Mu opioid receptors on hippocampal GABAergic interneurons are critical for the antidepressant effects of tianeptine.

TitleMu opioid receptors on hippocampal GABAergic interneurons are critical for the antidepressant effects of tianeptine.
Publication TypeJournal Article
Year of Publication2021
AuthorsHan J, Andreu V, Langreck C, Pekarskaya EA, Grinnell SG, Allain F, Magalong V, Pintar J, Kieffer BL, Harris AZ, Javitch JA, Hen R, Nautiyal KM
JournalNeuropsychopharmacology
Date Published2021 Sep 30
ISSN1740-634X
Abstract

Tianeptine is an atypical antidepressant used in Europe to treat patients who respond poorly to selective serotonin reuptake inhibitors (SSRIs). The recent discovery that tianeptine is a mu opioid receptor (MOR) agonist has provided a potential avenue for expanding our understanding of antidepressant treatment beyond the monoamine hypothesis. Thus, our studies aim to understand the neural circuits underlying tianeptine's antidepressant effects. We show that tianeptine induces rapid antidepressant-like effects in mice after as little as one week of treatment. Critically, we also demonstrate that tianeptine's mechanism of action is distinct from fluoxetine in two important aspects: (1) tianeptine requires MORs for its chronic antidepressant-like effect, while fluoxetine does not, and (2) unlike fluoxetine, tianeptine does not promote hippocampal neurogenesis. Using cell-type specific MOR knockouts we further show that MOR expression on GABAergic cells-specifically somatostatin-positive neurons-is necessary for the acute and chronic antidepressant-like responses to tianeptine. Using central infusion of tianeptine, we also implicate the ventral hippocampus as a potential site of antidepressant action. Moreover, we show a dissociation between the antidepressant-like phenotype and other opioid-like phenotypes resulting from acute tianeptine administration such as analgesia, conditioned place preference, and hyperlocomotion. Taken together, these results suggest a novel entry point for understanding what circuit dysregulations may occur in depression, as well as possible targets for the development of new classes of antidepressant drugs.

DOI10.1038/s41386-021-01192-2
Alternate JournalNeuropsychopharmacology
PubMed ID34593976
Grant ListR21 MH116462 / MH / NIMH NIH HHS / United States
MH068542 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
NARSAD Young Investigator 2015 / / Brain and Behavior Research Foundation (Brain & Behavior Research Foundation) /
NARSAD Young Investigator 2018 / / Brain and Behavior Research Foundation (Brain & Behavior Research Foundation) /
RGA-13-003 / / Hope for Depression Research Foundation (Depression Research Foundation) /
K08 MH109735 / MH / NIMH NIH HHS / United States
K99/R00 106731 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
MH116462 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /