Inhibition of organic cation transporter 2 and 3 may be involved in the mechanism of the antidepressant-like action of berberine

Prog Neuropsychopharmacol Biol Psychiatry. 2014 Mar 3:49:1-6. doi: 10.1016/j.pnpbp.2013.11.005. Epub 2013 Nov 15.


Organic cation transporter 2 (OCT2) and 3 (OCT3) are low-affinity, high-capacity transporters (uptake-2) expressed in the central nervous system (CNS) and other major organs. Proven to be essential components in the CNS functions, OCT2 and OCT3 are suggested as potential targets of antidepressant therapeutics recently. Berberine, an active constituent derived from many medicinal plants, such as Coptis chinensis, has been reported to possess antidepressant-like action in the tail suspension test and forced swim test with elevated serotonin/norepinephrine/dopamine (5-HT/NE/DA) level in mouse brain; however the mechanism has not been elucidated. In consideration of the relation between OCT2/3 and antidepressant action, and the characteristic of berberine as an organic cation, we investigated the potential involvement of OCT2 and OCT3 in the antidepressant-like action of berberine in the present study. The results in mouse brain synaptosomes demonstrated that uptake-2 inhibition might play a notable role in enhanced serotonergic and noradrenergic effects induced by berberine. The inhibitory study in transfected MDCK cells displayed that berberine is a potent inhibitor of human OCT2 and OCT3, and its IC50 values for inhibition of transporter-mediated 5-HT/NE uptake are between 0.1 and 1μM. In addition, berberine was identified as a substrate of hOCT2 and hOCT3. In conclusion, berberine is a substrate and an inhibitor of hOCT2 and hOCT3, and its inhibition on OCT2- and OCT3-mediated 5-HT and NE uptake may contribute to the enhanced monoamine neurotransmission in mouse brain. It was deduced that the inhibition of OCT2 and OCT3 probably be implicated in the mechanism of antidepressant-like action.

Keywords: 1-methyl-4- phenylpyridinium; 5-HT; Antidepressant; Berberine; LC-MS/MS; MDCK; MPP(+); Madin-Daby canine kidney; NE; Organic cation transporter 2; Organic cation transporter 3; Uptake-2; hOCT; human organic cation transporter; liquid chromatography-tandem mass spectrometry; norepinephrine; serotonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Berberine / pharmacology*
  • Brain / drug effects
  • Brain / metabolism
  • Cells, Cultured
  • Dogs
  • Humans
  • Madin Darby Canine Kidney Cells
  • Male
  • Mice
  • Norepinephrine / metabolism
  • Organic Cation Transport Proteins / antagonists & inhibitors*
  • Organic Cation Transporter 2
  • Serotonin / metabolism
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism


  • Antidepressive Agents
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • solute carrier family 22 (organic cation transporter), member 3
  • Berberine
  • Serotonin
  • Norepinephrine