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Despite more than 30 years of widespread use of lithium to
control psychiatric disorders, such as bipolar disorder,
scientists have been uncertain about how this drug actually
works on a molecular level.

However, in a paper published in the January 11th issue of
Cell, a Duke University Medical Center team has found that
lithium may alleviate manic and depressive-like behaviors by
interrupting the signaling of a dopamine receptor in the brain.
The team was led by Marc G. Caron, Ph.D., James B. Duke
Professor in the Department of Cell Biology, Medicine and
Neurobiology, and Martin Beaulieu, Ph.D., now at Université
Laval.

Over the years, lithium has been shown to act principally on
two targets in the brain. It is known to inhibit enzymes that
maintain a signaling pathway from the cell membrane. And it
inhibits an enzyme called glycogen synthase kinase 3 (GSK-3),
which is important in the cell's response to many signaling
molecules. But, whether these targets are important for the
therapeutic effects of lithium has been unclear.

Caron and Beaulieu previously showed that one of the
dopamine receptors in the brain, the D2 receptor, transmits its
signal by engaging a pathway involving GSK-3. The D2 receptor
regulates this pathway with a signaling complex made up of the
receptor and enzymes held together by a protein called
beta-arrestin 2.

When placed in a new environment, mice genetically
engineered to have an overactive dopamine system typically run
around frantically. Similar hyperactivity and mania-like state
can be seen in mice treated with amphetamines. Previous
research by Caron and Beaulieu had shown that treatment with
lithium calms these mice by interfering with the D2
receptor/GSK3 pathway. Caron and his colleagues set out to
investigate how lithium produced these effects.

"In humans, lithium alleviates the mood swings and
excitability characteristic of bipolar disorder. However, the
concentrations at which lithium is clinically effective are
usually lower that those necessary to affect the presumed
targets like GSK3 in preclinical studies. So there had to be
another mechanism," said Caron.

The team focused on whether lithium was acting on the
beta-arrestin signaling complex after finding that in another
line of genetically engineered mice lacking the gene for the
beta-arrestin 2 protein, many of the actions of the D2 receptor
were absent.

"We found that lithium destabilizes the signaling complex
necessary for the D2 receptor to engage the GSK3 signaling
pathway," said Beaulieu, the lead author of the study. In the
mice that lack beta-arrestin 2, the researchers found that
lithium had no effects on a number of mouse behaviors thought
to correlate with symptoms of depression and mania in
humans.

"We found that the destabilizing effects of lithium on this
signaling complex are observed at concentrations of lithium
that are in the range of the clinically effective doses used in
the treatment of humans," said Caron, the senior author of the
study.

Over the past several years, studies by another contributor
to this study, Robert J. Lefkowitz, James B. Duke Professor and
HHMI Investigator at Duke, have shown that many other
receptorss, similar to D2 receptors, can signal through the
formation of complexes organized by the protein beta-arrestin
2.

The researchers propose that targeting these beta-arrestin
signaling complexes might be an effective target to control
cell signaling. "We feel that this mechanism is a new principle
of pharmacology and could lead to drugs for a host of
disorders," said Caron.