Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression

Alejandro Orrico-Sanchez (1) , Laetitia Chausset-Boissarie (2) , Rodolphe Alves de Sousa (2) , Basile Coutens (3) , Sara Rezai Amin (1) , Vincent Vialou (1) , Franck Louis (1) , Assia Hessani (2) , Patrick Dansette (2) , Teodoro Zornoza (4) , Carole Gruszczynski (1) , Bruno Giros (1, 5) , Bruno Guiard (3) , Francine Acher (2) , Nicolas Pietrancosta (6) , Sophie Gautron (1)

1 NPS - Neuroscience Paris Seine
2 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
3 CRCA - Centre de Recherches sur la Cognition Animale - UMR5169
4 UV - Universitat de València
5 McGill University = Université McGill [Montréal, Canada]
6 LBM UMR 7203 - Laboratoire des biomolécules

Current antidepressants act principally by blocking monoamine reuptake by high-affinity transporters in the brain. However, these antidepressants show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients with major depression disorder. Here, we report the development of a prodrug targeting organic cation transporters (OCT), atypical monoamine transporters recently implicated in the regulation of mood. Using molecular modeling, we designed a selective OCT2 blocker, which was modified to increase brain penetration. This compound, H2-cyanome, was tested in a rodent model of chronic depression induced by 7-week corticosterone exposure. In male mice, prolonged administration of H2-cyanome induced positive effects on several behaviors mimicking symptoms of depression, including anhedonia, anxiety, social withdrawal, and memory impairment. Importantly, in this validated model, H2-cyanome compared favorably with the classical antidepressant fluoxetine, with a faster action on anhedonia and better anxiolytic effects. Integrated Z-scoring across these depression-like variables revealed a lower depression score for mice treated with H2-cyanome than for mice treated with fluoxetine for 3 weeks. Repeated H2-cyanome administration increased ventral tegmental area dopaminergic neuron firing, which may underlie its rapid action on anhedonia. H2-cyanome, like fluoxetine, also modulated several intracellular signaling pathways previously involved in antidepressant response. Our findings provide proof-of-concept of antidepressant efficacy of an OCT blocker, and a mechanistic framework for the development of new classes of antidepressants and therapeutic alternatives for resistant depression and other psychiatric disturbances such as anxiety.

Domaines: Neurosciences

Alejandro Orrico-Sanchez, Laetitia Chausset-Boissarie, Rodolphe Alves de Sousa, Basile Coutens, Sara Rezai Amin, et al.. Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression. Molecular Psychiatry, 2020, 25 (6), pp.1245-1259. ⟨10.1038/s41380-019-0548-4⟩. ⟨inserm-03943549⟩