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Paris, 16 September 2010
Press release
How does Prozac act? By acting on the microRNA…
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 in France. 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 all living organisms, ribonucleic acid, or RNA, this is used as an intermediate genetics support by our genes to manufacture
proteins which they require. The recently discovered microRNA are small RNA (20 nucleotides) which do not lead to the
synthesis of any proteins. Their function is to attach themselves to RNA targets to block the translation of the genetic protein
message.
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 miR16.
Comment les neurones à noradrénaline deviennent sensibles
au Prozac ?
Situation normale
Sérotonine (5-HT)
Fente synaptique
miR16
Neurones à sérotonine
Neurone à noradrénaline
Traitement au Prozac
Prozac
SERT
Signal ( S100β)
Sensibilité au Prozac
Induction
Le Prozac bloque la recapture de la sérotonine par le
transporteur (SERT) présent sur les neurones à sérotonine
Signal ( S100β) émis par les neurones à sérotonine
La baisse d’un microARN, miR16, déverrouille l’expression du
SERT.
Les neurones à noradrénaline devienntent sensibles au
Prozac.
How do noradrenaline neurons become sensitive to Prozac?
Normal situation
Serotonin (5-HT)
Synaptic gap
miR16
Serotonergic neurons
Noradrenaline neurons
Prozac treatment
Prozac
SERT
Signal (S100β)
Sensitivity to Prozac
Induction
Prozac blocks the recapture of serotonin by the transporter
(SERT) which is present in the serotonergic neurons
The signal (S100β) is emitted by the serotonergic neurons
The drop in levels of one microRNA, miR16, unlocks SERT
expression.
The noradrenaline neurons become sensitive to Prozac
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.
Pour en savoir plus
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, 17 septembre 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: [email protected]
Jean-Marie Launay
PU-PH, Hôpital Lariboisière, Biochemistry department
Tel: +33 (0)1 49 95 64 33
E-mail: [email protected]
Press contact
Séverine Ciancia
Inserm press office
Tel: +33 (0)1 44 23 60 86
E-mail: [email protected]