Group I mGlu receptors potentiate synaptosomal [3H]glutamate release independently of exogenously applied arachidonic acid.

In the current study, we have characterized group I metabotropic glutamate (mGlu) receptor enhancement of 4-aminopyridine (4AP)-evoked [3H]glutamate release from rat cerebrocortical synaptosomes. The broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD, 10 microM) increased 4AP-evoked [3H]glutamate release (143.32+/-2.73% control) only in the presence of exogenously applied arachidonic acid; an effect reversed by the inclusion of bovine serum albumin (BSA, fatty acid free). In contrast, the selective group I mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) potentiated (EC50 = 1.60+/-0.25 microM; Emax = 147.61+/-10.96% control) 4AP-evoked [3H]glutamate release, in the absence of arachidonic acid. This potentiation could be abolished by either the selective mGlu1 receptor antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA, 1 mM) or the selective PKC inhibitor (Ro 31-8220, 10 microM) and was BSA-insensitive. The selective mGlu5 receptor agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG, 300 microM) was without effect. DHPG (100 microM) also potentiated both 30 mM and 50 mM K+ -evoked [3H]glutamate release (121.60+/-12.77% and 121.50 +/-4.45% control, respectively). DHPG (100 microM) failed to influence both 4AP-stimulated 45Ca2+ influx and 50 mM K+ -induced changes in synaptosomal membrane potential. Possible group I mGlu receptor suppression of tonic adenosine A1 receptor, group II/III mGlu receptors or GABA(B) receptor activity is unlikely since 4AP-evoked [3H]glutamate release was insensitive to the selective inhibitory receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine, (R,S)-alpha-cyclopropyl-4-phosphonophenylglycine or CGP55845A, respectively. These data suggest an 'mGlu1 receptor-like' receptor potentiates [3H]glutamate release from cerebrocortical synaptosomes in the absence of exogenously applied arachidonic acid. This PKC dependent effect is unlikely to be via modulation of synaptosomal membrane potential or voltage-activated Ca2+ channels and not via a suppression of tonically active inhibitory adenosine A1 receptor, group II/III mGlu receptors or GABA(B) receptors.