title: Pharmacology of metabotropic glutamate receptor inhibition of cyclic AMP formation in the adult rat hippocampus.
abstract: Phosphoinositide-linked metabotropic glutamate receptors have been well characterized in a variety of CNS tissues. In this study the pharmacology of metabotropic glutamate receptors negatively coupled to cAMP formation was investigated in cross-chopped slices of the adult rat hippocampus. Excitatory amino acid agonists and antagonists were examined for effects on forskolin (30 microM)-simulated cAMP formation. The selective metabotropic glutamate agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and various nonselective metabotropic/ionotropic agonists were found to inhibit forskolin-stimulated cAMP formation. Inhibition of cAMP formation was observed using 1S,3R-ACPD (57% at 100 microM), quisqualate (92% at 500 microM), ibotenate (44% at 500 microM), L-glutamate (41% at 1000 microM), and L-aspartate (59% at 1000 microM). Inhibition of forskolin-stimulated cAMP formation induced by these agonists was observed even in the presence of the ionotropic antagonists MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione. Up to 500 microM of the ionotropic agonists N-methyl-D-aspartate, AMPA, and kainate did not inhibit forskolin-stimulated cAMP formation. L-2-amino-3-phosphonopropionate (500 microM) greatly inhibited the stimulatory effect of 1S,3R-ACPD on phosphoinositide hydrolysis, even in the presence of forskolin. However when measuring cAMP formation, L-2-amino-3-phosphonoproprionate (500 microM) mimicked the effect of 1S,3R-ACPD, producing 64% inhibition of forskolin-stimulated cAMP. These studies show that in the adult rat hippocampus metabotropic glutamate receptors that are negatively linked to cAMP formation have a pharmacology that is distinct from ionotropic glutamate receptors and phosphoinositide-linked metabotropic glutamate receptors.
authors.affiliation: CNS Research, Eli Lilly and Company, Indianapolis, IN 46285.
authors.forename: D D
authors.initials: DD
authors.lastname: Schoepp
authors.forename: B G
authors.initials: BG
authors.lastname: Johnson
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005971:Glutamates / Q000502:physiology; D018698:Glutamic Acid; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000502:physiology*
chemical_list: D005971:Glutamates; D017470:Receptors, Glutamate; C000211:2-amino-3-phosphonopropionic acid; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D005576:Colforsin; D018698:Glutamic Acid; D000242:Cyclic AMP; D000409:Alanine