RT Journal Article
SR Electronic
T1 Modulation of Group II Metabotropic Glutamate Receptor Signaling by Chronic Cocaine
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 608
OP 615
DO 10.1124/jpet.102.039735
VO 303
IS 2
A1 Xi, Zheng-Xiong
A1 Ramamoorthy, Sammanda
A1 Baker, David A.
A1 Shen, Hui
A1 Samuvel, Devadoss J.
A1 Kalivas, Peter W.
YR 2002
UL http://jpet.aspetjournals.org/content/303/2/608.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics