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.
journal_name
Mol Psychiatryjournal_title
Molecular psychiatryauthors
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,Gautron Sdoi
10.1038/s41380-019-0548-4subject
Has Abstractpub_date
2020-06-01 00:00:00pages
1245-1259issue
6eissn
1359-4184issn
1476-5578pii
10.1038/s41380-019-0548-4journal_volume
25pub_type
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