Co-existence and interaction between facilitatory and inhibitory metabotropic glutamate receptors and the inhibitory adenosine A1 receptor in cerebrocortical nerve terminals.

We have investigated the interaction between facilitatory and inhibitory metabotropic glutamate receptors (mGluRs) and the inhibitory adenosine A1 receptor in cerebrocortical nerve terminals from young (3 weeks postnatal) rats. The adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA) (1 microM) and the mGluR agonist L-2-amino-4-phosphonobutyrate (L-AP4) (100 microM) inhibited Ca(2+)-dependent release of glutamate evoked by depolarization of synaptosomes with 30 mM KCl to 33 +/- 6 and 30 +/- 4% of control values, respectively. The CHA and L-AP4 inhibition of release was consistent with the reduction of a component of Ca2+ entry in nerve terminals which was also sensitive to omega-Aga-IVA. When the inhibitory agonists were co-applied at optimal concentrations, no additivity of the inhibitory effects on either glutamate release or [Ca2+]c was observed. The nerve terminals from young rats also exhibit the facilitatory pathway for glutamate release that is observed during 4-aminopyridine-evoked depolarization after stimulation of mGluRs with the agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD) in the presence of arachidonic acid (AA). The addition of ACPD or AA alone did not alter the ability of CHA and L-AP4 to reduce the release, however the co-application of AA and ACPD abolished the inhibitory effect induced by CHA and L-AP4 whether alone or in combination. These results indicate the co-existence of the three modulatory pathways of glutamate release and the dominant role of the ACPD/AA activated facilitatory pathway in its interaction with the inhibitory pathways activated by L-AP4 and CHA.