Lithium is not the only answer to manic depression
While lithium treatment has proven to be a godsend for many of the two
million Americans with bipolar disorder, it is not without its downside.
People on the drug may develop hypothyroidism, tremors, cognitive
impairment, and excessive thirst and urination and gain weight.
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.
PACAP protein is found throughout the central nervous system, said the
researchers. They cited studies demonstrating that mice in which the gene is
knocked out show hyperactivity and defects in their circadian (day-night)
behavior--both also characteristic of humans with bipolar disorder. Also, in
animals, lithium has been shown to affect such circadian behavior. The
protein also has been found to affect the activity of a key
neurotransmitter, dopamine, in the brain, said the researchers. What's more,
they found two other genes--PAM and GCH--that are involved in producing
PACAP to be upregulated in the treated brain tissue.
Brandish and his colleagues said that such findings "suggest a coordinated
upregulation of genes leading to increased dopamine signaling. In the light
of the recent clinical data and human genetic linkage, it is tempting to
speculate that PACAP night be a therapeutic effector of lithium in bipolar
disorder."
They concluded that "the data presented here warrant further investigation
of PACAP signaling in the brain and of the orphan receptor GPR88 as
potential new targets in bipolar disorder."
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