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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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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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 (2019) doi:10.1038/s41380-019-0548-4