INHIBITION BY NMDA OF CARBACHOL-STIMULATED INOSITOL TETRAKISPHOSPHATEACCUMULATION IN RAT-BRAIN CORTICAL SLICES

The present studies examined the effect of NMDA on carbachol-stimulate d accumulation of inositol polyphosphates, with emphasis on the accumu lation of inositol 1,3,4,5-tetrakisphosphate (Ins 1,3,4,5-P-4), at sho rt time periods in rat brain cortical slices. There was a stimulatory effect of NMDA on accumulation of labeled inositol mono-, bis- and tri sphosphates but not on labeled inositol tetrakisphosphates. In the pre sence of carbachol Ins 1,3,4,5-P-4 accumulation was preferentially inh ibited by NMDA at early time periods (within 30 seconds after NMDA add ition). Subsequently, total phosphoinositide breakdown was inhibited b y NMDA. NMDA did not stimulate accumulation of total Ins 1,3,4,5-P-4 b ut immediately inhibited carbachol stimulated accumulation of Ins 1,3, 4,5-P-4. The inhibitory effect of NMDA (1 mM) was not mimicked by incr easing K+ in the medium from 10 to 30 mM. However 30 mM K+ reversed th e inhibitory effect of 1 mM NMDA on carbachol-stimulated Ins 1,3,4,5-P -4. Parallel experiments with veratridine (a sodium channel activator) suggest that the early inhibitory effects-of NMDA on Ins 1,3,4,5-P-4 accumulation are not due to decreases in ATP availability or elevation s in intracellular Na+. These data indicate that NMDA increases inosit ol mono-, bis- and trisphosphate accumulation; while blocking muscarin ic cholinergic stimulated accumulation of Ins 1,3,4,5-P-4: (C) 1996 El sevier Science Ltd.