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

Abstract

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.

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Acknowledgements

We thank J-P Guilloux (UMRS 1178, Université Paris-Saclay) for help with z-scoring, F. Machulka at the rodent phenotyping facility of Institut de Biologie Paris-Seine for expert assistance with animal care, and C. Betancur for critical reading of the paper. Financial support was provided by the Agence Nationale de la Recherche (ANR-13-SAMENTA-0003-01) and SATT Lutech.

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NP, FA, and SG conceived the study. NP conceived and performed molecular modeling, and designed the compounds. NP, AH, and PMD performed microsomal fraction analysis. NP, LC-B, and RAD.S synthetized the compounds. AOS, SRA, and VV performed behavioral analyses. BPG designed the electrophysiological studies. BPG and BC performed and analyzed the electrophysiological studies. AOS performed western blot analyses. AOS and TZ participated in HPLC/MS analysis. BG provided key facilities, equipment, and advice. FL and CG performed the histochemical experiments. SG coordinated the study. NP, AOS, BPG, and SG wrote the paper. All authors reviewed and approved the paper.

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Correspondence to Nicolas Pietrancosta or Sophie Gautron.

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Orrico-Sanchez, A., Chausset-Boissarie, L., Alves de Sousa, R. et al. Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression. Mol Psychiatry 25, 1245–1259 (2020). https://doi.org/10.1038/s41380-019-0548-4

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