Dopaminergic Modulation of NMDA-Induced Whole Cell Currents in Neostriatal Neurons in Slices: Contribution of Calcium Conductances

Abstract

The present experiments were designed to examine dopamine (DA) modulation of whole cell currents mediated by activation of N-methyl-D-aspartate (NMDA) receptors in visualized neostriatal neurons in slices. First, we assessed the ability of DA, D1 and D2 receptor agonists to modulate membrane currents induced by activation of NMDA receptors. The results of these experiments demonstrated that DA potentiated NMDA-induced currents in medium-sized neostriatal neurons. Potentiation of NMDA currents occurred at three different holding potentials, although it was more pronounced at -30 mV. It was mediated by D1 receptors, because it was mimicked by D1 agonists and blocked by exposure to a D1 antagonist. Activation of D2 receptors produced inconsistent effects on NMDA-induced membrane currents. Either decreases, increases, or no effects on NMDA currents occurred. Second, we examined the contributions of intrinsic, voltage-dependent conductances to DA potentiation of NMDA currents. Blockade of K+ conductances did not prevent DA enhancement of NMDA currents. However, voltage-activated Ca2+ conductances provided a major contribution to DA modulation. The dihydropyridine L-type Ca2+ channel blockers, nifedipine, and methoxyverapamil (D-600), markedly reduced but did not totally eliminate the ability of DA to modulate NMDA currents. The D1 receptor agonist SKF 38393 also enhanced Ba2+ currents in neostriatal neurons. Together, these findings provide evidence for a complex interplay between DA, NMDA receptor activation and dihydropyridine-sensitive Ca2+ conductances in controlling responsiveness of neostriatal medium-sized neurons.

Dopamine Receptor-mediated Ca2+ Signaling in Striatal Medium Spiny Neurons

“…3D). These results indicate that the dopamine-induced Ca 2ϩ oscillations in our experiments were mediated predominantly by D1 class DARs, but not by 5-HT 2 (16,18,19,53). To evaluate a possible role of these channels in dopamine-induced Ca 2ϩ oscillations, we used a combination of specific blockers of L-type Ca 2ϩ channels (10 M nifedipine), AMPA receptors (20 M CNQX), and NMDA receptors (10 M (ϩ)-MK801).…”

“…PKA phosphorylates DARPP-32 and Inhibitor-1 proteins, converting them into potent inhibitors of PP1 (1). Activation of PKA and inhibition of PP1 lead to increased phosphorylation and activation of L-type Ca 2ϩ channels, NMDA receptors, and AMPA receptors (16,17,(21)(22)(23) and InsP 3 R1 (39). We recently discovered an association of neuronal InsP 3 R1 with AKAP9⅐PKA, which is mediated by a LIZ motif in the InsP 3 R1 sequence (40).…”

“…In contrast, activation of D2 class DARs reduces L-type Ca 2ϩ currents (7) and NMDA receptor activity (20). D1/D5 receptormediated facilitation of L-type Ca 2ϩ channels and AMPA and NMDA receptors results from increased phosphorylation of these channels by protein kinase A (PKA) (16,21) and decreased dephosphorylation of these channels by protein phosphatase-1 (PP1) (17,22,23). DARPP-32 (dopamine-and cAMPregulated phosphoprotein of M r 32,000) (24,25) is partly responsible for inhibition of PP1 activity following activation of D1/D5 receptors (26).…”

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance

“…Such a mechanism has been described in other brain regions (42), but, in the striatum, has been linked mainly, but not exclusively, to the induction of LTP, not LTD (38,40,41,43,44). Given that the unaltered ratio between NMDA and AMPA currents indicated no increase in NMDA receptors of Foxp2 hum/hum mice, and that dopamine is critical for striatal synaptic plasticity, one alternative is that an altered dopamine-dependent modulation of NMDA receptors could be responsible for the humanized effect we observed in these mice (45)(46)(47).…”

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

“…Together, these results indicate that D1-like receptor stimulation is necessary, but not sufficient, for the reinstatement of cocaine-seeking behavior, similar to instrumental responding maintained by conditioned reinforcement (Winstanley et al, 2006). Conditioned stimuli elicit prolonged increases in dopamine neurotransmission (Garris et al, 1993;Sesack et al, 1998), which may permit the OFC to maintain the internal motivational representation of cocaine-paired contextual stimuli by facilitating glutamatergic inputs to the OFC (Cepeda et al, 1998a;Lapish et al, 2006;Schultz, 2002;Seamans et al, 2003). Furthermore, this phenomenon likely involves glutamatergic afferents from the BLA (Fuchs et al, 2005(Fuchs et al, , 2004Lasseter et al, 2009Lasseter et al, , 2011.…”