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The Journal of Neuroscience, May 1, 2000, 20(9):3496-3503

Synergistically Interacting Dopamine D1 and NMDA Receptors Mediate Nonvesicular Transporter-Dependent GABA Release from Rat Striatal Medium Spiny Neurons

Anton N. M. Schoffelmeer, Louk J. M. J. Vanderschuren, Taco J. De Vries, Francois Hogenboom, George Wardeh, and Arie H. Mulder

Research Institute Neurosciences Vrije Universiteit, Department of Pharmacology, Free University, Medical Faculty, 1081 BT Amsterdam, The Netherlands

Given the complex interactions between dopamine D1 and glutamate NMDA receptors in the striatum, we investigated the role of these receptors in transporter-mediated GABA release from cultured medium spiny neurons of rat striatum. Like NMDA receptor-mediated [³H]-GABA release, that induced by prolonged (20 min) dopamine D1 receptor activation was enhanced on omission of external calcium, was action potential-independent (tetrodotoxin-insensitive), and was diminished by the GABA transporter blocker nipecotic acid, indicating the involvement of transporter-mediated release. Interestingly, lowering the external sodium concentration only reduced the stimulatory effect of NMDA. Blockade of Na⁺/K⁺-ATPase by ouabain enhanced NMDA-induced but abolished dopamine-induced release. Moreover, dopamine appeared to potentiate the effect of NMDA on [³H]-GABA release. These effects of dopamine were mimicked by forskolin. µ-Opioid receptor-mediated inhibition of adenylyl cyclase by morphine reduced dopamine- and NMDA-induced release. These results confirm previous studies indicating that NMDA receptor activation causes a slow action potential-independent efflux of GABA by reversal of the sodium-dependent GABA transporter on sodium entry through the NMDA receptor channel. Moreover, our data indicate that activation of G-protein-coupled dopamine D1 receptors also induces a transporter-mediated increase in spontaneous GABA release, but through a different mechanism of action, i.e., through cAMP-dependent inhibition of Na⁺/K⁺-ATPase, inducing accumulation of intracellular sodium, reversal of the GABA carrier, and potentiation of NMDA-induced release. These receptor interactions may play a crucial role in the behavioral activating effects of psychostimulant drugs.

Key words: dopamine D1 receptors; NMDA receptors; µ-opioid receptors; Na⁺/K⁺-ATPase; GABA transporter; GABA release; striatum

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2093496-08$05.00/0

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