March 30, 2000
Mice Show How to Calm Anxiety
Scientists have found a genetic switch that helps calm anxiety in
"stressed out" mice.
In three articles published in the April 2000 issue of the journal
Nature Genetics, three independent groups of researchers report
that Crhr2 (corticotropin-releasing hormone receptor-2), which is found
in pituitary gland tissue and in other areas of the brain, actually
quells the stress response in mice.
“It has long been known that many severe psychiatric disturbances show a heightening of the anxiety response.”
Michael G. Rosenfeld
One of the leaders of the research efforts, Michael
G. Rosenfeld, an HHMI investigator at the University of California,
San Diego (UCSD), cautioned that the discoveries represent only a
beginning in understanding the complexities of the stress response.
"It has long been known that many severe psychiatric disturbances
show a heightening of the anxiety response," Rosenfeld said. "With
these findings, we provide an initial motivation for further dissecting
two distinct receptor systems in terms of potential drug discovery
programs."
Rosenfeld's research group included his former UCSD colleague
Toshimitsu Kishimoto, who is now at Yoshitomi Pharmaceuticals in Japan,
and Jelena Radulovic and Joachim Spiess at the Max Planck Institute for
Experimental Medicine in Germany. The other groups were from the Oregon
Health Sciences University and The Salk Institute.
When a human or animal is stressed, the hypothalamus secretes the
hormone, corticotropin-releasing hormone (Crh), which stimulates the
pituitary gland to release additional hormones. These hormones from the
pituitary gland cause the adrenal gland to secrete hormones that stoke
the stress response, increasing anxiety, energy and blood pressure, and
suppressing immune responses.
According to Rosenfeld, previous studies by his group and by other
researchers revealed the existence of two distinct receptors for
Crh— Crhr1 and Crhr2 —in the pituitary and in other brain
regions involved in emotional and autonomic functions, as well as in
the periphery.
"These two receptors had overlapping but clearly distinct anatomical
patterns of expression in the brain," said Rosenfeld. "Also, previous
research had found that Crhr2 also responds to a different chemical
trigger, called eucortin.
"So, we set out to differentiate the potential distinct roles of the
Crhr2 receptor by creating a mouse in which the gene for the Crhr2
receptor was functionally deleted," said Rosenfeld.
Once the researchers produced mice that lacked a functional
Crhr2 gene, they measured the animals' anxiety by observing the
animals' response to stress-inducing situations such as bright light
and heights.
They discovered that male mice lacking Crhr2 showed a higher
level of anxious behavior than did normal mice. They also found that
male mice that lacked a single copy of the Crhr2 gene showed
anxiety levels that fell somewhere between those seen in normal mice
and those in mice that lacked two copies of Crhr2. In additional
experiments, the researchers showed that they could also induce anxiety
in mice by feeding them a drug that selectively blocked the Crhr2
receptor.
Further tests, in which the researchers used drugs to turn the Crhr1
receptor on or off, ruled out the Crhr1 receptor as a cause of
anxiety-producing activity.
And, in an intriguing finding, the researchers discovered that
female Crhr2-deficient mice did not show increased anxiety,
perhaps due to some compensating effect in those mice, speculated
Rosenfeld.
The scientists also found evidence that anxiety caused by
Crhr2-deficiency did not appear to be related to changes in the
receptor's function in the "hypothalamic-pituitary-adrenal" response to
stress. They believe the anxiety could be caused by a lack of Crhr2 in
specific areas of the brain that govern emotional and autonomic
functions. The scientists have begun to identify how anxiety is
triggered in those brain regions, where they have found markedly lower
levels of phosphorylation of the gene-regulatory transcription factor
CREB, in the absence of Crhr2 activity.
"Basically, we have found that the Crhr2 receptor in some areas of
the brain responds to Crh and acts to oppose the anxiety response,"
says Rosenfeld. "One might think of this activity of Crhr2 as a
focusing of the anxiety response. Thus, instead of having the animal
exhibit a full anxiety response to a stressful situation— with
many areas of the brain mediating a Crhr1-dependent anxiety
effect— other areas may exert specific anxiolytic actions on the
activity of the Crhr2 receptor."
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