Original Article

Neuropsychopharmacology advance online publication 19 April 2017; doi: 10.1038/npp.2017.60

The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor

Benjamin Adam Samuels1,6, Katherine M Nautiyal2,6, Andrew C Kruegel3, Marjorie R Levinstein2, Valerie M Magalong2, Madalee M Gassaway3, Steven G Grinnell2, Jaena Han4, Michael A Ansonoff5, John E Pintar5, Jonathan A Javitch2, Dalibor Sames3 and René Hen2

  1. 1Department of Psychology, Behavioral & Systems Neuroscience, Rutgers, The State University of New Jersey-New Brunswick, Piscataway, NJ, USA
  2. 2Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, USA
  3. 3Department of Chemistry and NeuroTechnology Center, Columbia University, New York, NY, USA
  4. 4Department of Biology, Columbia University, New York, NY, USA
  5. 5Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA

Correspondence: Dr R Hen, Departments of Psychiatry and Pharmacology, Columbia University, New York State Psychiatric Institute, 1051 Riverside Dr, Box 87, New York, NY 10032, USA, Tel: 212 543 5328, Fax: 646 774 7102, E-mail: rh95@cumc.columbia.edu

6These authors contributed equally to this work.

Received 24 April 2016; Revised 28 February 2017; Accepted 2 March 2017
Accepted article preview online 17 March 2017; Advance online publication 19 April 2017



Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors, are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously unknown mechanism of action. We recently reported that tianeptine is a full agonist at the mu opioid receptor (MOR). Here we demonstrate that the acute and chronic antidepressant-like behavioral effects of tianeptine in mice require MOR. Interestingly, while tianeptine also produces many opiate-like behavioral effects such as analgesia and reward, it does not lead to tolerance or withdrawal. Furthermore, the primary metabolite of tianeptine (MC5), which has a longer half-life, mimics the behavioral effects of tianeptine in a MOR-dependent fashion. These results point to the possibility that MOR and its downstream signaling cascades may be novel targets for antidepressant drug development.

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