ONTOGENIC AND PHARMACOLOGICAL STUDIES ON METABOTROPIC GLUTAMATE RECEPTORS COUPLED TO PHOSPHOLIPASE-D ACTIVATION

The present study was aimed at characterizing the metabotropic recepto r subtype which is involved in the activation of phospholipase D (PLD) by glutamate in rat hippocampal slices. We first observed that the on togenetic profile of glutamate-induced hydrolysis of phosphoinositides and of phosphatidylcholine was strikingly similar. Both pathways were significantly activated by glutamate in tissue taken from 3-, 8- and 15-day old rats, but not in adult rats. PLD activation was strongest i n slices taken from 8-day old rats. At this age, quisqualate had a hig her potency for PLD activation (EC50: 0.6 mu M) than 1S,3R-ACPD (EC50: 16 mu M) and DHPG, a specific activator of group I, mGluR, was a full agonist at PLD activation (EC50: 3.5 mu M) indicating an involvement of a group I mGluR (mGluR1 and 5). MCPG and AIDA, two putative antagon ists at mGluR1 receptors, caused a small but (in the case of MCPG) sig nificant inhibition. DCG-IV, an activator of group II mGluR, was a wea k partial agonist at PLD activation (EC50: 22 nM) while L-AP 4, an act ivator at group III mGluR, was totally inactive. Likewise, forskolin, a stimulant of cyclic AMP formation, was inactive either alone, or in combination with glutamatergic agonists. Pretreatment of the slices wi th pertussis toxin did not affect PLD activation. In summary, the glut amate-mediated activation of hippocampal PLD, which occurs transiently during postnatal development, is mediated by a group I mGluR, possibl y involving mGluR5. (C) 1997 Elsevier Science Ltd.