Repeated cocaine administration suppresses HVA-Ca2+ potentials and enhances activity of K+ channels in rat nucleus accumbens neurons

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.