SAMENTA - Santé Mentale - Addictions

ORGANIC CATION TRANSPORTERS AS NOVEL TARGETS FOR DEPRESSION THERAPY – ANTIDOCT

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Submission summary

Mood disorders represent widespread and invalidating disorders, with up to 16% of the world population affected by various symptoms of the depression spectrum. The etiology of depression and other mood-related disorders like anxiety and bipolar disorder is still poorly understood, although both genetic predisposition and risks factors in the environment, such as stressful events, are believed to play a decisive role. Antidepressants traditionally used to treat major depression, dysthymia and anxiety disorders include selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), which are believed to exert their actions mainly by elevating extracellular serotonin (5-HT) and norepinephrine (NE) levels. These 5-HT and NE uptake inhibitors, however, do not provide positive treatment outcomes for all depressed patients. Important shortcomings in current treatments still include unpredictable resistance, poor efficacy and slow action onset.
Our recent work identified organic cation transporter 2 (OCT2) as an important post-synaptic determinant of 5-HT and NE clearance and a potential pharmacological target for mood disorders therapy. In particular, it indicated that this transporter directly regulates mood-related behaviors such as anxiety, and is required for the full long-term effects of the SNRI venlafaxine in a validated chronic depression model. Our goal is to associate the expertise of several teams in the fields of neurobiology, pharmacology and chemistry to investigate the role of OCT2 in antidepressant efficacy and develop specific OCT modulators in preclinical studies. In addition, we will study its role in antidepressant response in humans through collaboration with geneticists and psychiatrists.
One part of our project focuses on characterizing the mechanisms underlying the role of OCT2 in long-term antidepressant efficacy, with main objectives i) to investigate whether OCT2 is also implicated in the efficacy of other classical antidepressants, and ii) to define the contribution of different processes, such as aminergic signaling, neurogenesis and intracellular signaling pathways, to OCT2-mediated potentiation of antidepressant response. Another part of the project aims to develop new specific OCT ligands that can modulate their activity in vivo, thereby improving antidepressant efficacy. The last part of the project focuses on establishing the importance of OCT activity antidepressant response in humans. To this end, we will determine the impact of genetic variations in OCT genes on the response to antidepressants treatment in a french cohort of well-characterized patients with major depression.
The results obtained from these complementary approaches should shed light on the importance of this new category of monoamine transporters in antidepressant response in humans, and help develop original drugs that target OCTs to improve antidepressant efficacy.

Project coordination

Sophie GAUTRON (Physiopathologie des Maladies du système Nerveux central UMR 7224)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Inserm U955, EQ15 Inserm U955, Psychiatrie Génétique
MPV Laboratoire de Mémoire, Plasticité, Viellissement (MPV) UPS -CNRS
UMR8601 UMR8601-CNRS, Université Paris Descartes Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques
PMSNC Physiopathologie des Maladies du système Nerveux central UMR 7224

Help of the ANR 548,316 euros
Beginning and duration of the scientific project: September 2013 - 48 Months

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