Dopamine D1-like receptor activation depolarizes medium spiny neurons of the mouse nucleus accumbens by inhibiting inwardly rectifying K+ currents through a cAMP-dependent protein kinase A-independent mechanism

摘要: Dopamine/cAMP signaling has been reported to mediate behavioral responses related drug addiction. It also modulates the plasticity and firing properties of medium spiny neurons (MSNs) in nucleus accumbens (NAc), although effects cAMP on resting membrane potential (RMP) MSNs not specifically defined. In this study, activation dopamine D1-like receptors (D1Rs) by SKF-38393 elicited depolarization inward currents from NAc core 14-17 day-old mice. Similar results were obtained following stimulation adenylyl cyclase (AC) activity with forskolin or application exogenous cAMP. Forskolin occluded SKF-38393's effects, thus indicating that D1R action is mediated AC/cAMP signaling. Accordingly, AC blockade SQ22536 significantly inhibited SKF-38393. Effects increased levels unaffected protein kinase A (PKA) C (PKC) mimicked Epac agonist, 8CPT-2Me-cAMP. Responses modified cyclic nucleotide-gated (CNG) channel blockade. Forskolin-induced was associated input resistance. Voltage-clamp experiments revealed due inhibition K(+) exhibiting rectification at hyperpolarized potentials a reversal (around -90 mV) shifted extracellular concentration. agonist abolished rectifier (Kir)-channel blocker, BaCl(2). Collectively, these data suggest postsynaptic D1Rs causes inhibiting Kir currents. This effect but it independent PKA, PKC, CNG activation, suggesting may stem cAMP's direct interaction channels. D1R/cAMP-mediated excitatory influence generation output signals facilitating their transition quiescent down-state functionally active up-state.