Abstract
Our previous studies have demonstrated that repeated cocaine (COC) administration reduces voltage-sensitive sodium and calcium currents (INa or VSSCs and ICa or VSCCs, respectively) in medium spiny nucleus accumbens (NAc) neurons of rats. The present findings further indicate that chronic COC-induced INa reduction in NAc neurons is regulated by decreased dephosphorylation and enhanced phosphorylation of Na+ channels. Whole-cell voltage-clamp recordings revealed that dephosphorylation of Na+ channels by calcineurin (CaN) enhanced INa, while inhibition of protein phosphatase 1 (PP1) by phosphorylated dopamine- and cAMP-regulated phosphoprotein (Mr=32 kDa) (DARPP-32) at the site of threonine 34 (p-Thr.34-DARPP-32) suppressed INa, in freshly dissociated NAc neurons of saline-pretreated rats. However, the effects of CaN on enhancing INa were significantly attenuated, and the action of p-Thr.34-DARPP-32 to decrease INa was mimicked, although not potentiated, by repeated COC pretreatment. Dephosphorylation of Na+ channels by PP1 also enhanced INa, but this effect of PP1 on INa was not apparently affected by repeated COC administration. Western blot analysis indicates that the protein levels of CaN and DARPP-32 were significantly decreased and increased, respectively, while the PP1 levels were unchanged, in the COC-withdrawn NAc as compared to saline-pretreated controls. Combined with previous findings, our results indicate that both CaN and PP1 modulate the increase in INa via enhancing dephosphorylation, while p-Thr.34-DARPP-32 reduces INa by inhibiting PP1-induced dephosphorylation, thereby stabilizing the phosphorylation state, of Na+ channels in NAc neurons. They also suggest that chronic COC-induced INa reduction may be attributed to a reduction in Ca2+ signaling, which disrupts the physiological balance of phosphorylation and dephosphorylation of Na+ channels.
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Acknowledgements
We acknowledge Carolyn Grevers for her excellent technical assistance. We also thank Drs Pastor P Couceyro, Ann K Snyder, and Judy Potashkin for their helpful suggestions in Western blot analysis. This study was supported by USPHS Grant DA-04093 and Research Scientist Development Award DA 00456.
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Hu, XT., Ford, K. & White, F. Repeated Cocaine Administration Decreases Calcineurin (PP2B) but Enhances DARPP-32 Modulation of Sodium Currents in Rat Nucleus Accumbens Neurons. Neuropsychopharmacol 30, 916–926 (2005). https://doi.org/10.1038/sj.npp.1300654
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DOI: https://doi.org/10.1038/sj.npp.1300654
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