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Dopamine D₂ Receptor-Activated Ca²⁺ Signaling Modulates Voltage-Sensitive Sodium Currents in Rat Nucleus Accumbens Neurons

Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois

Submitted 29 July 2004; accepted in final form 3 November 2004

Receptor-mediated dopamine (DA) modulation of neuronal excitability in the nucleus accumbens (NAc) has been shown to be critically involved in drug addiction and a variety of brain diseases. However, the mechanisms underlying the physiological or pathological molecular process of DA modulation remain largely elusive. Here, we demonstrate that stimulation of DA D₂ class receptors (D₂R) enhanced voltage-sensitive sodium currents (VSSCs, I_Na) in freshly dissociated NAc neurons via suppressing tonic activity of the cyclic AMP/PKA cascade and facilitating intracellular Ca²⁺ signaling. D₂R-mediated I_Na enhancement depended on activation of G_i/o proteins and was mimicked by direct inhibition of PKA. Furthermore, increasing free [Ca²⁺]_in by activating inositol 1,4,5-triphosphate receptors (IP₃Rs), blocking Ca²⁺ reuptake, or adding buffered Ca²⁺, all enhanced I_Na. Under these circumstances, D₂R-mediated I_Na enhancement was occluded. In contrast, D₂R-mediated I_Na enhancement was blocked by inhibition of IP₃Rs, chelation of free Ca²⁺, or inhibition of Ca²⁺/calmodulin-activated calcineurin (CaN), but not by inhibition of phospholipase C (PLC). Although stimulation of muscarinic cholinergic receptors (mAChRs) also increased I_Na, this action was blocked by PLC inhibitors. Our findings indicate that D₂Rs mediate an enhancement of VSSCs in NAc neurons, in which cytosolic free Ca²⁺ plays a crucial role. Our results also suggest that D₂R-mediated reduction in tonic PKA activity may increase free [Ca²⁺]_in, primarily via disinhibition of IP₃Rs. IP₃R activation then facilitates Ca²⁺ signaling and subsequently enhances VSSCs via decreasing PKA-induced phosphorylation and increasing CaN-induced dephosphorylation of Na⁺ channels. This study provides insight into the complex and dynamic role of D₂Rs in the NAc.

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