title: The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor.
abstract: 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.
authors.affiliation: Department of Psychology, Behavioral &Systems Neuroscience, Rutgers, The State University of New Jersey-New Brunswick, Piscataway, NJ, USA.
authors.forename: Benjamin Adam
authors.initials: BA
authors.lastname: Samuels
authors.affiliation: Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Nautiyal
authors.affiliation: Department of Chemistry and NeuroTechnology Center, Columbia University, New York, NY, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kruegel
authors.affiliation: Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Marjorie R
authors.identifier: http://orcid.org/0000-0003-4360-1503
authors.initials: MR
authors.lastname: Levinstein
authors.affiliation: Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Magalong
authors.affiliation: Department of Chemistry and NeuroTechnology Center, Columbia University, New York, NY, USA.
authors.forename: Madalee M
authors.initials: MM
authors.lastname: Gassaway
authors.affiliation: Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Grinnell
authors.affiliation: Department of Biology, Columbia University, New York, NY, USA.
authors.forename: Jaena
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ansonoff
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Pintar
authors.affiliation: Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.affiliation: Department of Chemistry and NeuroTechnology Center, Columbia University, New York, NY, USA.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Sames
authors.affiliation: Department of Psychiatry, Columbia University, and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: René
authors.initials: R
authors.lastname: Hen
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D009020:Morphine / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013841:Thiazepines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D000929:Antidepressive Agents, Tricyclic; C485764:OPRM1 protein, human; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; D013841:Thiazepines; C050504:tianeptine; D009020:Morphine