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 paradoxical depolarization of mesencephalic dopaminergic neurons and increases dopamine release. Thus indirect excitation appears to preclude observation of inhibitory GABA(A) effects on dopamine release in intact tissue. The present study used cultures of isolated cells from rat ventral mesencephalon to characterize effects of GABA(A) and GABA(B) receptor activation on evoked dopamine release. The GABA(A) receptor agonist, muscimol, produced a potent and complete inhibition of N-methyl-D-aspartate (NMDA)-evoked [H-3]dopamine release. This effect was blocked by the GABA(A) receptor antagonist, picrotoxin, and enhanced by flunitrazepam. Omission of Mg2+ greatly reduced the inhibitory effect of muscimol on NMDA-evoked [H-3]dopamine release. Muscimol had little or no effect on [H-3]dopamine release evoked by the non-NMDA receptor agonists, quisqualate and kainate. The GABA(B) receptor agonist, baclofen, slightly inhibited NMDA-evoked [H-3]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 [H-3]dopamine release mainly via a GABA(A) receptor-mediated mechanism. This is suggested by the observations that NMDA-evoked [H-3]dopamine release was potentiated by picrotoxin but not by the GABA(B) receptor antagonist, phaclofen, and that blockade of extracellular GABA removal, with amino-oxyacetic acid and beta-alanine, inhibited NMDA-evoked [H-3]dopamine release in a picrotoxin-sensitive manner. In conclusion, use of isolated mesencephalic cells in culture allows the demonstration of inhibitory effects of GABA(A) receptor activation on evoked dopamine release and reveals a selective GABA(A)-NMDA interaction modulating dopamine release. The data further suggest that hyperpolarization of dopaminergic 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.