Zhang L, Weiner J L, Carlen P L
Toronto Hospital Research Institute, Department of Physiology, University of Toronto, Ontario, Canada.
J Pharmacol Exp Ther. 1993 Sep;266(3):1227-35.
Previous studies have demonstrated age-dependent changes in the expression of gamma-aminobutyric acid type A (GABAA) benzodiazepine receptor binding sites and mRNAs encoding GABAA receptor subunits during postnatal development. However, little is known about the pharmacology of GABAA-mediated synaptic events in immature brain neurons. The effects of pentobarbital and diazepam were examined on the GABAA-mediated inhibitory postsynaptic current (IPSC) in postnatal 2- to 8-day-old (PN 2-8) and 18- to 30-day-old (PN 18-30) hippocampal CA1 neurons, using whole-cell recordings in brain slices. In both age groups of immature neurons recorded with an internal solution containing 2 mM ATP, application of diazepam at a concentration as low as 10 nM consistently potentiated the IPSC and Cl- currents evoked by local ejection of GABA (GABA currents). Pretreatment with the benzodiazepine antagonist, flumazenil, blocked the diazepam-induced potentiation of the IPSC, which suggested a direct action of diazepam on the GABAA/benzodiazepine receptor complex. With a patch pipette solution containing no added ATP, similar application of diazepam caused consistent potentiation of the IPSC in PN 18-30 neurons but not in PN 2-8 neurons. In contrast, pentobarbital potentiated the IPSCs with or without internally applied ATP in the neurons of both age groups. The authors suggest that functional GABAA/benzodiazepine receptors are expressed in neonatal CA1 hippocampal neurons. However, their sensitivity to benzodiazepines is altered by intracellular ATP.
先前的研究表明，在出生后发育过程中，γ-氨基丁酸A型（GABAA）苯二氮䓬受体结合位点的表达以及编码GABAA受体亚基的mRNA存在年龄依赖性变化。然而，对于未成熟脑神经元中GABAA介导的突触事件的药理学知之甚少。本研究使用脑片全细胞记录技术，检测了戊巴比妥和地西泮对出生后2至8日龄（PN 2 - 8）和18至30日龄（PN 18 - 30）海马CA1神经元中GABAA介导的抑制性突触后电流（IPSC）的影响。在两组未成熟神经元中，当细胞内液含有2 mM ATP时，低至10 nM浓度的地西泮持续增强IPSC以及由局部喷射GABA诱发的Cl-电流（GABA电流）。用苯二氮䓬拮抗剂氟马西尼预处理可阻断地西泮诱导的IPSC增强，这表明地西泮对GABAA/苯二氮䓬受体复合物有直接作用。当膜片钳微管溶液中不添加ATP时，类似地西泮的应用使PN 18 - 30神经元中的IPSC持续增强，但对PN 2 - 8神经元无效。相反，戊巴比妥在两组神经元中，无论细胞内是否应用ATP，均能增强IPSC。作者认为，功能性GABAA/苯二氮䓬受体在新生海马CA1神经元中表达。然而，它们对苯二氮䓬的敏感性受细胞内ATP的影响。
