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NEUROPHARMACOLOGY

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

Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, the Chicago Medical School, North Chicago, Illinois

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 However, the effects of Ba²⁺ on RMP and hyperpolarized membrane potentials were significantly attenuated in cocaine-withdrawn neurons compared with saline-pretreated cells.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.

Address correspondence to: Dr. Xiu-Ti Hu, Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, Chicago Medical School, 3333 Green Bay Road, North Chicago, Illinois 60064. E-mail: xiu-ti.hu{at}rosalindfranklin.edu

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