(1) We previously reported that the mood-stabilizer lithium, when chronically administered to rats at a therapeutically relevant concentration, down-regulates brain arachidonic acid release and metabolism by targeting the enzymes cytosolic phospholipase A2 (cPLA2) and cyclooxygenase (COX)-2. We examined whether the effect of lithium is selectively directed to cPLA2 or also affects Ca2+-dependent secretory sPLA2 protein and enzyme activity and whether other arachidonic acid metabolizing enzymes (5-lipoxygenase and cytochrome P450 epoxygenase) are altered. We found that chronic lithium did not significantly change sPLA2 activity or protein level in rat brain. 5-lipoxygenase and cytochrome P450 epoxygenase protein levels were unchanged, as were levels of the terminal PGE synthase. These results indicate that the effect of lithium selectively involves the cPLA2/COX-2 pathway, which might be responsible for its therapeutic effect in bipolar disorder. (2) Carbamazepine is an anticonvulsant used as monotherapy or as an adjunct to lithium in the treatment of bipolar disorder. Based on evidence that lithium and valproate, other mood-stabilizers, reduce brain arachidonic acid turnover and its conversion via cyclooxygenase to prostaglandin E2 in rat brain, one possibility is that carbamazepine also targets the arachidonic acid cascade. To test this hypothesis, we administered carbamazepine, at therapeutically relevant plasma concentrations, to rats for 30 days. We found that carbamazepine down-regulated cPLA2-mediated release of arachidonic acid and its subsequent conversion to prostaglandin E2 by COX. These effects may contribute to its therapeutic effect in bipolar disorder. (3) We used oligonucleotide microarrays to determine the effect of chronic administration of valproate, at therapeutically relevant concentrations, on gene expression in rat brain. Valproate affected the expression of genes involved in synaptic transmission, ion channels and transport, G-protein signaling, lipid, glucose and amino acid metabolism, transcriptional and translational regulation, the phosphoinositol cycle, protein kinases and phosphatases, and apoptosis. Our results suggest that the therapeutic effect of valproate involves the modulation of multiple signaling pathways. (4) Phase II clinical trials with the anticonvulsant, topiramate, suggested that this drug may be effective for the treatment of bipolar disorder. To see if topiramate has effects similar to those of lithium, valproate and carbamazepine on brain arachidonic acid metabolsim, we gave topiramate to rats for two weeks. Topiramate did not modify the expression of the enzymes involved in brain arachidonic acid metabolism, as did the other drugs. If topiramate proves effective in bipolar disorder, it may be acting through a different pathway.
