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Nobelist discovers antidepressant protein in mouse brain

A protein that seems to be pivotal in lifting depression has been discovered by a Nobel Laureate researcher funded by the National Institutes of Health's National Institute of Mental Health (NIMH).

"Mice deficient in this protein, called p11, display depression-like behaviors, while those with sufficient amounts behave as if they have been treated with antidepressants," explained Paul Greengard, Ph.D., a Rockefeller University neuroscientist who received the 2000 Nobel Prize in Physiology or Medicine for discoveries about the workings of such neuronal signaling systems. He and his colleagues found that p11 appears to help regulate signaling of the brain messenger chemical serotonin, a key target of antidepressants, which has been implicated in psychiatric illnesses such as depression and anxiety disorders. They report on their findings in the January 6, 2005 issue of Science.

Brain cells communicate with each other by secreting messengers, such as serotonin, which bind to receptors located on the surface of receiving cells. Serotonin selective reuptake inhibitors (SSRIs), medications commonly prescribed for anxiety and depression, compensate for reduction in serotonin signaling by boosting levels and binding of serotonin to receptors. Previous studies have suggested that serotonin receptors are essential in regulating moods and in mediating the effects of SSRIs, but given the complexity of the serotonin system, exactly how these receptors work remains a mystery.

To explore how a particular serotonin receptor (5-HT1B) functions, Greengard and colleagues conducted tests to find out what proteins these receptors interact with in brain cells. They found that 5-HT1B interacts with p11, and according to Greengard, p11 plays a role in the recruitment of receptors to the cell surface where they are more functional.

This finding led the researchers to suspect that p11 levels might be directly involved in the development of depression, anxie ty and similar psychiatric illnesses thought to involve faulty serotonin receptors. To test this idea, the researchers examined p11 levels in the brains of depressed humans and "helpless" mice, considered a model of depression since they exhibit behaviors similar to those of depressed humans. They compared these two groups to non-depressed humans and control mice. Levels of p11 were found to be substantially lower in depressed humans and helpless mice, which suggests that altered p11 levels may be involved in the development of depression-like symptoms.

The researchers also examined the effect of treatments designed to boost weak serotonin systems on p11 levels in brain cells by administering to mice two types of antidepressants ?a tricyclic, a monoamine oxidase (MAO) inhibitor ?and electroconvulsive therapy (ECT).

"These three different ways of treating depression all caused an increase in the amount of p11 in the brains of these mice," said Greengard. "They all work in totally different ways, but in all cases they caused the same biochemical change. So, it's pretty convincing that p11 is associated with the main therapeutic action of antidepressant drugs."

Since humans and mice with symptoms of depression were found to have substantially lower levels of p11 in brain cells compared to non-depressed animals, Greengard and colleagues hypothesized that if p11 levels were increased, mice would exhibit antidepressant-like behaviors, and if p11 were reduced, mice would exhibit depression-like symptoms.

As hypothesized, mice with over-expressed p11 genes, compared to control mice, had increased mobility in a test that is used to measure antidepressant-like activity. They also had more 5-HT1B receptors at the cell surface that were capable of increased serotonin transmission.

The opposite occurred when researchers molecularly knocked out the p11 gene in mice. Compared to control mice, knockout mice had fewer receptors at the ce ll surface, reduced serotonin signaling, decreased responsiveness to sweet reward, and were less mobile, behaviors which are considered depression-like. Also, the 5-HT1B receptors of p11 knockout mice were less responsive to serotonin and antidepressant drugs compared to those of control mice, which further implicates p11 in the main action of antidepressant medications.

"Manipulations that are antidepressant in their activity increased the level of the protein and those which are depressant reduce it," said Greengard. "It seems as though antidepressant medications need to increase p11 levels in order to achieve their effect." Future studies should elucidate exactly how antidepressants increase levels of this molecule, he added.

Also participating in the study: Per Svenningsson, Ilan Rachleff, Marc Flajolet, The Rockefeller University; Karima Chergui, Xiaoqun Zhang, Karolinska Institute; Malika El Yacoubi, Jean-Marie Vaugeois, Faculty of Medicine and Pharmacy, Rouen Cedex, France; George G. Nomikos, Eli Lilly and Company.


Source:NIH/National Institute of Mental Health

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