3,5-DIHYDROXYPHENYLGLYCINE IS A HIGHLY SELECTIVE AGONIST FOR PHOSPHOINOSITIDE-LINKED METABOTROPIC GLUTAMATE RECEPTORS IN THE RAT HIPPOCAMPUS

Metabotropic glutamate receptors (mGluRs) are a heterogeneous family o f G protein-coupled glutamate receptors that are linked to multiple se cond messenger systems in the CNS. In this study the selectivity of mG luR agonists for different mGluR second messenger effects was characte rized in slices of the rat hippocampus. The mGluR agonists (1S,3R)-1-a minocyclopentane-1,3-dicarboxylic acid and (2S,3S,4S)alpha-(carboxycyc lopropyl)glycine produced multiple effects on second messengers that i ncluded enhanced phosphoinositide hydrolysis in both adult and neonata l rat hippocampus, inhibition of forskolin-stimulated cyclic AMP (cAMP ) formation in adult tissue, and increases in basal cAMP formation in the neonatal hippocampus. In contrast, 3,5-dihydroxyphenylglycine was potent and effective in increasing phosphoinositide hydrolysis in both adult and neonatal hippocampus but unlike the other mGluR agonists di d not inhibit forskolin-stimulated cAMP formation (in the adult) or su bstantially enhance basal cAMP formation (in the neonate). Thus, in th e rat hippocampus mGluR agonist-mediated increases or decreases in cAM P formation are not secondary to mGluR-mediated changes in phosphoinos itide hydrolysis. Furthermore, 3,5-dihydroxyphenylglycine can be used to activate subpopulations of mGluRs coupled to phosphoinositide hydro lysis with minimal effects on cAMP-mGluR second messenger systems.