Mechanisms Of Action: Lithium And Other Antimanic Drugs

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(1) Chronic lithium administration reduced arachidonic acid turnover in rat brain phospholipids by 80%, without affecting turnover of docosahexaenoic or palmitic acid. The brain concentration of arachidonoyl-CoA, the precursor for arachidonic acid incorporation into phospholipids, was reduced by 50%. Lithium also reduced mRNA and protein levels and enzyme activity of an arachidonate selective cytosolic phospholipase A2 (cPLA2), which releases arachidonic acid from phospholipids during receptor-mediated signal transduction. cPLA2 and the arachidonic acid cascade may be a target of lithium in the treatment of bipolar disorder. (2) Rats were chronically administered valproic acid, an anticonvulsant used to treat bipolar disorder. Arachidonic acid turnover within brain phospholipids was reduced by 30%, but cPLA2 protein was unchanged. Both valproate and lithium may act against bipolar disorder by inhibiting brain arachidonate turnover, lithium by targeting cPLA2, valproate by an as yet unknown mechanism. (3) 1H-magnetic resonance spectroscopy (MRS) showed an elevated brain myoinositol concentration in the trisomy 65Dn mouse, a model for Down syndrome (trisomy 21). A similar reduction in brain myoinositol was reported in Down syndrome. Chronic lithium treatment further reduced brain myoinositol in the mouse, consistent with a hypothesis that lithium inhibits brain inositol monophosphatase and the phosphatidylinositol cycle. (4) A mass spectrometry method was developed and used to show that turnover of myoinositol in phosphatidylinositol of cultured fetal mouse neurons was quite rapid, 10.3% per hour. The spectrometric method with an accompanying mathematical model can also quantify myoinositol turnover in the rodent brain in vivo.