Synergistically interacting dopamine D1 and NMDA receptors mediate nonvesicular transporter-dependent GABA release from rat striatal medium spiny neurons

Given the complex interactions between dopamine D1 and glutamate NMDA recep tors in the striatum, we investigated the role of these receptors in transp orter-mediated GABA release from cultured medium spiny neurons of rat stria tum. Like NMDA receptor-mediated [H-3]-GABA release, that induced by prolon ged (20 min) dopamine D1 receptor activation was enhanced on omission of ex ternal calcium, was action potential-independent (tetrodotoxin-insensitive) , and was diminished by the GABA transporter blocker nipecotic acid, indica ting the involvement of transporter-mediated release. Interestingly, loweri ng the external sodium concentration only reduced the stimulatory effect of NMDA. Blockade of Na+/K+-ATPase by ouabain enhanced NMDA-induced but aboli shed dopamine-induced release. Moreover, dopamine appeared to potentiate th e effect of NMDA on [H-3]-GABA release. These effects of dopamine were mimi cked by forskolin. mu-Opioid receptor-mediated inhibition of adenylyl cycla se by morphine reduced dopamine- and NMDA-induced release. These results co nfirm previous studies indicating that NMDA receptor activation causes a sl ow action potential-independent efflux of GABA by reversal of the sodium-de pendent 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 GA BA release, but through a different mechanism of action, i.e., through cAMP -dependent inhibition of Na+/K+ ATPase, inducing accumulation of intracellu lar sodium, reversal of the GABA carrier, and potentiation of NMDA-induced release. These receptor interactions may play a crucial role in the behavio ral activating effects of psychostimulant drugs.