Li+, beginning at a concentration as low as 1 mm, produced a time-and dose-dependent increase in accumulation of and Ins(1,3,4,5)P4 accumulation in these species, but we could reverse this inhibition by adding 10-30 mM-inositol; we then observed a Li'-induced increase in Ins(1,4,5)P3 and Ins(1,3,4,5)P4. The species differences observed in the absence of supplemented inositol were explained by the fact that a much higher concentration of inositol was required to bring the Li+-elevated levels of CDP-diacylglycerol (CDPDG) down to baseline in the rat and mouse. These data suggest that inositol is more rate-limiting for phosphatidylinositol synthesis in the presence of Li+ in rat and mouse, which can account for the previous reports of inhibition of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 accumulation by this ion in these species. Thus, in all species examined, Li+ could be shown to increase accumulation of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 in cholinergically stimulated brain cortex slices if the slices were supplemented with sufficient inositol to bring the Li'-elevated level of CDPDG down to near baseline, as seen in the absence of Li'. In guinea-pig brain cortex slices, increases in Ins(1,4,5)P3and Ins(1,3,4,5)P4 accumulation could then be seen at Li+ concentrations as low as 1 mm, which falls within the therapeutic range of plasma concentrations in the treatment of manic-depressive disorders. These observations may have therapeutic implications.
INTRODUCTIONReceptor activation of phosphodiesteratic cleavage of phosphoinositides generates intracellular second-messenger
