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DR. RAE MATSUMOTO - University of Mississippi, Oxford
The Research: Potential Benefits of Having the Ocean On Your Mind
Rae Matsumoto's laboratory is focused on the development of new treatments for neurological
and psychiatric disorders, with a focus on pharmaceutical treatments for drug abuse,
anti-depressants, and pain management.
Prior to arriving at Ole Miss, Matsumoto's work dealt mainly with screening synthetic
compounds, and she had no marine science background whatsoever. However, she viewed the
chance to screen marine natural products as a major motivator for coming to Ole Miss,
with its strong marine program. Once she joined the team in the School of Pharmacology,
she began taking advantage of school's the vast marine natural products resources by
starting a screening program for compounds from her colleagues' collections. This work
has led to some extremely positive early results.
 - VIDEO CLIP 1: "Natural Products Research at the Cochran Research Center"
 Early Promise
A key focus of Matsumoto's marine natural products screening work has been anti-depressants. Soon after this work
began, she and her lab group identified compounds that proved "very, very powerful" in bioassays for this
application. "They produced antidepressant-like effects that are as good as and in many cases better than
known antidepressant medications, and so they look very promising, and very interesting for further studies,"
she says. Natural products from terrestrial sources have, historically, provided a wealth of medications for
diseases related to the central nervous system. Because of this, and the vast chemical diversity of marine
natural products, says Matsumoto, "we have a very good chance of identifying totally new drug classes that
could be potential antidepressant drugs."
- VIDEO CLIP 2: "Focus on Promising Marine Products: Potential as Anti-Depressants"
How Antidepressants Work
The mechanism of action for antidepressants is complicated, and much about them remains a mystery to
researchers. However, certain aspects of the activity are well known. In general, antidepressant drugs
work by interacting with proteins in the brain that transport serotonin, a chemical that constricts
blood vessels, acts as a neurotransmitter, and has critical effects in controlling moods. Antidepressants
interact with these serotonin transporters to increase serotonin's activity in the brain.
One confounding factor is that patients prescribed antidepressants generally have to take the drugs for
several weeks before beneficial effects occur. The real therapeutic activity of the drugs must therefore
stem from changes that occur after they interact with the serotonin transporters, and better understanding
this process is an ongoing research focus in the field.
Antidepressants such as the famous Prozac are one of the largest drug markets in the U.S. But Matsumoto
says there is a great need for new antidepressants because of the long time it takes for currently used
drugs to take effect, and to reduce relatively recently identified side effects of Prozac and other drugs
such as increased risk of suicide.
- VIDEO CLIP 3: "Of Mice and Medication: Compound Evaluation Using Animal Models"
How Do You Make a Mouse Depressed?
As with all pharmaceuticals, researchers must first study the effects of a potential drug on animals such as mice
before human clinical trials can begin. However, developing an animal model for depression poses an obvious
challenge. In 1977, a group of French researchers published a solution to this challenge in the journal Nature
after Science rejected their paper calling it "not sufficiently interesting." The work proved extremely enduring
nonetheless as the same basic test remains the one most widely used, and one that Matsumoto uses extensively.
The basic concept is that if a rat or mouse is placed into a cylinder of water from which it cannot escape,
after thrashing about quite a bit it will eventually give up and float, making only movements necessary to keep
their heads above water. If placed back in the cylinder 24 hours later, an animal will quickly resume this
inactive posture. That is, unless the animal receives an antidepressant. In that case, the animal's swimming
and attempts to get out of the cylinder increase measurably. The thinking is that the immobility reflects
a sort of despair in the mice that mimics to some extent human depression.
The lead researcher for the technique, Roger Porsolt, had moved to Paris in 1975 to work as a behavioral
pharmacologist. His adviser wanted him to set up new behavioral models and had given him a number of articles
about "helpless behavior" in dogs exposed to "inescapable shock." Being rather fond of dogs he was not very
enthusiastic about the concept and at any rate did not see how a useful test could be developed based on this
work. However, at that time he was doing learning experiments on rats using a water maze. He noticed that some
of the rats, after exploring a bit, simply gave up and stopped moving. With the dog work in mind, it occurred
to him that the rats may have thought there was no way to escape the maze and simply given up.
Though some of his colleagues mocked the idea, Porsolt decided to set up experiments to see how rats would
react in water in different kinds of containers. Porsolt recalls inviting even more skepticism when he started
looking at the effects of antidepressants on rats placed in the containers but the results were encouraging
enough to publish.
The test has remained in wide use because it is very simple to perform, has proven effective at identifying
a wide range of potential antidepressants, and because results of forced swim tests have proven extremely
reproducible between countless laboratories. (Reference: Porsolt R.D., Le Pichon M. and M. Jalfre. 1977.
Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730-732.)
- VIDEO CLIP 4: "Limitations of Current Anti-Depressants"
Education
Rae Matsumoto received a bachelor's from Creighton University in Omaha Nebraska, and master's and Ph.D. degrees
from Brown University in Providence, R.I. She completed postdoctoral research at both Brown and Northwestern
before taking a professorship at the Univ. of Calif., Irvine. Matsumoto then worked at the Oklahoma University
Health Science Center for nearly a decade before taking her current position at the University of Mississippi.
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