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Repeated Cocaine Administration Suppresses HVA-Ca²⁺ Potentials and Enhances Activity of K⁺ Channels in Rat Nucleus Accumbens Neurons

Neuropsychopharmacology Laboratory, Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064-3095

Submitted 4 March 2004; accepted in final form 3 May 2004

The nucleus accumbens (NAc) is an important forebrain area involved in sensitization, withdrawal effects, and self-administration of cocaine. However, little is known about cocaine-induced alterations in the neuronal excitability and whole cell neuroplasticity in this region that may affect behaviors. Our recent investigations have demonstrated that repeated cocaine administration decreases voltage-sensitive sodium and calcium currents (VSSCs and VSCCs, respectively) in freshly dissociated NAc neurons of rats. In this study, current-clamp recordings were performed in slice preparations to determine the effects of chronic cocaine on evoked Ca²⁺ potentials and voltage-sensitive K⁺ currents in NAc neurons. Repeated cocaine administration with 3–4 days of withdrawal caused significant alterations in Ca²⁺ potentials, including suppression of Ca²⁺-mediated spikes, increase in the intracellular injected current intensity required for generation of Ca²⁺ potentials (rheobase), reduced duration of Ca²⁺ plateau potentials, and abolishment of secondary Ca²⁺ potentials associated with the primary Ca²⁺ plateau potential. Application of nickel (Ni²⁺), which blocks low-voltage activated T-type Ca²⁺ channels, had no impact on evoked Ca²⁺ plateau potentials in NAc neurons, indicating that these Ca²⁺ potentials are high-voltage activated (HVA). In addition, repeated cocaine pretreatment also hyperpolarized the resting membrane potential, increased the amplitude of afterhyperpolarization in Ca²⁺ spikes, and enhanced the outward rectification observed during membrane depolarization. These findings indicate that repeated cocaine administration not only suppressed HVA-Ca²⁺ potentials but also significantly enhanced the activity of various K⁺ channels in NAc neurons. They also demonstrate an integrative role of whole cell neuroplasticity during cocaine withdrawal, by which the subthreshold membrane excitability of NAc neurons is significantly decreased.

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