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Research on LSD and other drugs yields clue to schizophrenia
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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