However, better treatments for bipolar disorder depend on a better understanding of the still-mysterious mechanism by which lithium damps the highs and lows of the disorder. Now, researchers led by Philip Brandish of Merck & Co., Inc., and Edward Scolnick of the Broad Institute (formerly of Merck and Co., Inc.) have identified genes whose activity appears to be switched on by lithium, suggesting more direct targets for drugs to treat the disorder.

Lithium is known to inhibit the production of an important cellular switch, called inositol monophosphate, so the researchers set out to find genes that were activated by this inhibition. They treated slices of rat brain with lithium chloride as well as a chemical that depletes inositol. The also treated other slices with the two chemicals, but added inositol.

The researchers used DNA microarrays--so-called "gene chips"--to detect genes that were unequivocally activated when inositol was depleted in the brain slices.

They discovered several genes that they concluded "suggest new directions toward the treatment of bipolar disorder."

The behavior of one such activated gene, called GPR88, has been found to be associated with a rat model of mania, they said. This gene codes for a protein that is an "orphan receptor"--that is, its cellular function in sensing external chemical signals is unknown.

The researchers also found that the gene called AD-CYAP1 was upregulated in the treated brain slices. This gene codes for a signaling molecule called PACAP in the brain and is known to be close to a chromosomal region that genetic studies have shown to be associated with a higher risk of bipolar disorder.

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Contact: Heidi Hardman
hhardman@cell.com
1-617-397-2879
Cell Press
23-Mar-2005