Chaudieu I, St-Pierre J A, Quirion R, Boksa P
Douglas Hospital Research Centre, Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
Eur J Pharmacol. 1994 Nov 3;264(3):361-9. doi: 10.1016/0014-2999(94)00492-7.
Direct activations of both GABAA and GABAB receptors are known to hyperpolarize dopaminergic neurons. However systemic or intra-ventral tegmental administration of a GABAA receptor agonist produces paradoxical depolarization of mesencephalic dopaminergic neurons and increases dopamine release. Thus indirect excitation appears to preclude observation of inhibitory GABAA effects on dopamine release in intact tissue. The present study used cultures of isolated cells from rat ventral mesencephalon to characterize effects of GABAA and GABAB receptor activation on evoked dopamine release. The GABAA receptor agonist, muscimol, produced a potent and complete inhibition of N-methyl-D-aspartate (NMDA)-evoked [3H]dopamine release. This effect was blocked by the GABAA receptor antagonist, picrotoxin, and enhanced by flunitrazepam. Omission of Mg2+ greatly reduced the inhibitory effect of muscimol on NMDA-evoked [3H]dopamine release. Muscimol had little or no effect on [3H]dopamine release evoked by the non-NMDA receptor agonists, quisqualate and kainate. The GABAB receptor agonist, baclofen, slightly inhibited NMDA-evoked [3H]dopamine release and had no effect on release evoked by quisqualate or kainate. Endogenous GABA released by the mesencephalic cells also appeared to inhibit NMDA-evoked [3H]dopamine release mainly via a GABAA receptor-mediated mechanism. This is suggested by the observations that NMDA-evoked [3H]dopamine release was potentiated by picrotoxin but not by the GABAB receptor antagonist, phaclofen, and that blockade of extracellular GABA removal, with amino-oxyacetic acid and beta-alanine, inhibited NMDA-evoked [3H]dopamine release in a picrotoxin-sensitive manner.(ABSTRACT TRUNCATED AT 250 WORDS)
已知GABAA和GABAB受体的直接激活会使多巴胺能神经元超极化。然而，全身或腹侧被盖区内给予GABAA受体激动剂会产生中脑多巴胺能神经元的反常去极化，并增加多巴胺释放。因此，间接兴奋似乎排除了在完整组织中观察到GABAA对多巴胺释放的抑制作用。本研究使用大鼠腹侧中脑分离细胞培养物来表征GABAA和GABAB受体激活对诱发的多巴胺释放的影响。GABAA受体激动剂蝇蕈醇对N-甲基-D-天冬氨酸（NMDA）诱发的[3H]多巴胺释放产生了强效且完全的抑制作用。这种作用被GABAA受体拮抗剂印防己毒素阻断，并被氟硝西泮增强。去除Mg2+会大大降低蝇蕈醇对NMDA诱发的[3H]多巴胺释放的抑制作用。蝇蕈醇对非NMDA受体激动剂 quisqualate和 kainate诱发的[3H]多巴胺释放几乎没有影响。GABAB受体激动剂巴氯芬略微抑制了NMDA诱发的[3H]多巴胺释放，对quisqualate或kainate诱发的释放没有影响。中脑细胞释放的内源性GABA似乎也主要通过GABAA受体介导的机制抑制NMDA诱发的[3H]多巴胺释放。这是由以下观察结果表明的：NMDA诱发的[3H]多巴胺释放被印防己毒素增强，但未被GABAB受体拮抗剂巴氯芬增强，并且用氨氧基乙酸和β-丙氨酸阻断细胞外GABA的清除以印防己毒素敏感的方式抑制了NMDA诱发的[3H]多巴胺释放。（摘要截短于250字）
