MODULATION OF CYCLIC-AMP FORMATION BY PUTATIVE METABOTROPIC RECEPTOR AGONISTS

1 The effects of various metabotropic glutamate receptor agonists on [H-3]-cyclic AMP accumulation and phosphoinositide hydrolysis were investigated in guinea-pig cerebral cortical slices prelabelled with [H-3]-adenine or [H-3]-inositol. 2 1 -Aminocyclopentane-1S,3R-dicarboxylate (1S,3R-ACPD), L-2-amino-4-phosphonobutanoate (L-AP4) and (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I), elicited concentration-dependent inhibitions of forskolin-stimulated [3H]-cyclic AMP accumulation, with IC50 values of 2.1 +/- 0.3, 71 +/- 17 and 0.2 +/- 0.1 mu M respectively. 3 1S,3R-ACPD and L-CCG-I increased the cyclic AMP responses to histamine H-2 receptor stimulation with EC(50) values of 7 +/- 2 mu M and 19 +/- 2 mu M respectively. 1S,3R-ACPD (EC, value 17 +/- 2 mu M) and L-CCG-I (ECS, value 15 +/- 3 mu M) potentiated the cyclic AMP responses to the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA, 1O mu M). This potentiating effect of L-CCG-I was reduced in the presence of a protein kinase C inhibitor, and also in the absence of extracellular calcium. In contrast, L-AP4 inhibited the NECA response in a concentration-dependent manner, with an IC50 value of 120 +/- 20 mu M. 4 L-AP4 (at concentrations up to 1 mM) failed to stimulate phosphoinositide hydrolysis in guinea-pig cerebral cortical slices, but both 1S,3R-ACPD (EC(50) value 35 +/- 6 mu M) and L-CCG-I (approximately 160 mu M) elicited concentration-dependent stimulations of phosphoinositide turnover. 5 These results confirm the existence of at least two distinct subtypes of metabotropic receptor in guinea-pig cortex. The data also substantiate previous studies indicating the importance of the agonist L-CCG-I as a pharmacological tool for distinguishing metabotropic receptor subtypes.