on presynaptic GABAergic neurons. Sarin had no effect on the amplitude or kinetics of GABA- or glutamate-mediated miniature postsynaptic currents (MPSCs) recorded in the presence of the Na+-channel blocker TTX (300 nM), indicating that the OP does not interact with GABA(A) or glutamate receptors. Further, sarin did not alter the frequency of GABAergic or glutamatergic MPSCs, a finding that led to the conclusion that this OP does not affect the TTX-insensitive release of neurotransmitters. A selective reduction by sarin of the action potential-dependent release of GABA in the hippocampus can account for the occurrence of seizures in intoxicated subjects.
在本研究中，采用膜片钳技术的全细胞模式，对大鼠海马切片CA1锥体层神经元进行研究，以探讨有机磷酸酯类（OP）沙林对场刺激诱发的以及由A型γ-氨基丁酸（GABA）受体或AMPA型谷氨酸受体激活介导的河豚毒素（TTX）不敏感的突触后电流（PSC）的影响。在0.3 - 1 nM浓度下，沙林降低了GABA介导的PSC幅度，而对通过场刺激与所研究神经元突触连接的神经元诱发的谷氨酸能PSC幅度没有影响。沙林对诱发的GABA能PSC的作用与胆碱酯酶抑制无关，在用无沙林的外部溶液冲洗神经元后部分逆转，并且是由OP与突触前GABA能神经元上存在的毒蕈碱型乙酰胆碱受体直接相互作用介导的。在存在Na⁺通道阻滞剂TTX（300 nM）的情况下记录时，沙林对GABA或谷氨酸介导的微小突触后电流（MPSC）的幅度或动力学没有影响，表明该OP不与GABA(A)或谷氨酸受体相互作用。此外，沙林没有改变GABA能或谷氨酸能MPSC的频率，这一发现得出结论，该OP不影响TTX不敏感的神经递质释放。沙林对海马中依赖动作电位的GABA释放的选择性降低可以解释中毒患者癫痫发作的发生。
