%0 Journal Article %A Anton N. M. Schoffelmeer %A Louk J. M. J. Vanderschuren %A Taco J. De Vries %A Francois Hogenboom %A George Wardeh %A Arie H. Mulder %T Synergistically Interacting Dopamine D1 and NMDA Receptors Mediate Nonvesicular Transporter-Dependent GABA Release from Rat Striatal Medium Spiny Neurons %D 2000 %R 10.1523/JNEUROSCI.20-09-03496.2000 %J The Journal of Neuroscience %P 3496-3503 %V 20 %N 9 %X 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. %U https://www.jneurosci.org/content/jneuro/20/9/3496.full.pdf