Dopamine enhancement of NMDA currents in dissociated medium-sized striatal neurons: role of D1 receptors and DARPP-32.
Dopamine (DA), via activation of D1 receptors, enhances N-methyl-D-aspartate (NMDA)-evoked responses in striatal neurons. The present investigation examined further the properties of this enhancement and the potential mechanisms by which this enhancement might be effected. Dissociated medium-sized striatal neurons were obtained from intact rats and mice or mutant mice lacking the DA and cyclic adenosine 3',5' monophosphate (cAMP)-regulated phosphoprotein of M(R) 32,000 (DARPP-32). NMDA (10-1,000 microM) induced inward currents in all neurons. In acutely dissociated neurons from intact rats or mice, activation of D1 receptors with the selective agonist, SKF 81297, produced a dose-dependent enhancement of NMDA currents. This enhancement was reduced by the selective D1 receptor antagonist SKF 83566. Quinpirole, a D2 receptor agonist alone, produced small reductions of NMDA currents. However, it consistently and significantly reduced the enhancement of NMDA currents by D1 agonists. In dissociated striatal neurons, in conditions that minimized the contributions of voltage-gated Ca(2+) conductances, the D1-induced potentiation was not altered by blockade of L-type voltage-gated Ca(2+) conductances in contrast to results in slices. The DARPP-32 signaling pathway has an important role in D1 modulation of NMDA currents. In mice lacking DARPP-32, the enhancement was significantly reduced. Furthermore, okadaic acid, a protein phosphatase 1 (PP-1) inhibitor, increased D1-induced potentiation, suggesting that constitutively active PP-1 attenuates D1-induced potentiation. Finally, activation of D1 receptors produced differential effects on NMDA and gamma aminobutyric acid (GABA)-induced currents in the same cells, enhancing NMDA currents and inhibiting GABA currents. Thus simultaneous activation of D1, NMDA, and GABA receptors could predispose medium-sized spiny neurons toward excitation. Taken together, the present findings indicate that the unique potentiation of NMDA receptor function by activation of the D1 receptor signaling cascade can be controlled by multiple mechanisms and has major influences on neuronal function.
Flores-Hernández
Jorge
J
Mental Retardation Research Center, University of California, Geffen School of Medicine, Los Angeles, California 90095, USA.
Cepeda
Carlos
C
Hernández-Echeagaray
Elizabeth
E
Calvert
Christopher R
CR
Jokel
Eve S
ES
Fienberg
Allen A
AA
Greengard
Paul
P
Levine
Michael S
MS
D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology; D048429:Cell Size; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004553:Electric Conductivity; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology*
D020746:Calcium Channels, L-Type; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D004298:Dopamine