title: Synergistically interacting dopamine D1 and NMDA receptors mediate nonvesicular transporter-dependent GABA release from rat striatal medium spiny neurons.
abstract: 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 [(3)H]-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 [(3)H]-GABA release. These effects of dopamine were mimicked by forskolin. mu-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.
authors.affiliation: Research Institute Neurosciences Vrije Universiteit, Department of Pharmacology, Free University, Medical Faculty, 1081 BT Amsterdam, The Netherlands. ANM.Schoffelmeer.Pharm@med.vu.nl
authors.forename: A N
authors.initials: AN
authors.lastname: Schoffelmeer
authors.forename: L J
authors.initials: LJ
authors.lastname: Vanderschuren
authors.forename: T J
authors.initials: TJ
authors.lastname: De Vries
authors.forename: F
authors.initials: F
authors.lastname: Hogenboom
authors.forename: G
authors.initials: G
authors.lastname: Wardeh
authors.forename: A H
authors.initials: AH
authors.lastname: Mulder
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D027361:Organic Anion Transporters; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D000242:Cyclic AMP; D004298:Dopamine