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Identification of mood stabilizer-regulated genes by differential-display PCR.

An increasing body of evidence demonstrates that lithium and valproate have a regulatory effect on signal transduction pathways. Alteration of signalling molecules triggers changes in gene expression which are thought to contribute to the therapeutic effects of these drugs on bipolar disorder. Differential-display PCR was used to identify genes in rat cerebral cortex that are regulated by chronic treatment with lithium and valproate. One novel lithium-regulated gene was identified and was characterized and studied further with 5'-RACE-PCR and library screening. We also found that valproate regulated the expression of the 78-kDa glucose-regulated protein (GRP78). Chronic treatment with valproate has also been found to increase gene transcription, mRNA and protein levels of GRP78. These results suggest novel targets for lithium and valproate that may be relevant to their mechanism of action. The data further our understanding of the mechanism of the action of mood stabilizers, and help identify new targets for genetic studies and therapeutic strategies in bipolar disorder.