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Vol. 303, Issue 2, 608-615, November 2002
Department of Physiology and Neuroscience, Medical University of
South Carolina, Charleston, South Carolina
Repeated cocaine produces enduring neuroadaptations in glutamate
transmission in the nucleus accumbens that are thought to contribute to
addiction. Group II metabotropic glutamate autoreceptors (mGluR2/3)
regulate glutamate release, and this study investigates whether
repeated cocaine injection produces long-lasting alterations in
mGluR2/3 content, phosphorylation, and physiology. Rats were administered cocaine daily for 1 week, and 3 weeks after the last injection, mGluR2/3 protein levels were altered in the accumbens and
prefrontal cortex (PFC) but not in the dorsal striatum or ventral
tegmental area. The level of mGluR2/3 dimer was elevated in the
accumbens and PFC and the monomer was reduced in the PFC only.
Furthermore, the relative Ser phosphorylation state of the monomer was
elevated in both the accumbens and PFC of cocaine-pretreated subjects,
whereas the dimer demonstrated negligible phosphorylation in either
treatment group. These changes in mGluR2/3 level and phosphorylation
state were associated with reduced mGluR2/3 agonist-induced guanosine
5'-3-O -(thio)triphosphate binding in the
accumbens and PFC, but not in the dorsal striatum. Stimulation of
mGluR2/3 reduces extracellular glutamate by inhibiting
Ca2+-dependent and cystine/glutamate antiporter-mediated
glutamate release. The capacity of the mGluR2/3 agonist
2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) to inhibit [35S]cystine uptake via
cystine/glutamate antiporter in accumbens tissue slices was reduced by
repeated cocaine. Also, the capacity of APDC to reduce the basal and
potassium-stimulated extrasynaptic glutamate was significantly blunted
in the accumbens of cocaine-pretreated subjects. Together, these data
demonstrate that repeated cocaine produces an enduring reduction in
mGluR2/3 function in the nucleus accumbens.
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