GABAA receptor-mediated inhibition of N-methyl-D-aspartate-evoked [3H]dopamine release from mesencephalic cell cultures.

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)