The mice -- which have a defect in a gene -- are expected to be useful as a new model organism in the effort to develop more effective medications for specific forms of depression. The research, led by Bernhard Luscher, a professor of biology at Penn State, will be published in the journal Biological Psychiatry.
"A mouse can't tell us if it is feeling depressed, so we used a number of different kinds of tests -- including some new ones that we developed -- to gauge behavioral and hormonal changes, or phenotypes, of a type of depression that, in humans, does not respond well to some antidepressant drugs," Luscher said. "These indicators include reduced exploration of novel or otherwise aversive environments, failure to escape from a highly stressful situation, and reduced pleasure-seeking behavior such as a reduced preference for sweet over plain water."The genetic defect in the depressed mice interferes with the function of a protein in the brain called the GABA-A receptor, which controls the response to the neurotransmitter gamma-aminobutryic acid. Reduced function of these receptors has been known to be be involved in anxiety disorders -- but not in depression -- because currently available drugs that activate the GABA-A receptor are ineffective as antidepressants. "We have shown in this paper that this long-held conviction is flawed," Luscher said. "Our research shows that the GABA-A receptor is, in fact, an important part of the brain circuitry that is not working properly in depression."
One of the interesting results of Luscher's new research is that some antidepressant drugs completely reverse the behavioral and hormonal symptoms of depression in the GABA-A-receptor-deficient mice, bringing their behavior to the level of normal, "wild-type" mice. At the same time, the normal mice had almost no reaction to the drugs. "This result is expected of a mouse model that mimics depression because normal people do not seem to gain anything from taking antidepressants," Luscher explained. These experiments show that this strain of genetically defective mice is a useful animal model for laboratory studies that could be useful for understanding human depression.
One of the major gaps of knowledge about depression in humans is that scientists do not know why some antidepressant drugs fail to help about 30 percent of depressed patients. Because doctors don't have a way of knowing which drug has the best chance of working for a particular patient, they resort to trying one after another hoping to find one that will work. This problem is compounded by the fact that it can take weeks before the drugs show any measurable benefit.
Luscher's team tested two kinds of antidepressant drugs in the mice and found that one of the drugs reduced symptoms of anxiety, but not of depression, whereas the other drug reduced both anxiety and depression symptoms. "The one that did not normalize depression-related behaviors is fluoxetine -- the generic name for Prozac -- which works on the neurotransmitter serotonin," Luscher said. The drug that reduced both depression and anxiety symptoms in the mice is desipramine, which works on a different neurotransmitter, noradrenaline. These results are interesting because there is a large group of depressed patients that do not respond well to Prozac. "In human patients with a type of depression called melancholic depression, fluoxetine/Prozac doesn't work as an antidepressant but desipramine does work. These mice are a bit like those patients who don't respond to Prozac," Luscher said.
Patients who don't respond to Prozac have increased serum levels of the hormone cortisol, which in mice is called corticosterone. "Our mice also showed abnormal corticosterone levels analogous to those patients who don't respond to Prozac," Luscher said. "In people, the cortisol level is corrected by drugs such as desipramine, and so it is in our mice. Desipramine corrects corticosterone levels in our mice but fluoxetine does not."
Luscher's paper also describes how he has begun to use this mouse model of drug-resistant depression to learn about the role of developmental factors in the onset of depression. His research suggests that the hormonal defect alone is not sufficient to produce the behavioral symptoms of depression, at least not if the hormonal abnormality is present only in adulthood. "Some research indicates that if you are born with certain types of risk factors, and something highly stressful happens in your life, such as a war experience -- then that event can trigger a mood disorder if you already have a risk factor," Luscher said.
"One of the many things we now want to explore is whether a slightly different strain of GABA-A-receptor-deficient mice, which are behaviorally normal but have increased levels of stress hormones, are at risk of developing depression if they experience additional excessive stress," Luscher said. "We also want to understand in greater detail what happens in these mice biochemically -- to understand which genes throughout the entire genome are affected by the defect in this one gene, and the resulting depression-like brain state."
This research was supported by research grants from the U. S. National Institutes of Mental Health and the Pennsylvania Department of Health.
[ Barbara K. Kennedy ]CONTACTS
Barbara K. Kennedy | EurekAlert!
Neutrons produce first direct 3D maps of water during cell membrane fusion
21.09.2018 | DOE/Oak Ridge National Laboratory
Narcolepsy, scientists unmask the culprit of an enigmatic disease
20.09.2018 | Universitätsspital Bern
The building blocks of matter in our universe were formed in the first 10 microseconds of its existence, according to the currently accepted scientific picture. After the Big Bang about 13.7 billion years ago, matter consisted mainly of quarks and gluons, two types of elementary particles whose interactions are governed by quantum chromodynamics (QCD), the theory of strong interaction. In the early universe, these particles moved (nearly) freely in a quark-gluon plasma.
This is a joint press release of University Muenster and Heidelberg as well as the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt.
Then, in a phase transition, they combined and formed hadrons, among them the building blocks of atomic nuclei, protons and neutrons. In the current issue of...
Thin-film solar cells made of crystalline silicon are inexpensive and achieve efficiencies of a good 14 percent. However, they could do even better if their shiny surfaces reflected less light. A team led by Prof. Christiane Becker from the Helmholtz-Zentrum Berlin (HZB) has now patented a sophisticated new solution to this problem.
"It is not enough simply to bring more light into the cell," says Christiane Becker. Such surface structures can even ultimately reduce the efficiency by...
A study in the journal Bulletin of Marine Science describes a new, blood-red species of octocoral found in Panama. The species in the genus Thesea was discovered in the threatened low-light reef environment on Hannibal Bank, 60 kilometers off mainland Pacific Panama, by researchers at the Smithsonian Tropical Research Institute in Panama (STRI) and the Centro de Investigación en Ciencias del Mar y Limnología (CIMAR) at the University of Costa Rica.
Scientists established the new species, Thesea dalioi, by comparing its physical traits, such as branch thickness and the bright red colony color, with the...
Scientists have succeeded in observing the first long-distance transfer of information in a magnetic group of materials known as antiferromagnets.
An international team of researchers has mapped Nemo's genome, providing the research community with an invaluable resource to decode the response of fish to...
21.09.2018 | Event News
03.09.2018 | Event News
27.08.2018 | Event News
21.09.2018 | Physics and Astronomy
21.09.2018 | Life Sciences
21.09.2018 | Event News