Effects of lithium on phosphoinositide metabolism in vivo.
All of the known pathways for metabolizing the phospholipase C (EC 3.1.4.10) products of phosphoinositide metabolism eventually lead to myo-inositol monophosphates and products that are hydrolyzed by myo-inositol 1-phosphatase (EC 3.1.3.25). That enzyme is inhibited by lithium (Ki about 1 mM). In animals treated with LiCl, elevations of myo-inositol 1-phosphate (1-IP) occur in brain that appear to result from endogenous neural activity for they are diminished by the anesthetics halothane and pentobarbital. Lithium is thus a useful tool for assessing endogenous in vivo cerebral phosphoinositide metabolism. The 1-IP elevation is also useful for revealing in vivo central nervous system (CNS) receptor activity that is stimulated by endogenous or exogenous processes such as the effects of centrally acting drugs and of seizures. Stimulation of the CNS in the presence of lithium causes myo-inositol to be sequestered in 1-IP in proportion to the amount of stimulation. Thus if the inositol level falls sufficiently resynthesis of the phosphoinositides may be compromised and receptor response to stimuli may be reduced. Evidence for such an occurrence would support the theory that this is one mechanism by which lithium acts in the therapy of manic illness. We extended our efforts to identify such a lowering of phosphoinositide levels to mice where cerebral metabolism can be halted more rapidly than in rats. However, the only change detected was a small elevation in phosphatidylinositol 4-phosphate. We were successful, however, in causing all of the phosphoinositides to be reduced in rat cerebral cortex by pilocarpine stimulation after lithium treatment, a procedure that causes seizures. The same procedure causes the largest reduction in cortical myo-inositol levels that we have observed, and thus may represent the point where the inositol decrement is sufficient to interfere with resynthesis of the lipids.
D000818:Animals; D001714:Bipolar Disorder / Q000188:drug therapy; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010716:Phosphatidylinositols / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D010738:Type C Phospholipases / Q000378:metabolism*
D010716:Phosphatidylinositols; D010862:Pilocarpine; D008094:Lithium; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D010738:Type C Phospholipases