Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression
Por:
Orrico-Sanchez A, Chausset-Boissarie L, Alves de Sousa R, Coutens B, Rezai Amin S, Vialou V, Louis F, Hessani A, Dansette PM, Zornoza T, Gruszczynski C, Giros B, Guiard BP, Acher F, Pietrancosta N and Gautron S
Publicada:
1 jun 2020
Ahead of Print:
16 oct 2019
Resumen:
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.
Filiaciones:
:
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, 75005, Paris, France
Chausset-Boissarie L:
Université Paris Descartes, CNRS, 75006, Paris, France
Alves de Sousa R:
Université Paris Descartes, CNRS, 75006, Paris, France
Coutens B:
Université Paul Sabatier, CNRS, Research Center on Animal Cognition, 31062, Toulouse, France
Rezai Amin S:
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, 75005, Paris, France
Vialou V:
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, 75005, Paris, France
Louis F:
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, 75005, Paris, France
Hessani A:
Université Paris Descartes, CNRS, 75006, Paris, France
Dansette PM:
Université Paris Descartes, CNRS, 75006, Paris, France
Zornoza T:
Department of Pharmacy and Pharmacy Technology and Parasitology, University of Valencia, Valencia, 46010, Spain
Gruszczynski C:
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, 75005, Paris, France
Giros B:
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, 75005, Paris, France
Department of Psychiatry, Douglas Mental Health Research Center, McGill University, Montreal, QC, H3A 1A, Canada
Guiard BP:
Université Paul Sabatier, CNRS, Research Center on Animal Cognition, 31062, Toulouse, France
Acher F:
Université Paris Descartes, CNRS, 75006, Paris, France
Pietrancosta N:
Université Paris Descartes, CNRS, 75006, Paris, France.
Sorbonne Université, École normale supérieure, PSL University, CNRS, Laboratoire des Biomolécules, 75005, Paris, France.
Gautron S:
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, 75005, Paris, France.
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