Discovery could lead to new therapies for anxiety and other mental disorders

John johnhkm at
Wed Sep 1 09:07:40 EST 1999

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Discovery could lead to new therapies for anxiety and other mental disorders

Irvine, Calif., Aug. 30, 1999 — Our ability to cope with stressful
situations may be due partly to a tiny protein in the brain, a UC Irvine
scientist and his colleagues have found. The finding in mice is the first to
demonstrate how this protein works with other chemicals in the brain to
control reactions to stress and eventually could result in new therapies and
drugs to cope better with stress-related mental disorders.
Pharmacology researcher Rainer Reinscheid, Professor Olivier Civelli and
researcher Hans-Peter Nothacker of UCI's College of Medicine and a team from
Switzerland and Germany found that mice that were unable to produce the
protein called orphanin FQ/nociceptin were unusually anxious in stressful
situations, and were unable to adapt to stresses as well as mice that could
produce the protein. The findings appear in the Aug. 31 edition of the
Proceedings of the National Academy of Sciences.
Orphanin FQ/nociceptin is a small protein that Reinscheid and Civelli
discovered about four years ago. It is found in a part of the brain called
the amygdala and in regions of the hypothalamus, areas known to regulate
reactions to stressful events such as pain and fear. Since their initial
discovery, Reinscheid and his colleagues have been exploring the roles
orphanin FQ/nociceptin may play in handling stress. The researchers' latest
study shows that mice lacking the genes that produce this protein reacted
more nervously to new situations than mice that could produce it. In
addition, they found that mice without the gene never seemed to adapt to
repeated stresses; they instead continued to react with the same intensity.
Usually, the body adapts to repeated stresses with increasingly calm
responses: pulse rates slow, the body produces less adrenaline and other
stress hormones, and behavior is less abrupt.
"By knocking out the gene that makes orphanin FQ/nociceptin, we can see for
the first time what types of behavior this protein controls in the brain,"
Reinscheid said. "This experiment not only confirmed that orphanin
FQ/nociceptin is essential for the body to manage stress, but that it is
also needed for long-term adaptation to repeated stressful situations."
The research suggests that orphanin FQ/nociceptin normally acts against the
body's tendency to create a "fight—or—flight" reaction to stress. This
reaction includes the production of hormones by the adrenal and pituitary
glands and increased activity in parts of the brain that control awareness
and motor reactions. The reactions provide animals with an extra metabolic
"boost," so they can either escape from or fight off threats.
Reinscheid believes that orphanin FQ/nociceptin's opposition to this "fight
or flight" system results in carefully modulated responses to stress. If
stress continues for too long or is severe, however, the body can develop
adverse reactions. Mental illnesses such as anxiety disorders, depression or
obsessive-compulsive disorders ultimately may develop.
The researchers now are looking at how orphanin FQ/nociceptin works on parts
of the brain to alleviate stress and what controls the genes that help
produce orphanin FQ/nociceptin.
"By looking further at how mice that lack the protein fail to adapt to
stress, we may be able to determine exactly how orphanin FQ/nociceptin works
against the stress-inducing hormones and neurotransmitters in the brain,"
Reinscheid said. "Eventually, knowing how this protein works could provide
us with new drugs or other therapies that treat mental illnesses that are
often caused by prolonged stress."
The UCI researchers were assisted by Anja Koester, Francois Jenck and
Jean-Luc Moreau at Hoffman-La Roche in Basel, Switzerland; Alexandra
Montkowski, Eva-Maria Stuebe and Kristina Knaudt of the University of
Hamburg, Germany, and Stefan Schulz of Otto-von-Guericke University,
Magdeburg, Germany.


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