The constitutively expressed (CC) Homer protein Homer2a/b actively regulates behavioral and neurochemical sensitivity to cocaine in both rats and mice. The present study employed standard immunoblotting techniques to compare the effects of withdrawal from repeated cocaine (7 x 30 mg/kg) upon the protein expression of Homer2a/b with a related CC-Homer protein Homer1b/c, as well as their associated glutamate receptors, within brain regions implicated in cocaine addiction. To determine whether or not the observed cocaine-induced changes in Homer and glutamate receptor expression generalized across mammalian species, immunoblotting was conducted on tissue derived from both male Sprague-Dawley rats and male C57BL/6J mice. In both species, withdrawal from repeated cocaine administration down-regulated Homer1b/c and Homer2a/b within the shell, but not the core, of the nucleus accumbens (NAC), and the reduced Homer levels were accompanied by decreases in mGluR1a, NR2a and NR2b. In the PFC, repeated cocaine up-regulated Homer2a/b, mGluR1 and NR2b expression, without affecting Homer1b/c levels. Cocaine-induced increases in Homer1b/c, Homer2a/b, mGluR1a and NR2a were observed in the hippocampus of both rats and mice, while in dorsal striatum, NR2a levels were elevated but Homer and Group1 mGluR levels were unchanged. Thus, withdrawal from repeated cocaine alters the expression of CC-Homer isoforms and their associated glutamate receptors in a regionally-distinct manner. As CC-Homer proteins, Group1 mGluRs and NMDA receptors actively regulate cocaine-induced neuroplasticity in vivo, these data support the hypothesis that cocaine-induced changes in mGluR-Homer-NMDA signaling pathways may be important neuroadaptations mediating the enduring changes in behavior produced by repeated cocaine experience.