Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response

Mol Psychiatry. 2012 Sep;17(9):926-39. doi: 10.1038/mp.2011.87. Epub 2011 Jul 19.


High-affinity transporters for norepinephrine (NE) and serotonin (5-HT), which ensure neurotransmitter clearance at the synapse, are the principal targets of widely used antidepressant drugs. Antidepressants targeting these high-affinity transporters, however, do not provide positive treatment outcomes for all patients. Other monoamine transport systems, with lower affinity, have been detected in the brain, but their role is largely unknown. Here we report that OCT2, a member of the polyspecific organic cation transporter (OCT) family, is expressed notably in the limbic system and implicated in anxiety and depression-related behaviors in the mouse. Genetic deletion of OCT2 in mice produced a significant reduction in brain tissue concentrations of NE and 5-HT and in ex vivo uptake of both these neurotransmitters in the presence of the dual 5-HT-NE transport blocker, venlafaxine. In vivo clearance of NE and 5-HT evaluated using microiontophoretic electrophysiology was diminished in the hippocampus of OCT2(-/-) mice in the presence of venlafaxine, thereby affecting postsynaptic neuronal activity. OCT2(-/-) mice displayed an altered sensitivity to acute treatments with NE- and/or 5-HT-selective transport blockers in the forced-swim test. Moreover, the mutant mice were insensitive to long-term venlafaxine treatment in a more realistic, corticosterone-induced, chronic depression model. Our findings identify OCT2 as an important postsynaptic determinant of aminergic tonus and mood-related behaviors and a potential pharmacological target for mood disorders therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology
  • Antidepressive Agents, Second-Generation / therapeutic use*
  • Anxiety / drug therapy
  • Brain / drug effects
  • Brain / metabolism*
  • Corticosterone
  • Cyclohexanols / pharmacology
  • Cyclohexanols / therapeutic use*
  • Depression / chemically induced
  • Depression / drug therapy*
  • Disease Models, Animal
  • Female
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiology
  • Limbic System / drug effects
  • Limbic System / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Imaging / methods
  • Molecular Imaging / psychology
  • Norepinephrine / metabolism*
  • Organic Cation Transport Proteins / biosynthesis
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / physiology*
  • Organic Cation Transporter 2
  • Radioligand Assay / methods
  • Radioligand Assay / psychology
  • Serotonin / metabolism*
  • Venlafaxine Hydrochloride


  • Antidepressive Agents, Second-Generation
  • Cyclohexanols
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • Slc22a2 protein, mouse
  • Serotonin
  • Venlafaxine Hydrochloride
  • Corticosterone
  • Norepinephrine