Pharmacological blockade of 5-HT7 receptors as a putative fast acting antidepressant strategy

Ouissame Mnie-Filali (1) , Céline Faure (1) , Laura Lambás-Señas (1) , Mostafa El Mansari (1) , Hassina Belblidia (1) , Elise Gondard (1) , Adeline Etievant (1) , Helene Scarna (1) , Anne Didier (1) , Anne Berod (1) , Pierre Blier (1) , Nasser Haddjeri (1)

1 Neuropharmacology

Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT7) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT7 receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT7 receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a one-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behaviour in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviours in adulthood. Together, these findings indicate that the 5-HT7 receptor antagonists may represent a new class of antidepressants with faster therapeutic action.

Mots clés: Mood; Anxiety; Stress Disorders; Neuropharmacology; Serotonin; Receptor Pharmacology; electrophysiology; 5-HT7 receptors; antidepressant; dorsal raphe; neurogenesis

Ouissame Mnie-Filali, Céline Faure, Laura Lambás-Señas, Mostafa El Mansari, Hassina Belblidia, et al.. Pharmacological blockade of 5-HT7 receptors as a putative fast acting antidepressant strategy. Neuropsychopharmacology, 2011, ⟨10.1038/npp.2011.13⟩. ⟨hal-00614744⟩