Inhibition by NMDA of carbachol-stimulated inositol tetrakisphosphate accumulation in rat brain cortical slices.

The present studies examined the effect of NMDA on carbachol-stimulated accumulation of inositol polyphosphates, with emphasis on the accumulation of inositol 1,3,4,5-tetrakisphosphate (Ins 1,3,4,5-P4), at short time periods in rat brain cortical slices. There was a stimulatory effect of NMDA on accumulation of labeled inositol mono-, bis- and trisphosphates but not on labeled inositol tetrakisphosphates. In the presence of carbachol Ins 1,3,4,5-P4 accumulation was preferentially inhibited by NMDA at early time periods (within 30 seconds after NMDA addition). Subsequently, total phosphoinositide breakdown was inhibited by NMDA. NMDA did not stimulate accumulation of total Ins 1,3,4,5-P4 but immediately inhibited carbachol stimulated accumulation of Ins 1,3,4,5-P4. The inhibitory effect of NMDA (1 mM) was not mimicked by increasing K+ in the medium from 10 to 30 mM. However 30 mM K+ reversed the inhibitory effect of 1 mM NMDA on carbachol-stimulated Ins 1,3,4,5-P4. Parallel experiments with veratridine (a sodium channel activator) suggest that the early inhibitory effects of NMDA on Ins 1,3,4,5-P4 accumulation are not due to decreases in ATP availability or elevations in intracellular Na+. These data indicate that NMDA increases inositol mono-, bis- and trisphosphate accumulation while blocking muscarinic cholinergic stimulated accumulation of Ins 1,3,4,5-P4.