Plasticity of L-type Ca2+ channels after cocaine withdrawal.
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 Ca(2+) influx, most likely through high-voltage activated (HVA) L-type Ca(2+) channels, but the mechanism underlying the enhanced Ca(2+) 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-Ca(v)1.2 L-type channels in pyramidal neurons in deep layers of the mPFC. These changes in Ca(v)1.2 L-channels were time dependent and subtype specific (i.e., differed from those observed for Ca(v)1.3 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 Ca(2+) currents after cocaine withdrawal could be enhanced as a result of both increased activity and number of HVA-Ca(v)1.2 L-channels on the cell surface. By increasing the suprafiring 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.
Ford
Kerstin A
KA
Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
Wolf
Marina E
ME
Hu
Xiu-Ti
XT
D000704:Analysis of Variance; D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000009:adverse effects*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors
C514350:CACNA1C protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D003432:Cross-Linking Reagents; D018765:Dopamine Uptake Inhibitors; C093712:Cacna1d protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D003042:Cocaine