Repeated cocaine treatment decreases whole-cell calcium current in rat nucleus accumbens neurons.
Dopamine D1 receptors within the nucleus accumbens (NAc) are intricately involved in the rewarding effects of cocaine and in withdrawal symptoms after cessation of repeated cocaine administration. These receptors couple to a variety of ion channels to modulate neuronal excitability. Using whole-cell recordings from dissociated adult rat NAc medium spiny neurons (MSNs), we show that, as in dorsal striatal MSNs, D1 receptor stimulation suppresses N- and P/Q-type Ca(2+) currents (I(Ca)) by activating a cAMP/protein kinase A/protein phosphatase (PP) signaling system, presumably leading to channel dephosphorylation. We also report that during withdrawal from repeated cocaine administration, basal I(Ca) density is decreased by 30%. Pharmacological isolation of specific I(Ca) components indicates that N- and R-type, but not P/Q- or L-type, currents are significantly reduced by repeated cocaine treatment. Inhibiting PP activity with okadaic acid enhances I(Ca) in cocaine withdrawn, but not control, NAc neurons, suggesting an increase in constitutive PP activity. This suggestion was supported by a significant decrease in the ability of D1 receptor stimulation and direct activation of cAMP signaling to suppress I(Ca) in cocaine-withdrawn NAc neurons. Chronic cocaine-induced reduction of I(Ca) in NAc MSNs will globally impact Ca(2+)-dependent processes, including synaptic plasticity, transmitter release, and intracellular signaling cascades that regulate membrane excitability. Along with our previously reported reduction in whole-cell Na(+) currents during cocaine withdrawal, these findings further emphasize the important role of whole-cell plasticity in reducing information processing during cocaine withdrawal.
Zhang
Xu-Feng
XF
Department of Cellular and Molecular Pharmacology, Finch University of Health Sciences, The Chicago Medical School,3333 Green Bay Road, North Chicago, IL 60048, USA.
Cooper
Donald C
DC
White
Francis J
FJ
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine