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Research on LSD and other drugs yields clue to schizophrenia
BY RENEE TWOMBLY
The same protein responsible for the bizarre behavior
that characterizes people on LSD and other drugs may be a new target in the
treatment of schizophrenia, Rockefeller scientists say.
A study on mice reported in the November 21 issue of Science shows that although
three different drugs — LSD, PCP (or “angel dust”) and
amphetamine — each act on a different chemical transmitter in the
brain, they are all eventually processed by the same protein.
The protein is called DARPP-32, and the research, led
by Paul Greengard, Vincent Astor Professor and head of the Laboratory of
Molecular and Cellular Neuroscience, suggests it works like the thin neck
in an hourglass. Because all three drugs are processed through the same
pathway, they all produce very similar schizophrenia-like symptoms.
“For the first time, we can explain through a
molecular model why these drugs all produce the same kind of
behavior,” says the study’s first author, Per Svenningsson, a
research assistant professor in Greengard’s lab.
Like many other proteins, DARPP-32 can be activated by
the addition of a phosphate molecule to (a process called phosphorylation)
or by removal of a phosphate molecule from (dephosphorylation) any of
several specific amino acid sites of DARPP-32. The Rockefeller team found
that DARPP-32 was phosphorylated or dephosphorylated at three sites by the
three drugs. To understand the precise functional importance of these three
phosphorylation sites, the scientists created a series of
“knockin” mice, in which each of these sites on the DARPP-32
protein were mutated. The behavior of these mice in response to the drugs
was then compared to that of non-mutant mice, and it turned out that the
mutant mice acted normally even after taking stimulating doses of LSD, PCP
and amphetamine.
The research team was also able to abolish the effects
of the drugs by experimentally blocking the function of one of the 205
DARPP-32 amino acids.
The study does not suggest that DARPP-32 is the root
cause of schizophrenia in people, but it does provide new avenues for
treating the disease, says Greengard. “The results are remarkable
because they show that a single amino acid on a single protein, by being
altered, can abolish the effects of these psychotomimetic drugs on
behavior,” says Greengard, who shared the 2000 Nobel Prize in
Medicine or Physiology for his work on neurotransmitters and signalling in
the nervous system. “The research certainly indicates new targets for
the development of antipsychotic drugs.”
The study also answers a long-standing debate in
psychiatry about the neurotransmitter primarily responsible for
schizophrenia. “It turns out everyone was right, because each of
these drugs work on a common pathway regulated by DARPP-32,” says
Greengard.
Previous research by Svenningsson and Greengard also
has demonstrated that DARPP-32 regulates the actions of medications such as
Prozac, to treat depression, as well as drugs such as cocaine, opiates and
nicotine. “We have begun to believe that DARPP-32 is really a master
molecule that integrates information coming in from all parts of the brain,
and is involved in mediating and regulating the actions of many, many
neurotransmitters,” says Greengard.
December 12, 2003
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