Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

21.11.2003


Findings may lead to new drug targets for treating schizophrenia



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.

"This is remarkable because it shows 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 DARPP-32. "The research certainly indicates new targets for the development of antipsychotic drugs."

The study also answers a long-standing debate in psychiatry as to which neurotransmitter is primarily responsible for schizophrenia, says Greengard, because researchers have known that drugs like LSD, PCP and amphetamines, which act on different transmitters, create the same psychoses as seen in 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 of abuse 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.

The investigators knew that, like many such proteins, DARPP-32 can be activated by the addition of a phosphate molecule (a process called "phosphorylation") or by removal of a phosphate molecule ("dephosphorylation") on specific amino acid sites.

In the findings reported in Science, the Rockefeller team found that DARPP-32 was phosphorylated or dephosphorylated at three sites by the studied psychotomimetics, in a pattern that worked together to inhibit an enzyme downstream of DARPP-32 called protein phosphatase-1 (PP-1). PP-1 helps regulate its own series of biochemical reactions that lead to physiological responses.

In order 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 behavioral responsively to LSD, PCP and amphetamine were thereafter compared between these mutant mice and normal mice. It turned out that single mutations in the amino acid sequence of DARPP-32 virtually abolished the behavioral actions of the psychotomimetics.

Schizophrenia-like symptoms such as repetitive movements and sensory perception defects induced by the psychotomimetics were strongly attenuated in two of the three different mutant mouse lines, implicating a critical involvement of two distinct, but interacting, phosphorylation sites of DARPP-32 in the actions of LSD, PCP and amphetamine, says Svenningsson.

Ongoing research is aimed at further understanding how DARPP-32 can process a wide variety of neurotransmitters that affect behavior, he says. "This master molecule seems to be involved in many behaviors, including those related to mood and the way we perceive the world," says Svenningsson.


Co-authors of the study, funded by the National Institutes of Health, include researchers from Rockefeller University (Robert Carruthers and Ilan Rachleff), Eli Lilly and Company (Eleni Tzavara, David McKinzie, George Nomikos), Lexicon Genetics, Inc. (Sigrid Wattler and Michael Nehls) and Intra-Cellular Therapies (Allen Fienberg). Fienberg also is affiliated with Rockefeller University.

Joseph Bonner | EurekAlert!
Further information:
http://www.rockefeller.edu/

More articles from Health and Medicine:

nachricht Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University

nachricht Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>