Paris, 18 avril 2007

A newcomer in the treatment of mood disorders : nitric oxide

A team of researchers from the Institut de génomique fonctionnelle (Inserm / CNRS / Universités Montpellier 1 and Montpellier 2) has discovered the key role played by the enzyme nitric oxide synthase in the activity of the transporter of serotonin, a compound used in mood regulation treatment. This is a particularly valuable demonstration because nitric oxide is also known for its role in anxiety. This research work, to be published in the Proceedings of the National Academy of Science could open up new paths for therapy among patients for whom standard antidepressants prove ineffective.

Serotonin has long been recognized as having a crucial role in mood regulation and in some psychiatric disorders such as depression, anxiety and aggressivity. The receptors and the transporter of this neurotransmitter(1) moreover attract a great deal of attention, as they are also involved in other major pathologies such as depression and schizophrenia. Owing to this they are the target of many drugs and therapeutic agents (antidepressants, anxiolytics, antipsychotics, hallucinogenic compounds, ecstasy, cocaine etc.).


In the synapse the concentration of serotonin is controlled directly by its recapture by the serotonin transporter. The latter is the prime target of many antidepressants the best known of which is Prozac®. These agents prevent the serotonin recapture by the neurones, and hence artificially increase its concentration and re-establish normal serotoninergic transmission.


Mood disorders affect between 5 and 10% of the population in France and, if not dealt with, can cause types of behaviour that could lead to suicide. Action against such disturbances is not easy and treatments do not always give convincing results. Some patients (30%) show no response to any available antidepressant treatment, but the reasons for this resistance are still unknown. The main idea therefore is a simple one, as Joël Bockaert, head of the Institut de génomique fonctionnelle in Montpellier, states: “The more potential therapeutic targets there are the more we increase the chances of responses to treatment”.

The research team therefore focused on another messenger, synthesized in the central nervous system and involved in mood regulation: nitric oxide (NO). Thanks to a proteomic approach(2), the team brought out evidence of a physical interaction between the serotonin transporter and the enzyme responsible for synthesizing nitric oxide in the brain, neuronal NO-synthase. This interaction between the two proteins allows the reciprocal modulation of their functional activity. The contact between these two proteins inhibits the recapture of serotonin and at the same time allows new production of NO. Manipulation of this interaction could thus prove to be a promising therapeutic strategy for the treatment of mood disorders.


1) Serotonin is a neurotransmitter, in other words a compound which modulates the action of neurones in the brain.

2) The proteomic approach offers the possibility of identifying and quantifying the proteins expressed in a given biological system in a variety of physiological and pathological contexts.


Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity
B. Chanrion*†‡§_, C. Mannoury la Cour_, F. Bertaso*†‡§, M. Lerner-Natoli*†‡§, M. Freissmuth**, M. J. Millan, J. Bockaert*†‡§††, and P. Marin*†‡§
*Centre National de la Recherche Scientifique, UMR 5203,
†Institut National de la Santé et de la Recherche Médicale, U661,
‡Université de Montpellier I,
§Université Montpellier II, F-34094 Montpellier, France;
Institut de Génomique Fonctionnelle, Département de Neurobiologie, 141 Rue de la Cardonille, F-34094 Montpellier Cedex 5, France;
_IDR Servier, 78290 Croissy-sur-Seine, Paris, France;
**Institute of Pharmacology, University of Vienna, Wahringer Strasse 13a, A-1090 Vienna, Austria



Joël Bockaert
Unité Inserm 661,UMR CNRS 5203 « Institut de Génomique Fonctionnelle »
141 rue de la Cardonille
Tel : +33 (0)6 07 27 43 49
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Philippe Marin
Unité Inserm 661,UMR CNRS 5203 « Institut de Génomique Fonctionnelle »
141 rue de la Cardonille
Tel: +33 (0)4 67 14 29 83
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