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

Mol Psychiatry. 2020 Jun;25(6):1245-1259. doi: 10.1038/s41380-019-0548-4. Epub 2019 Oct 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anhedonia / drug effects
  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacokinetics
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use*
  • Anxiety / drug therapy
  • Depression / drug therapy*
  • Disease Models, Animal
  • Fluoxetine / therapeutic use
  • Humans
  • Male
  • Memory / drug effects
  • Mice
  • Organic Cation Transport Proteins / antagonists & inhibitors*

Substances

  • Antidepressive Agents
  • Organic Cation Transport Proteins
  • Fluoxetine