Introduction: Dopamine/cAMP signaling mediates behavioral responses related to drug addiction. It also modulates the plasticity and firing properties of medium spiny neurons (MSNs) in the nucleus accumbens (NAc). Objectives: Our aim was to study the effects of postsynaptic dopamine D1-like receptor (D1R) activation on resting membrane potential (RMP) of NAc MSNs. Methods: In brain slices of C57BL/6 mice we performed whole-cell current- and voltage-clamp recordings from MSNs in the NAc core. Results: Activation of D1Rs by SKF-38393 elicited membrane depolarization and inward currents in MSNs. Similar results were obtained following adenylyl cyclase (AC) stimulation with forskolin or exogenous cAMP application. These effects were unaffected by protein kinase (PK) A or PKC blockade and were not mimicked by the Epac agonist, 8CPT-2Me-cAMP. Forskolin-induced depolarization was associated with increased membrane input resistance. Voltage-clamp experiments revealed that forskolin and SKF-38393 effects were due to inhibition of resting K+ currents exhibiting inward rectification at hyperpolarized potentials and a reversal potential that shifted with the extracellular K+ concentration. The inward rectifier K+ (Kir)-channel blocker, BaCl2, abolished forskolin and D1R agonist effects. Conclusions: These data suggest that postsynaptic D1R stimulation in MSNs of the NAc core causes membrane depolarization by inhibiting Kir currents. This effect is mediated by AC/cAMP signaling but it is independent on PKA, PKC and Epac suggesting that it may stem from cAMP’s direct interaction with Kir channels. D1R/cAMP-mediated excitatory effects may influence the generation of output signals from MSNs by facilitating their transition from the quiescent down-state to the functionally active up-state. Because a specific role in cocaine-seeking behavior has been attributed to the NAc core our findings may contribute to the understanding of pathophysiological mechanisms underlying drug dependence.
|Numero di pagine||1|
|Stato di pubblicazione||Pubblicato - 2011|
|Evento||14th European Congress on Clinical Neurophysiology - Roma|
Durata: 21 giu 2011 → 24 giu 2011
- Adenyly cyclase