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.
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Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine
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This work was supported by the Hope for Depression Research Foundation. (RH/JH), NIH Grant MH068542 (RH), NIMH K99/R00 106731 (KMN), NIH Grant MH116462 (JP/RH), NIH Grant DA05010 (BLK), NIMH K08 MH109735 (AZH), NARSAD Young Investigator Awards from the Brain Behavior Research Foundation (to AZH and KMN).
RH is a consultant for Psychogenics. RH and JAJ are co-founders of Kures Inc and co-inventors on patents on tianeptine analogs held by Columbia University and licensed to Kures. All other authors have no competing interests to declare.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Han, J., Andreu, V., Langreck, C. et al. Mu opioid receptors on hippocampal GABAergic interneurons are critical for the antidepressant effects of tianeptine. Neuropsychopharmacol. 47, 1387–1397 (2022). https://doi.org/10.1038/s41386-021-01192-2
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