Repeated cocaine administration increases membrane excitability of pyramidal neurons in the rat medial prefrontal cortex

Although the medial prefrontal cortex (mPFC) plays a critical role in cocaine addiction, the effects of chronic cocaine on mPFC neurons remain poorly understood. Here, we performed visualized current-clamp recordings to determine the effects of repeated cocaine administration on the membrane excitability of mPFC pyramidal neurons in rat brain slices. Following repeated cocaine administration ( 15 mg/kg/ day i.p. for 5 days) with a 3-day withdrawal, alterations in membrane properties, including increased input resistance, reduced intensity of intracellular injected currents required for generation of Na+-dependent spikes ( rheobase), and an increased number of spikes evoked by depolarizing current pulses were observed in mPFC neurons. The current-voltage relationship was also altered in cocaine-pretreated neurons showing reduced outward rectification during membrane depolarization and decreased inward rectification during membrane hyperpolarization. Application of the K+ channel blocker Ba2+ depolarized the resting membrane potential (RMP) and enhanced membrane potential response to injection of hyperpolarizing current pulses. However, the effects of Ba2+ on RMP and hyperpolarized membrane potentials were significantly attenuated in cocaine-withdrawn neurons compared with saline-pretreated cells. These findings indicate that repeated cocaine administration increased the excitability of mPFC neurons after a short-term withdrawal, possibly via reducing the activity of the potassium inward rectifiers ( K-ir) and voltage-gated K+ currents. Similar changes were also observed in cocaine-pretreated mPFC neurons after a long-term ( 2 - 3 weeks) withdrawal, revealing a persistent increase in excitability. These alterations in mPFC neuronal excitability may contribute to the development of behavioral sensitization and withdrawal effects following chronic cocaine exposure.