Schmid G, Bonanno G, Raiteri M
Istituto di Farmacologia e Farmacognosia, Genova, Italy.
Neuroscience. 1996 Aug;73(3):697-704. doi: 10.1016/0306-4522(96)00085-1.
Studies of molecular cloning predict great heterogeneity for the GABAA receptor; however, evidence for functionally and pharmacologically distinct native GABAA receptors is relatively scarce. In this work we have compared some of the functional and pharmacological properties of two GABAA receptors previously shown to be present in the adult rat central nervous system. In superfused hippocampal synaptosomes activation of GABAA receptors increased the basal release of [3H]noradrenaline (EC50 for GABA = 3.2 microM). In contrast, the overflow evoked by depolarization with high-K+ (12 or 35 mM) was not affected. Conversely, GABAA receptor activation led to potentiation of the K(+)-evoked overflow of [3H]D-aspartate from cerebellar synaptosomes (EC50 for GABA = 1.3 microM) whereas the basal release remained unchanged. GABA and muscimol also potentiated the K(+)-evoked overflow of endogenous glutamate in cerebellum. Diazepam enhanced the GABA (3 microM)-evoked [3H]noradrenaline release (EC50 = 65 nM). The diazepam potentiation of the GABA- or muscimol-evoked release of [3H]noradrenaline was inversely related to the agonist concentration. The effect of diazepam was reversed by the benzodiazepine antagonist flumazenil. Zolpidem mimicked diazepam (EC50 = 14 nM). The increase of the K(+)-evoked overflow of [3H]D-aspartate (or of endogenous glutamate) elicited by GABA or muscimol in cerebellar synaptosomes was not affected by benzodiazepines (diazepam or clonazepam) or by zolpidem. On the other hand, Ro 15-4513, an inverse agonist at the benzodiazepine site, strongly inhibited (EC50 = 7 nM) the enhancement by GABA (3 microM) of the K(+)-evoked [3H]D-aspartate overflow in cerebellar synaptosomes; the effect of Ro 15-4513 was reversed by flumazenil. These results suggest the existence in the central nervous system of the adult rat of two native pharmacological-subtypes of the GABAA receptor having different function, regional distribution and neuronal location; the receptors require different membrane potential to be activated and display different sensitivity to benzodiazepines and to drugs acting at benzodiazepine sites.
分子克隆研究预测γ-氨基丁酸A型（GABAA）受体具有高度异质性；然而，功能和药理学特性不同的天然GABAA受体的证据相对较少。在本研究中，我们比较了先前已证实在成年大鼠中枢神经系统中存在的两种GABAA受体的一些功能和药理学特性。在灌流的海马突触体中，GABAA受体的激活增加了[3H]去甲肾上腺素的基础释放（GABA的半数有效浓度[EC50] = 3.2微摩尔/升）。相比之下，高钾（12或35毫摩尔/升）去极化引起的递质溢出不受影响。相反，GABAA受体激活导致小脑突触体中钾离子诱发的[3H]D-天冬氨酸递质溢出增强（GABA的EC50 = 1.3微摩尔/升），而基础释放保持不变。GABA和蝇蕈醇也增强了小脑中钾离子诱发的内源性谷氨酸递质溢出。地西泮增强了GABA（3微摩尔/升）诱发的[3H]去甲肾上腺素释放（EC50 = 65纳摩尔/升）。地西泮对GABA或蝇蕈醇诱发的[3H]去甲肾上腺素释放的增强作用与激动剂浓度呈负相关。地西泮的作用被苯二氮䓬拮抗剂氟马西尼逆转。唑吡坦模拟了地西泮的作用（EC50 = 14纳摩尔/升）。GABA或蝇蕈醇在小脑突触体中引起的钾离子诱发的[3H]D-天冬氨酸（或内源性谷氨酸）递质溢出增加不受苯二氮䓬类药物（地西泮或氯硝西泮）或唑吡坦的影响。另一方面，苯二氮䓬位点的反向激动剂Ro 15 - 4513强烈抑制（EC50 = 7纳摩尔/升）GABA（3微摩尔/升）对小脑突触体中钾离子诱发的[3H]D-天冬氨酸递质溢出的增强作用；Ro 15 - 4513的作用被氟马西尼逆转。这些结果表明，成年大鼠中枢神经系统中存在两种天然药理学亚型的GABAA受体，它们具有不同的功能、区域分布和神经元定位；这些受体需要不同的膜电位来激活，并对苯二氮䓬类药物和作用于苯二氮䓬位点的药物表现出不同的敏感性。
