Increased reactivity of certain frontal cortical brain regions to cocaine re-exposure or drug-associated cues in cocaine-abstinent human addicts is linked to drug craving. Similarly, in rats tested after withdrawal from repeated cocaine exposure, cocaine or other strong excitatory stimuli produce greater activation of pyramidal neurons in the medial prefrontal cortex (mPFC). Our recent findings indicate that the increased mPFC neuronal activation depends primarily upon enhanced voltage-sensitive Ca2+ influx, most likely through high-voltage activated (HVA) L-type Ca2+ channels, but the mechanism underlying the enhanced Ca2+ currents is unknown. In this study, we used a protein crosslinking assay to show that repeated cocaine injections, resulting in behavioral sensitization, increased total protein levels and cell surface expression of HVA-Cav1.2 L-type channels in pyramidal neurons in deep layers of the mPFC. These changes in Cav1.2 L-channels were time dependent and subtype specific (i.e., differed from those observed for Cav1.3 L-channels). Furthermore, we found enhanced PKA activity in the mPFC of cocaine-sensitized rats that persisted for 21 days after withdrawal. PKA phosphorylation of L-channels increases their activity, so Ca2+ currents after cocaine withdrawal could be enhanced as a result of both increased activity and number of HVA-Cav1.2 L-channels on the cell surface. By increasing the supra-firing threshold excitability of mPFC pyramidal neurons, excessive upregulation of HVA L-channel activity and number may contribute to the cortical hyper-responsiveness that enhances vulnerability to cocaine craving and relapse. More generally, our results are the first to demonstrate that repeated cocaine exposure alters the membrane trafficking of a voltage-sensitive ion channel.
- Behavioral sensitization
- Bis- sulfosuccinimidyl-suberate
- Medial prefrontal cortex
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience