Repeated cocaine administration alters dopamine modulation of K+ current in rat prefrontal cortex pyramidal neurons

Orlando

Congreso; 2002 Society for Neuroscience Meeting; 2002

Dopamine (DA) modulation of prefrontal cortex (PFC) has been implicated in several aspects of cocaine addiction. We previously characterized DA D1 receptor (D1R) mediated modulation of voltage-gated outward K+ current (VGKC) and inwardly rectifying K+ current (IRKC) in PFC pyramidal neurons. Here, we focused on cocaine-induced alterations in whole-cell K+ currents and their modulation by D1Rs. Rats were treated with 15mg/kg cocaine for 5 consecutive days, followed by three days of withdrawal. Rats were then sacrificed and pyramidal neurons were acutely dissociated from the medial PFC. Both VGKC and IRKC were isolated with voltage-clamp techniques. The VGKC density was significantly reduced in the cocaine-pretreated neurons, whereas the IRKC density was not altered. Reduction in K+ current usually results in an increase in the overall excitability. This hypothesis was confirmed by a current-clamp study in PFC slices, in which the evoked firing rate was significantly increased in cocaine-pretreated neurons. Activation of DA D1R suppresses VGKC in PFC pyramidal neurons, an effect that was diminished in the cocaine-pretreated neurons. Activation of cAMP/PKA pathway by Sp-cAMP perfusion induced less suppression of VGKC, whereas inhibition of cAMP/PKA pathway by Rp-cAMP perfusion induced more enhancement of VGKC in the cocaine-pretreated neurons. We therefore argue that the elevated downstream D1 signaling is responsible for the reduced capacity of D1R modulation of VGKC, as well as the reduction in VGKC density in the cocaine-pretreated neurons.