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
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.
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
this work are published in the journal Science dated 17
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.
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).
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*.
known as miR-16, controls synthesis of the serotonin transporter.
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.
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.
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
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".
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.
tests have moreover confirmed the importance of miR-16 as an intermediary
in Prozac action.
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.
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.
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,
3 Assistance Publique-Hôpitaux de Paris Service de Biochimie,
RTRS Santé Mentale, Unité Inserm 942 Hôpital Lariboisière, Paris,
september 17th 2010, vol. 329, n°5998
INSERM (Institut national de la
santé et de la recherche médicale)
Professor, University Paris XI, ENS-Ulm delegate
Inserm Unit 747 "Cellules souches, Signalisation et Prions" Université
Tel: +33 (0)1 42 86 20 65
PU-PH, Hôpital Lariboisière, Biochemistry department
Tel: +33 (0)1 49 95 64 33