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Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois
Submitted 9 March 2006; accepted in final form 27 July 2006
The nucleus accumbens (NAc) is a forebrain area in the mesocorticolimbic dopamine (DA) system that regulates many aspects of drug addiction. Neuronal activity in the NAc is modulated by different subtypes of DA receptors. Although DA signaling has received considerable attention, the mechanisms underlying D2-class receptor (D2R) modulation of firing in medium spiny neurons (MSNs) localized within the NAc remain ambiguous. In the present study, we performed whole cell current-clamp recordings in rat brain slices to determine whether and how D2R modulation of K+ channel activity regulates the intrinsic excitability of NAc neurons in the core region. D2R stimulation by quinpirole or DA significantly and dose-dependently decreased evoked Na+ spikes. This D2R effect on inhibiting evoked firing was abolished by antagonism of D2Rs, reversed by blockade of voltage-sensitive, slowly inactivating A-type K+ currents (IAs), or eliminated by holding membrane potentials at levels in which IAs was inactivated. It was also mimicked by inhibition of cAMP-dependent protein kinase (PKA) activity, but not phosphatidylinositol-specific phospholipase C (PI-PLC) activity. Moreover, D2R stimulation also reduced the inward rectification and depolarized the resting membrane potentials (RMPs) by decreasing "leak" K+ currents. However, the D2R effects on inward rectification and RMP were blocked by inhibition of PI-PLC, but not PKA activity. These findings indicate that, with facilitated intracellular Ca2+ release and activation of the D2R/Gq/PLC/PIP2 pathway, the D2R-modulated changes in the NAc excitability are dynamically regulated and integrated by multiple K+ currents, including but are not limited to IAs, inwardly rectifying K+ currents (IKir), and "leak" currents (IK-2P).
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