Psychiatr News January 6, 2006
Volume 41, Number 1, page 28
© 2006 American Psychiatric Association
Search for Psychotropics Focuses on Receptors
Joan Arehart-Treichel
Canadian scientists have devised a radical new way to develop a class of
drugs that may be effective in dealing with addiction and psychosis. They call
their drugs "interference peptide drugs."
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Yu Tian Wang, M.D., Ph.D., and Anthony Phillips, Ph.D., are shown in
their lab at the University of British Columbia Hospital.
Joan Arehart-Treichel
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It's a typical November day in Vancouver, British Columbia—rain
drumming on roofs, wind thrashing the tips of firs—as pedestrians rush
toward the University of British Columbia Hospital.
The hospital entrance, however, is well lit and friendly. An intriguing
sign reads "Brain Research Centre."
Some research taking place in the center, in fact, is not just
novel—it might possibly revolutionize the design of psychotropic
drugs.
The research is headed by Anthony Phillips, Ph.D., director of the
University of British Columbia Institute of Mental Health, and by Yu Tian
Wang, M.D., Ph.D., a senior investigator at the Brain Research Centre.
"The concept that we are working on," Phillips explained with a
hint of a British accent, "could lead to a new generation of
psychotropic drugs that would target much more selectively the regulation of
nerve receptors in the brain than current psychotropic drugs do."
In essence, one of these so-called "interference peptide drugs"
would not block a receptor or activate a receptor, as current psychotropic
medications do, but rather would influence the movement of receptors in and
out of the membrane of nerve cells.
It all started with nerve cell plasticity, where a nerve changes its firing
in response to a stimulus it has received—say, through learning, through
the environment, or through substance abuse. To accomplish this change in
firing, neurons appear to alter the number of two types of glutamate receptors
on their synaptic membranes. These are the NMDA and AMPA receptors. The way
the neurons change the number of the receptors is either by adding them to the
membrane or by removing them from it.
"I think this is an incredibly important breakthrough. It is a new
concept in drug development that could have a real impact."
During the past five years or so, Wang discovered the identity of
phosphorylation sites on the AMPA receptor that are critical for its removal
from the nerve cell membrane. With that knowledge, he then designed a small
sequence of amino acids—a peptide—that would prevent
phosphorylation of a critical part of the AMPA receptor and in turn keep the
receptor from being removed from the nerve cell membrane.
"So what we have done," Phillips explained, "is that we
have prevented, with this very tiny peptide, the working of machinery that is
responsible for the movement of the AMPA receptor, which is one form of
synaptic plasticity. In other words, we have taken a good part of the nerve
cell's capacity to adapt to certain forms of experience out of
commission."
The next challenge facing Phillips, Wang, and their colleagues was figuring
out how to transport the tiny peptide from the bloodstream into the brain.
Here they capitalized on other scientists' discovery that there is a benign
part of the virus that causes AIDS that is able to cross the blood-brain
barrier. They thus coupled their little peptide to this viral sequence so that
the sequence could carry the peptide from the bloodstream into the brain.
"So now we have the peptide—the pay-load—inside the nerve
cell," Phillips explained. "There are millions of nerve cells in
the brain that contain these AMPA receptors. The beauty of this approach is
that our little `interference peptide drug' does not block all the AMPA
receptors in the brain; it only blocks a small portion that have been changed
through experience—say, through learning, through the environment, or
through substance abuse. So this provides unique specificity, which is very
hard to come by through conventional pharmacology. And when you have this
amount of specificity, you have far less chance of side effects."
But then another question arose: Does the peptide also change behavior?
Here, the researchers tested the peptide on experimental animals that had been
repeatedly exposed to amphetamines. They found that the peptide subdued the
animals' excited reactions to the amphetamines.
Thus, not only can the peptide get into the brain and block the removal of
AMPA receptors from nerve cells that have been changed through experience, but
it also seems to be able to alter behavior as a result. But how might it
benefit people with mental illness? Repeated exposure to amphetamines can
cause not just addiction, but psychosis, Phillips explained. So the drug might
be able to combat aspects of either drug addiction or psychosis, he
believes.
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The Brain Research Center in the UBC Hospital
Joan Arehart-Treichel
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"It is very encouraging," he said, "because in
preclinical experiments we have completely and selectively blocked enhanced
stereotype behaviors that result from repeated exposure to
amphetamines."
The drug might also be able to counter other kinds of psychosis than that
provoked by amphetamines, Phillips noted. "There are many theories about
glutamate being a critical receptor in schizophrenia—in the expression
of psychosis and a target for its control."
Phillips, Wang, and their team will conduct toxicology tests with the
peptide over the next year, and if the peptide is not harmful to animals, they
will then attempt to obtain permission from the U.S. Food and Drug
Administration and its Canadian counterpart to test the peptide in humans.
If such clinical trials get a green light, the researchers hope that a
pharmaceutical company will be willing to conduct them, Phillips said.
Meanwhile, said Phillips, "I think this is an incredibly important
breakthrough. It is a new concept in drug development that could have a real
impact. We have to get other researchers excited about it."
The latest study from Phillips, Wang, and their colleagues,
"Nucleus Accumbens Long-Term Depression and the Expression of Behavioral
Sensitization," was published in the November 25, 2005 Science.
An abstract is posted at
<www.sciencemag.org/cgi/content/abstract/310/5752/1340>.
Science 2005 310 1340[Abstract/Free Full Text]
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