Abstract
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 Ca2+ currents (ICa) 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 ICa density is decreased by 30%. Pharmacological isolation of specificICa 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 Inhibiting PP activity with okadaic acid enhancesICa in cocaine withdrawn, but not control, NAc neurons, suggesting an increase in constitutive PP activity.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decrease in the ability of D1 receptor stimulation and direct activation of cAMP signaling to suppress ICa in cocaine-withdrawn NAc neurons. Chronic cocaine-induced reduction ofICa in NAc MSNs will globally impact Ca2+-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.
Footnotes
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↵1 Current address: Department of Neurological and Urological Diseases Research, 47W, AP9A, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-6500.
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↵2 Current address: Department of Neurobiology and Physiology, Northwestern University, 2153 N. Campus Dr., Evanston, IL 60208.
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This work was supported by U.S. Public Health Service Grant DA-04093 from the National Institute on Drug Abuse and by National Institute on Drug Abuse Senior Scientist Award DA-00456 (to F.J.W.). D.C.C. was supported by Predoctoral National Research Service Award DA-05794.
- Abbreviations:
- DA
- dopamine
- MSN
- medium spiny neuron
- NAc
- nucleus accumbens
- PKA
- cAMP-dependent protein kinase
- BAPTA
- 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- CgTx
- ω-conotoxin GVIA
- AgTx
- ω-agatoxin TK
- 8-Br-cAMP
- 8-bromo-cAMP
- HVA
- high voltage-activated
- LVA
- low-voltage-activated
- PP
- protein phosphatase
- SCH 23390
- R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
- SKF 38393
- 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
- Received January 15, 2002.
- Accepted February 27, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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