Synergistically interacting dopamine D1 and NMDA receptors mediate nonvesicular transporter-dependent GABA release from rat striatal medium spiny neurons
Anm. Schoffelmeer et al., Synergistically interacting dopamine D1 and NMDA receptors mediate nonvesicular transporter-dependent GABA release from rat striatal medium spiny neurons, J NEUROSC, 20(9), 2000, pp. 3496-3503
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.