The antibipolar drug valproate mimics lithium in stimulating glutamate release and inositol 1,4,5-trisphosphate accumulation in brain cortex slices but not accumulation of inositol monophosphates and bisphosphates

Abstract

Valproic acid and lithium are effective antibipolar drugs. We recently showed that lithium stimulated the release of glutamate in monkey and mouse cerebral cortex slices, which, through activation of the N-methyl-D-aspartate receptor, increased accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. We show here that valproate behaves similarly to lithium in that at therapeutic concentrations it stimulates glutamate release and Ins(1,4,5)P3 accumulation in mouse cerebral cortex slices. The fact that these two effects are a common denominator for two structurally unrelated antibipolar drugs suggests that these effects are important in their antibipolar action. The effects of maximal concentrations of lithium and valproate on glutamate release are additive, suggesting different mechanisms for release, which are discussed. The additivity of the two drugs on glutamate release is consistent with the clinical benefit of combining the two drugs in the treatment of subsets of bipolar patients, e.g., in rapid cycling manic-depression. Unlike lithium, valproate does not increase accumulation of inositol monophosphates, inositol bisphosphates, or inositol 1,3,4-trisphosphate. This is additional evidence against the "inositol depletion" hypothesis, which states that, by trapping inositol in the form of inositol monophosphates and certain inositol polyphosphates, lithium exerts its antimanic action by inhibiting resynthesis of phosphoinositides with resultant blunting of Ins(1,4,5)P3 signaling.

Figure 1

Effect of valproate on glutamate release from mouse cerebral cortex slices. Slices were prepared, restored, and prelabeled as described in Experimental Procedures. Slices (average protein = 1.5 mg) were washed by incubating four times for 30 min in fresh buffer (3.2 ml). After washing, the slices were preincubated in the absence of Ca²⁺ with the indicated concentrations of sodium valproate for 60 min. The incubations were continued for 20 min with 1.2 mM Ca²⁺. Aliquots of the medium free of slices were analyzed enzymatically for glutamate as described under Experimental Procedures. ³H disintegrations per minute in the medium and tissue were measured, and the values were normalized to total disintegrations per minute to correct for differences in amounts of tissue. This figure combines three separate experiments.

Figure 2

Effects of high valproate (2 mM) and high lithium (25 mM) concentrations separately and in combination on extracellular glutamate. Mouse cerebral cortex slices were prepared, restored, prelabeled, and incubated as described in Experimental Procedures and in Fig. 1. Glutamate levels in the media of drug-treated slices all differed significantly from the control (P < 0.001). The percent increase above the control is shown (control, glutamate = 106 ± 1 nM).