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Brain's 'master molecule' produces same behavior in mice from three different psychostimulant drugs

A mouse study reported in this week's Science magazine shows that three drugs, each acting on a different chemical transmitter in the brain, all produce the same schizophrenia-like symptoms by acting on a single "master molecule" in the brain.

The findings, reported by researchers at Rockefeller University with collaboration from three pharmaceutical and biotech companies, provides, for the first time, a cellular model detailing how this crucial protein, known as DARPP-32, interacts with multiple neurotransmitter systems to produce behavior.

The scientists demonstrate that DARPP-32 acts like the thin neck in an hourglass, through which all signals taken into a nerve cell must pass and be processed, producing a wide variety of biochemical reactions. In this case, three different drugs of abuse, LSD, PCP ("angel dust") and amphetamine, work on three different neurotransmitters, serotonin, glutamate, and dopamine, respectively. All three drugs, which are classified as psychotomimetics or psychostimulants, are processed within the DARPP-32 hourglass neck through the same pathway, thus producing very similar physiological symptoms.

"For the first time, we can explain through a molecular model why these drugs all produce the same kind of behavioral symptoms," says the study's first author, Per Svenningsson, M.D., Ph.D., a research assistant professor in the Laboratory of Molecular and Cellular Neuroscience, headed by Paul Greengard, Ph.D.

Clinically, the study does not suggest that DARPP-32 is the root cause of schizophrenia, but it does provide new avenues in which to treat the disease, says Greengard, Vincent Astor Professor at Rockefeller and the study's principal investigator.

By experimentally blocking the function of one of the 205 amino acids that make up DARPP-32, the research team was able to abolish the effects of the drugs, all of which have long been known to produce schizophrenia-like behavior in both mice and humans
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Contact: Joseph Bonner
bonnerj@rockefeller.edu
212-327-8998
Rockefeller University
20-Nov-2003


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