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 Custom-tailored strategy against glioblastomas
26.09.2016 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht New leukemia treatment offers hope
23.09.2016 | King Abdullah University of Science and Technology

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: First quantum photonic circuit with electrically driven light source

Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.

Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...

Im Focus: OLED microdisplays in data glasses for improved human-machine interaction

The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.

“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...

Im Focus: Artificial Intelligence Helps in the Discovery of New Materials

With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.

Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...

Im Focus: Complex hardmetal tools out of the 3D printer

For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.

Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...

Im Focus: Launch of New Industry Working Group for Process Control in Laser Material Processing

At AKL’16, the International Laser Technology Congress held in May this year, interest in the topic of process control was greater than expected. Appropriately, the event was also used to launch the Industry Working Group for Process Control in Laser Material Processing. The group provides a forum for representatives from industry and research to initiate pre-competitive projects and discuss issues such as standards, potential cost savings and feasibility.

In the age of industry 4.0, laser technology is firmly established within manufacturing. A wide variety of laser techniques – from USP ablation and additive...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Experts from industry and academia discuss the future mobile telecommunications standard 5G

23.09.2016 | Event News

ICPE in Graz for the seventh time

20.09.2016 | Event News

Using mathematical models to understand our brain

16.09.2016 | Event News

 
Latest News

The Flexible Grid Involves its Users

27.09.2016 | Information Technology

Process-Integrated Inspection for Ultrasound-Supported Friction Stir Welding of Metal Hybrid-Joints

27.09.2016 | Machine Engineering

First quantum photonic circuit with electrically driven light source

27.09.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>