Repeated Cocaine Administration Increases Voltage-Sensitive Calcium Currents in Response to Membrane Depolarization in Medial Prefrontal Cortex Pyramidal Neurons

Abstract

The medial prefrontal cortex (mPFC) plays a critical role in cocaine addiction. However, evidence to elucidate how the mPFC is functionally involved in cocaine addiction remains incomplete. Recent studies have revealed that repeated cocaine administration induces various neuroadaptations in pyramidal mPFC neurons, including a reduction in voltage-gated K⁺ currents (VGKCs) and a possible increase in voltage-sensitive Ca²⁺ currents (I_Ca). Here, we performed both current-clamp recordings in brain slices and voltage-clamp recordings in freshly dissociated cells to determine whether I_Ca is altered in mPFC pyramidal neurons after chronic cocaine treatment with a short-term or long-term withdrawal. In addition, a critical role of VGKCs in regulating the generation of Ca²⁺ plateau potential was also studied in mPFC neurons. Repeated cocaine administration significantly prolonged the duration of evoked Ca²⁺ plateau potentials and increased the whole-cell I_Ca in mPFC neurons after a 3 d withdrawal. Selective blockade of L-type Ca²⁺ channels by nifedipine not only significantly increased the threshold but also reduced the duration and amplitude of Ca²⁺ plateau potentials in both saline- and cocaine-withdrawn mPFC neurons. However, there was no significant difference in the increased threshold, reduced duration, and decreased amplitude of Ca²⁺ potentials between saline- and cocaine-withdrawn neurons after blockade of L-type Ca²⁺ channels. Moreover, an increase in amplitude was also observed, whereas the prolonged duration persisted, in Ca²⁺ potentials after 2-3 weeks of withdrawal. These findings indicate that chronic exposure to cocaine facilitates the responsiveness of I_Ca, particularly via the activated L-type Ca²⁺ channels, to excitatory stimuli in rat mPFC pyramidal neurons.