Increased excitability of medial prefrontal cortex pyramidal neurons after long-term withdrawal from repeated cocaine administration

Chicago

Congreso; Society for Neuroscience Chicago Chapter, Chicago; 2005

The medial prefrontal cortex (mPFC) is involved in acquisition of cocaine self-administration and the development of behavioral sensitization induced by chronic cocaine treatment. We have recently demonstrated that repeated cocaine pretreatment decreases the rheobase, increases the number of evoked Na+ spikes, reduces voltage-gated K+ currents, and enhances voltage-sensitive Ca2+ currents, indicating increased excitability of mPFC neurons after a short-term (3-day) withdrawal. These changes in mPFC neurons would likely contribute to behavioral sensitization and the withdrawal effects of repeated cocaine pretreatment. Because glutamate output from the mPFC is promoted in cocaine-sensitized rats after 2-3 weeks of withdrawal, we hypothesize that the cocaine-induced increase of the mPFC excitability may also be present following prolonged cocaine withdrawal. Whole-cell current clamp recordings were conducted in rat brain slices in vitro to determine the effects of repeated administration of cocaine on the excitability of layer V-VI mPFC pyramidal neurons following prolonged withdrawal. After five daily injections of cocaine (15mg/kg, i.p.) followed by 2-3 weeks of withdrawal, the decreased rheobase and increased number of evoked Na+ spikes, which were previously observed with short-term withdrawal, were still present in mPFC neurons. Moreover, the amplitude and duration of Ca2+ plateau potentials were also increased. These changes indicate that enhanced Ca2+ channel function contributes to the increased excitability of mPFC neurons, while the involvement of Na+ and K+ currents needs further study. These findings also indicate that the increased excitability of mPFC neurons persists for a prolonged period of time after repeated cocaine pretreatment and could be a critical determinant for sensitization and the withdrawal effects of cocaine.