MECHANISMS UNDERLYING THE INHIBITION OF SOMAN ON NMDA-STIMULATED [H-3]NOREPINEPHRINE RELEASE FROM RAT CORTICAL SLICES, ROLE OF PHOSPHOLIPASE-C AND PROTEIN-KINASE-C

Our previous studies indicated that soman inhibits N-methyl-D-aspartat e (NMDA)-stimulated [H-3]norepinephrine (NE) release from rat cortical slices by acting at a non-cholinergic site. In order to characterize the mechanisms, neomycin, a phospholipase C (PLC) inhibitor, and polym yxin B (PMB), a rather selective protein kinase C (PKC) inhibitor, wer e used to examine a possible involvement of PLC and PKC in the inhibit ory effect of soman on NMDA-stimulated [H-3]NE release. The role of pe rtussis toxin (PTX)-sensitive G-protein was also investigated by appli cation of PTX. Neomycin (0.03-1.0 mM) inhibited the release in a conce ntration-dependent manner, which was inhibited by 1.0 mM soman. Howeve r, no significant interaction between soman and neomycin was observed. In addition. PMB (1.0 mu g/ml) significantly inhibited release by 15. 8%. With the presence of 1.0 mM soman, inhibition of release decreased from 29% (without PMB) to 5% (1.0 mu g/ml PMB). Furthermore, both in the presence and absence of 1.0 mM soman, no significant differences f or [H-3]NE release were found between PTX (1.0 mu g/ml)-treated and no n-treated slices. These results suggest that the mechanism of the inhi bitory effect of soman on NMDA-stimulated [H-3]NE release in cortical slices appear to involve the effect on PKC, but not PLC and PTX-sensit ive G-protein. (C) 1998 Elsevier Science Ltd. All rights reserved.