Lithium increases accumulation of second messenger inositol 1,4,5-trisphosphate in brain cortex slices in species...

Historical aspects of the phosphoinositide field are briefly reviewed. The effects of the anti-manic depressive drug, lithium, on inositol 1,4,5-trisphosphate accumulation in brain cortex slices in species ranging from mouse to monkey are presented. In the guinea pig, lithium, in the presence of acetylcholine, increases the accumulation of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate, but at therapeutic concentrations of lithium 1 mM inositol is required to see a statistically significant effect. In previous studies in rat brain cortex slices, lithium inhibited accumulation of inositol 1,4,5-trisphosphate by 15-20%. We have confirmed this and found a similar effect in mouse brain cortex slices. However, if we added 20-30 mM inositol we observed lithium-stimulated accumulations of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate in these two latter species. These observations in rat and mouse appear to relate to the following facts: (1) brain cortices of mouse and rat contain in vivo concentrations of inositol half that of guinea pig, (2) incubated rat brain cortex slices are depleted of inositol by 80% and (3) the slices require 10 mM inositol supplementation to restore in vivo concentrations. More recently, we have shown that in monkey brain cortex slices, therapeutic concentrations of Li+ increase accumulation of inositol 1,4,5-trisphosphate. Inositol 1,3,4,5-tetrakisphosphate is not increased. Neither inositol, nor an agonist, is required. The same effects are seen whether inositol 1,4,5-trisphosphate is measured by the [3H]inositol-prelabelling technique or by mass assay, although mass includes a pool of inositol 1,4,5-trisphosphate which is metabolically inactive. Thus, in a therapeutically relevant model for man, Li+ increases Ins(1,4,5)P3 in brain cortex slices, as was previously seen in lower mammals at nonrate-limiting concentrations of inositol.