Evidence that Lithium Alters Phosphoinositide Metabolism: Chronic Administration Elevates Primarily d-myo-Inositol-1-Phosphate in Cerebral Cortex of the Rat

The administration of LiCl (3.6 mequiv./kg/day) to adult male rats for 9 days results in an increase in the cerebral cortex level of myo-inositol-1-phosphate (M1P) to 4.43 +/- 0.52 mmol/kg (dry weight) compared with a control level of 0.24 +/- 0.02 mmol/kg. This establishes that the previously observed acute effect of lithium on M1P (Allison et al., 1976) is both prolonged and augmented by repeated doses of lithium. Larger doses of LiCl over a 3-5 day period result in even larger increases in M1P and a 35% decrease in myo-inositol. In each case, 90% of the increase is due to the D-enantiomer, evidence that lithium is largely producing this effect via phospholipase C-mediated phosphoinositide metabolism. Data are presented showing that lithium is an uncompetitive inhibitor of the hydrolysis of both D- and L-M1P by M1P'ase.