Differentiation of group 2 and group 3 metabotropic glutamate receptor cAMP responses in the rat hippocampus.
The effects of group 2- versus group 3-selective metabotropic glutamate (mGlu) receptor agonists were examined against forskolin (10 microM)-, vasoactive intestinal peptide (VIP; 1 microM)- and 5'-N-ethylcarboxamidoadenosine (NECA; 10 microM)-stimulated cAMP accumulations in adult rat hippocampal slices (in the presence of adenosine deaminase). Group 2 mGlu receptor-selective ((1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid (1S,3R-ACPD) and (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCG I)) and group 3 mGlu receptor-selective (L-2-amino-4-phosphonobutyric acid (L-AP4) and L-serine-O-phosphate) agonists greatly inhibited forskolin-stimulated cAMP formation ( > 80% at maximally effective concentrations). In contrast, stimulation of cAMP by VIP or NECA was inhibited by group 3, but not by group 2, mGlu receptor agonists. In fact, group 2 mGlu receptor agonists greatly potentiated cAMP accumulation evoked by NECA. Both the inhibitory effects of 1S,3R-ACPD on forskolin-stimulated cAMP and the potentiating effects on NECA-stimulated cAMP accumulation were reversed by the competitive group 1/2 mGlu receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG). However, (+)-MCPG had no effects on L-AP4 inhibition of cAMP. Thus, the effects of group 2 versus group 3 mGlu receptor agonists on cAMP coupling can be pharmacologically as well as functionally differentiated in the rat hippocampus.
Wright
R A
RA
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Schoepp
D D
DD
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000145:classification / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D000600:Amino Acids, Dicarboxylic; D000613:Aminobutyrates; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D005576:Colforsin; C035261:(alpha-carboxycyclopropyl)glycine; D019830:Adenosine-5'-(N-ethylcarboxamide); D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D000243:Adenosine Deaminase; C012729:2-amino-4-phosphonobutyric acid; D000241:Adenosine