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The Journal of Neuroscience, April 15, 2003, 23(8):3498
GABA Transmission in the Nucleus Accumbens Is Altered after
Withdrawal from Repeated Cocaine
Zheng-Xiong
Xi,
Sammanda
Ramamoorthy,
Hui
Shen,
Russell
Lake,
Devadoss J.
Samuvel, and
Peter W.
Kalivas
Department of Physiology and Neuroscience, Medical University of
South Carolina, Charleston, South Carolina 29425
Repeated cocaine causes enduring changes in dopamine and glutamate
transmission in the nucleus accumbens, and dopamine and glutamate
terminals synapse on GABAergic accumbens neurons. The present study
demonstrates that there are changes in GABA transmission in the
accumbens at 3 weeks after discontinuing daily cocaine injections.
No-net flux microdialysis revealed a significant increase in the basal
levels of extracellular GABA in the accumbens of cocaine-treated rats.
The elevated extracellular GABA was normalized by blocking
voltage-dependent Na+ channels and provided
increased tone on GABAB presynaptic autoreceptors and heteroreceptors because blocking GABAB receptors
produced a greater elevation in extracellular GABA, dopamine, and
glutamate in cocaine-treated compared with control subjects. For many
G-protein-coupled receptors, increased agonist can cause
receptor desensitization. Consistent with GABAB receptor
desensitization, baclofen-stimulated GTP S binding was reduced, and
the reduction in G-protein coupling was accompanied by reduced Ser
phosphorylation of the GABAB2 receptor subunit. No effect
by repeated cocaine was found in the levels of total GABAB1
or GABAB2 protein. Together, these data demonstrate that
withdrawal from repeated cocaine treatment produces an increase in the
basal levels of extracellular GABA in the accumbens that depends on
neuronal activity. The increase may be mediated in part by functional
desensitization of GABAB receptors, likely the result of
diminished Ser phosphorylation of the GABAB2 receptor.
Key words:
GABA; cocaine; immunoblot; phosphorylation; microdialysis; glutamate
Copyright © 2003 Society for Neuroscience 0270-6474/03/2383498-08$05.00/0
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