Repeated Cocaine Administration Increases Membrane Excitability of Pyramidal Neurons in the Rat Medial Prefrontal Cortex

摘要

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 intra-cellular injected currents required for generation of Na~+-depen-dent 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 Ba~(2+)depolarized the resting membrane potential(RMP)and enhanced membrane potential response to injection of hyperpolarizing current pulses.However,the effects of Ba~(2+)on RMP and hyperpolarized membrane potentials were significantly attenuated in cocaine-withdrawn neurons compared with saline-pretreated cells.These findings indicate that repeated cocaine administration increased the excitability of mPFC neurons after a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 sen-sitization and withdrawal effects following chronic cocaine exposure.