METABOTROPIC GLUTAMATE, RECEPTOR MODULATION OF CAMP ACCUMULATION IN THE NEONATAL RAT HIPPOCAMPUS

The pharmacology and cellular mechanism by which metabotropic glutamat e receptor (mGluR) activation modulates cAMP formation was studied in cross-chopped hippocampal slices from neonatal (7 day old) rats. The s elective mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid ( IS,3R-ACPD), and other non-selective mGluR agonists produced concentra tion-related stimulation of basal cAMP formation in this tissue. The r elative agonist potency order was 1S,3R-ACPD=quisqualate>ibotenate>>1R ,3S-ACPD. 1S,3R-ACPD stimulated cAMP accumulation was antagonized in a stereoselective manner by L-2-amino-3-phosphonopropionate (L-AP3), bu t not by higher chain homologues such as L-2-amino-4-phosphonobutyrate (L-AP4) and 2-amino-5-phosphonopentanoate (APS). 1S,3R-ACPD-enhanced cAMP formation was greatly inhibited by incubation with adenosine deam inase. In the adult rat hippocampus, 1S,3R-ACPD did not appreciably in crease basal cAMP, but inhibited forskolin-stimulated cAMP formation, and this effect was observed with or without adenosine deaminase. In t he presence of the adenosine receptor antagonist and cAMP phosphodiest erase inhibitor 3-isobutyl-l-methyl-xanthine (IBMX), 1S,3R-ACPD did no t enhance cAMP formation in the neonatal hippocampus, but inhibited fo rskolin-stimulated cAMP (like in the adult tissue). These results demo nstrate that mGluRs that increase cAMP in the neonatal hippocampus hav e a unique pharmacology when compared to mGluRs that decrease cAMP acc umulation and increase phosphoinositide hydrolysis. 1S,3R-ACPD stimula tion of cAMP in the neonatal rat hippocampal slice involves potentiati on of responses to endogenous adenosine. Negatively coupled cAMP linke d mGluRs are also present in the neonatal tissue, but are masked by th e predominence of the positively coupled mGluR cAMP response.