Repeated cocaine administration attenuates group I metabotropic glutamate receptor-mediated glutamate release and behavioral activation: A potential role for Homer

The present study aimed to characterize a functional role for group I metab otropic glutamate receptors (mGluRs) in the nucleus accumbens and the capac ity of repeated cocaine to elicit long-term changes in group I mGluR functi on. Reverse dialysis of the group I agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) into the nucleus accumbens resulted in an increase in extracellular glutamate levels that was mediated by the mGluR1 subtype and depended on v oltage-dependent Na+ and Ca2+ conductance. At 3 weeks after discontinuing 1 week of daily cocaine injections, the capacity of DHPG to induce glutamate release was markedly reduced. Similarly, DHPG induced an mGluR1-dependent increase in locomotor activity after microinjection into the nucleus accumb ens that was significantly blunted 3 weeks after repeated cocaine administr ation. Signaling through group I mGluRs is regulated, in part, by Homer pro teins, and it was found that the blunting of group I mGluR-induced glutamat e release and motor activity after repeated cocaine was associated with a r eduction in Homer1b/c protein that was selective for the medial nucleus acc umbens. These data show that repeated cocaine produces an enduring inhibiti on of the neurochemical and behavioral consequences of stimulating mGluR1 t hat is accompanied by changes in the mGluR scaffolding apparatus.