GABA(A) RECEPTOR-MEDIATED INHIBITION OF N-METHYL-D-ASPARTATE-EVOKED [H-3] DOPAMINE RELEASE FROM MESENCEPHALIC CELL-CULTURES

Direct activations of both GABA(A) and GABA(B) receptors are known to hyperpolarize dopaminergic neurons. However systemic or intra-ventral tegmental administration of a GABA(A) receptor agonist produces parado xical depolarization of mesencephalic dopaminergic neurons and increas es dopamine release. Thus indirect excitation appears to preclude obse rvation of inhibitory GABA(A) effects on dopamine release in intact ti ssue. The present study used cultures of isolated cells from rat ventr al mesencephalon to characterize effects of GABA(A) and GABA(B) recept or activation on evoked dopamine release. The GABA(A) receptor agonist , muscimol, produced a potent and complete inhibition of N-methyl-D-as partate (NMDA)-evoked [H-3]dopamine release. This effect was blocked b y the GABA(A) receptor antagonist, picrotoxin, and enhanced by flunitr azepam. Omission of Mg2+ greatly reduced the inhibitory effect of musc imol on NMDA-evoked [H-3]dopamine release. Muscimol had little or no e ffect on [H-3]dopamine release evoked by the non-NMDA receptor agonist s, quisqualate and kainate. The GABA(B) receptor agonist, baclofen, sl ightly inhibited NMDA-evoked [H-3]dopamine release and had no effect o n release evoked by quisqualate or kainate. Endogenous GABA released b y the mesencephalic cells also appeared to inhibit NMDA-evoked [H-3]do pamine release mainly via a GABA(A) receptor-mediated mechanism. This is suggested by the observations that NMDA-evoked [H-3]dopamine releas e was potentiated by picrotoxin but not by the GABA(B) receptor antago nist, phaclofen, and that blockade of extracellular GABA removal, with amino-oxyacetic acid and beta-alanine, inhibited NMDA-evoked [H-3]dop amine release in a picrotoxin-sensitive manner. In conclusion, use of isolated mesencephalic cells in culture allows the demonstration of in hibitory effects of GABA(A) receptor activation on evoked dopamine rel ease and reveals a selective GABA(A)-NMDA interaction modulating dopam ine release. The data further suggest that hyperpolarization of dopami nergic neurons by a GABA(A) receptor agonist may promote Mg2+ blockade of NMDA-evoked dopamine release; this mechanism could account for the selectivity of the interaction of GABA(A) receptors with NMDA versus other excitatory amino acid responses.