Format

Send to

Choose Destination
Mol Psychiatry. 2019 Oct 16. doi: 10.1038/s41380-019-0548-4. [Epub ahead of print]

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

Author information

1
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, 75005, Paris, France.
2
Université Paris Descartes, CNRS, 75006, Paris, France.
3
Université Paul Sabatier, CNRS, Research Center on Animal Cognition, 31062, Toulouse, France.
4
Department of Pharmacy and Pharmacy Technology and Parasitology, University of Valencia, Valencia, 46010, Spain.
5
Department of Psychiatry, Douglas Mental Health Research Center, McGill University, Montreal, QC, H3A 1A, Canada.
6
Université Paris Descartes, CNRS, 75006, Paris, France. nicolas.pietrancosta@upmc.fr.
7
Sorbonne Université, École normale supérieure, PSL University, CNRS, Laboratoire des Biomolécules, 75005, Paris, France. nicolas.pietrancosta@upmc.fr.
8
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, 75005, Paris, France. sophie.gautron@upmc.fr.

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.

PMID:
31619760
DOI:
10.1038/s41380-019-0548-4

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center