THE NOVEL METABOTROPIC GLUTAMATE-RECEPTOR AGONIST 2R,4R-APDC POTENTIATES STIMULATION OF PHOSPHOINOSITIDE HYDROLYSIS IN THE RAT HIPPOCAMPUS BY 3,5-DIHYDROXYPHENYLGLYCINE - EVIDENCE FOR A SYNERGISTIC INTERACTIONBETWEEN GROUP-1 AND GROUP-2 RECEPTORS

The mGlu receptor subtypes and second messenger pathways that mediate 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) responses in brain tissues are not fully understood. 1S,3R-ACPD differs from 3, 5-dihydroxyphenylglycine (DHPG) or quisqualate in that 1S,3R-ACPD also activates group 2 mGlu receptors (mGlu2 and mGlu3) that are negativel y Linked to cAMP formation. To investigate the contribution of group 2 mGlu receptor activity of 1S,3R-ACPD to the phosphoinositide response in the rat hippocampus, we examined the effects of the novel group 2 mGlu receptor agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4 R-APDC). 2R,4R-APDC did not activate or inhibit group 1 mGlu receptors (human mGlu1 alpha and mGlu5a) or group 3 mGlu receptors (human mGlu4 and mGlu7), but potently decreased forskolin-stimulated cAMP formatio n in human mGlu2 and mGlu3-expressing cells. In slices of the adult ra t hippocampus 2R,4R-APDC had no effect on basal phosphoinositide hydro lysis; however, it was found to greatly enhance phosphoinositide hydro lysis to DHPG or quisqualate. In the neonatal rat hippocampus, 2R,4R-A PDC enhanced the potency of DHPG, while not affecting the maximal resp onse to group 1 mGlu receptor agonists. Thus, the phosphoinositide res ponse in the rat hippocampus to 1S,3R-ACPD is mediated by a synergisti c interaction between group 1 and group 2 mGlu receptors. (C) 1997 Els evier Science Ltd.