(Press-News.org) The response time to antidepressants, such as Prozac, is around three weeks. How can we explain this? The adaptation mechanisms of the neurons to antidepressants has, until now, remained enigmatic. Research, published this week by the teams of Odile Kellermann (Inserm Unit 747 Cellules souches, Signalisation et Prions, Université Paris-Descartes) and of Jean-Marie Launay (Inserm Unit 942 Hôpital Lariboisière, Paris and the mental health network, Santé Mentale), sheds new light on the mechanisms of action of these drugs which have been used for more than 30 years and are heavily consumed over the world. In particular, the researchers have revealed, for the first time, a sequence of reactions caused by Prozac at the neuron level, which contributes to an increase in the amounts of serotonin, a chemical "messenger" essential to the brain, and deficient in depressive individuals.
Details of this work are published in the journal Science dated 17 September 2010.
Depressive states are associated with a deficit of serotonin (5-HT), one of the neurotransmitters essential for communication between neurons and particularly involved in eating and sexual behaviours, the sleep-wake cycle, pain, anxiety and mood problems.
Strategies employing antidepressant class I molecules, developed since the 1960s are thus primarily aimed at increasing the quantity of serotonin released in the synaptic gap, the space between two neurons, where the nervous communications take place via the neurotransmitters. Although it has been known for several years that antidepressants like Prozac have the effect of increasing the concentration of serotonin by blocking its recapture by the serotonin transporter (SERT) in the synapses, we did not hitherto know how to explain the delay in their action (3 weeks).
The teams of Odile Kellermann and of Jean-Marie Launay, in close collaboration with Hoffmann-LaRoche (Basel), have now characterised, for the first time, in vitro and then in vivo, the various reactions and intermediate molecules produced in the presence of Prozac, which are eventually responsible for an increased release of serotonin. In particular, the researchers have identified the key role of one particular microRNA in the active mechanisms of the antidepressants on the brain*.
This microRNA, known as miR-16, controls synthesis of the serotonin transporter.
Under normal physiological conditions, this transporter is present in the so-called "serotonergic" neurons, i.e. neurons specialised in production of this neurotransmitter. However, expression of this transporter is reduced to zero by miR-16 in so-called "noradrenaline" neurons, another neurotransmitter involved in attention, emotions, sleep, dreaming and learning.
In response to Prozac, the serotonergic neurons release a signal molecule, which causes the quantity of miR-16 to drop, which unlocks expression of the serotonin transporter in the noradrenaline neurons.
These neurons become sensitive to Prozac. They continue to produce noradrenaline, but they become mixed: they also synthesise serotonin. Ultimately, the quantity of released serotonin is increased both in the serotonergic neurons, via the direct effect of the Prozac which prevents its recapture, and in the noradrenaline neurons through the reduction of miR-16.
Hence, "this will work has revealed, for the first time, that antidepressants are able to activate a new 'source' of serotonin in the brain", explain the researchers "Furthermore, our results demonstrate that the effectiveness of Prozac rests on the 'plastic' properties of the noradrenaline neurons, i.e. their capacity to acquire the functions of serotonergic neurons".
To elucidate the mode of action of Prozac, the researchers from the Ile-de-France region used neuron stem cells which were able to differentiate themselves into neurons for manufacturing serotonin or noradrenaline. The cells, isolated and characterised by the two research teams, allowed them to reveal using pharmacological and molecular approaches, the functional links between Prozac, miR-16, serotonin transporter and the signal-molecule trigger, known as S100Beta. These links observed in vitro have been validated in vivo in mice, in the serotonergic neurons of the raphe and the noradrenaline neurons in the locus coeruleus. Dialogue between these two areas of the brain, situated under the cortex in the brainstem, is therefore one of the keys to Prozac action.
Behavioural tests have moreover confirmed the importance of miR-16 as an intermediary in Prozac action.
These results open up new avenues of research for the treatment of depressive states. Each of the "actors" in the sequence of reactions initiated by Prozac constitutes a potential pharmacological target.
The pharmacological dynamics of antidepressants, i.e. the study of the speed of action of these molecules, should also be the subject of new investigations in light of these new ideas.
INFORMATION:
Source
"miR-16 Targets the Serotonin Transporter: A New Facet for Adaptive Responses to Antidepressants"
Anne Baudry,1 Sophie Mouillet-Richard,1 Benoît Schneider,1, Jean-Marie Launay,2,3 Odile Kellermann1
1 Unité Inserm 747, Université Paris Descartes, « Cellules Souches, Signalisation et Prions » 75006 Paris, France.
2 Pharma Research Department, F. Hoffmann-La-Roche, CH-4070 Basel, Switzerland.
3 Assistance Publique-Hôpitaux de Paris Service de Biochimie, RTRS Santé Mentale, Unité Inserm 942 Hôpital Lariboisière, Paris, France
Science, september 17th 2010, vol. 329, n°5998
Research contacts
Odile Kellermann
Professor, University Paris XI, ENS-Ulm delegate
Inserm Unit 747 "Cellules souches, Signalisation et Prions" Université Paris Descartes
Tel: +33 (0)1 42 86 20 65
E-mail: odile.kellermann@parisdescartes.fr
Jean-Marie Launay
PU-PH, Hôpital Lariboisière, Biochemistry department
Tel: +33 (0)1 49 95 64 33
E-mail: jean-marie.launay@lrb.aphp.fr
What, in nature, drives the incredible diversity of flowers? This question has sparked debate since Darwin described flower diversification as an 'abominable mystery.' The answer has become a lot clearer, according to scientists at the University of Calgary whose research on the subject is published today in the on-line edition of the journal Ecology Letters.
Drs. Jana Vamosi and Steven Vamosi of the Department of Biological Sciences have found through extensive statistical analysis that the size of the geographical area is the most important factor when it comes to biodiversity ...
An ancestor of HIV that infects monkeys is thousands of years older than previously thought, suggesting that HIV, which causes AIDS, is not likely to stop killing humans anytime soon, finds a study by University of Arizona and Tulane University researchers.
The simian immunodeficiency virus, or SIV, is at least 32,000 to 75,000 years old, and likely much older, according to a genetic analysis of unique SIV strains found in monkeys on Bioko Island, a former peninsula that separated from mainland Africa after the Ice Age more than 10,000 years ago. The research, which appears ...
The moon is more geologically complex than previously thought, scientists report Sept. 17 in two papers published in the journal Science.
Their conclusion is based on data from the Diviner Lunar Radiometer Experiment aboard NASA's Lunar Reconnaissance Orbiter (LRO), an unmanned mission to comprehensively map the entire moon. The spacecraft orbits some 31 miles above the moon's surface.
The new data reveal previously unseen compositional differences in the moon's crustal highlands and have confirmed the presence of material surprisingly abundant in silica — a compound ...
Catalan researchers have studied the factors relating to urban transport service provision in 45 European cities, including Barcelona, Bilbao and Madrid. The study, published in the latest issue of Transportation research part E-logistics and transportation review, concludes that Central European cities have the best urban transport service provision in Europe. Capital cities are at the head of the league, both in terms of supply and demand.
"The geographic variables we studied show that Mediterranean countries have the least developed (offer the poorest range) in terms ...
Some intensive care patients develop post-traumatic stress syndrome (PTSD) after the trauma of a difficult hospital stay, and this is thought to be exacerbated by delusional or fragmentary memories of their time in the intensive care unit. Now researchers writing in BioMed Central's open access journal Critical Care have found that if staff and close relatives make a diary for patients, featuring information about their stay and accompanied by photographs, PTSD rates can be significantly reduced.
Professor Richard Griffiths and Christina Jones from the University of Liverpool, ...
People who have used cocaine run a great risk of becoming addicted, even after long drug-free periods. Now researchers at Linköping University and their colleagues can point to a specific molecule in the brain as a possible target for treatment to prevent relapses.
Drugs are addictive because they "hijack" the brain's reward system, which is actually intended to make it pleasurable to eat and have sex, behaviors that are necessary for survival and reproduction.
This "hijacking" is extremely long-lived and often leads to relapses into abuse, especially when the individual ...
London, UK (September 16, 2010) – Amid growing concern that synthetic life sciences pose biosecurity and biosafety risks, scrutiny is increasing into the burgeoning DNA sequence trade. Research published today in the Bulletin of the Atomic Scientists, published by SAGE, looks at the necessity of a global regulator for DNA trade, and the significant barriers to creating one.
Synthetic life sciences are making breakthroughs at a breakneck pace, and could offer technological fixes for our future ecological, technological, and biomedical challenges. But these benefits also ...
During the collision of India with the Eurasian continent, the Indian plate is pushed about 500 kilometers under Tibet, reaching a depth of 250 kilometers. The result of this largest collision in the world is the world's highest mountain range, but the tsunami in the Indian Ocean from 2004 was also created by earthquakes generated by this collision. The clash of the two continents is very complex, the Indian plate, for example, is compressed where it collides with the very rigid plate of the Tarim Basin at the north-western edge of Tibet. On the eastern edge of Tibet, the ...
A wall painting (fresco) of Tyche, the Greek goddess of fortune, was exposed during the 11th season of excavation at the Sussita site, on the east shore of the Sea of Galilee, which was conducted by researchers of the University of Haifa. Another female figure was found during this season, of a maenad, one of the companions of the wine god Dionysus.
"It is interesting to see that although the private residence in which two goddesses were found was in existence during the Byzantine period, when Christianity negated and eradicated idolatrous cults, one can still find clear ...
VIDEO:
New imaging technique developed by cardiologist, Dr. James A. White and colleagues at The University of Western Ontario shows 3-D image of the heart vasculature and myocardial scar tissue.
Click here for more information.
Cardiologists and surgeons may soon have a new tool to improve outcomes for patients requiring pacemakers, bypass surgery or angioplasties. Research led by Dr. James White and his colleagues at The University of Western Ontario has led to a new imaging ...