We examined the effect of ginseng total saponins (GTS) on phosphoinositide metabolism stimulated by activation of muscarinic receptor using rat cortical cultures. Carbachol stimulated formation of [3H]inositol phosphates ([3H]InsPs) by 3.3-fold over basal level in [3H]inositol-prelabeled cells. Pretreatment of GTS inhibited formation of [3H]InsPs evoked by carbachol by 70%-90%. Addition of GTS alone had no effect on the basal formation of [3H]InsPs. The inhibitory effect of the GTS on carbachol-stimulated formation of [3H]InsPs was dose- and time-dependent. IC50 was 6.0 +/- 2.8 microg/ml. We also examined the effect of GTS on [3H]InsP1, [3H]InsP2, or [3H]InsP3 formation evoked by carbachol. Although GTS had no effect on the basal [3H]InsP1, [3H]InsP2, or [3H]InsP3 formation, pretreatment of GTS inhibited [3H]InsP1, [3H]InsP2, or [3H]InsP3 formation evoked by carbachol, respectively. Addition of individual ginsenosides such as ginsenoside Rb1, Rc, Rd, Re, or Rg2 had no effect on the basal formation of [3H]InsPs, whereas pretreatment of ginsenoside Rb2, Rc, Rd, Re, Rf, Rg1 or Rg2 inhibited formation of [3H]InsPs evoked by carbachol by 79%-89%. The results suggest that the inhibitory effect of GTS and its individual ginsenosides on carbachol-stimulated formation of [3H]InsPs in cortical neurons could be one pharmacological action of Panax ginseng.