THE DEPOLARIZATION-INDUCED OUTFLOW OF D-[H-3]ASPARTATE FROM RAT-BRAINSLICES IS MODULATED BY METABOTROPIC GLUTAMATE RECEPTORS

Rat brain slices were used to study the effects of different metabotro pic glutamate receptor ligands on (i) the depolarization (30 mM KCl)-i nduced outflow of previously taken up D-[H-3]aspartate; (ii) the inhib ition of forskolin (30 mu M)-induced cyclic AMP accumulation; and (iii ) the hydrolysis of phosphoinositides. In addition, the localization o f mRNAs coding for different metabotropic glutamate receptor subtypes was detected using in situ hybridization. (1S,3R)-1-Aminocyclopentane- 1,3-dicarboxylic acid (30-300 mu M), a non selective metabotropic glut amate receptor agonist, significantly increased the KCl-induced output of radioactivity from cortical slices, whereas it inhibited the outpu t from striatal slices. Conversely, (1S,3S,4S)-carboxycyclopropylglyci ne (0.1-1 mu M), a relatively selective agonist of the mGluR2 metabotr opic glutamate receptor subtype, had an inhibitory effect on the outpu t of D-[H-3]aspartate from both cortical and striatal slices and prove d to be the most potent metabotropic glutamate receptor agonist in inh ibiting cyclic AMP accumulation, but not in stimulating phosphoinositi de hydrolysis. Since 2-amino-4-phosphonobutyrate (a mGluR4, mGluR6 and mGluR7 agonist) was not active in any of the assays tested, we hypoth esized that the mGluR2 subtype could be involved in these events. Acco rdingly, mGluR7 mRNA expression was abundant in cortical neurons proje cting to the striatum. Our experiments suggest that the stimulation of metabotropic glutamate receptors may either decrease or increase tran smitter release depending on the subtype that prevails in the region u nder study.