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

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.

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Fig. 1: Tianeptine shows antidepressant-like effects after as little as 7 days of treatment.
Fig. 2: Tianeptine has a distinct mechanism of action from fluoxetine.
Fig. 3: The acute and chronic antidepressant effects of tianeptine require MORs on GABAergic cells.
Fig. 4: The acute and chronic antidepressant effects of tianeptine require MORs on SST cells.
Fig. 5: MORs in the ventral hippocampus may mediate tianeptine’s acute antidepressant-like effects.

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Funding

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).

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JH, VA, VMM, and KMN performed behavioral experiments and RNAscope ISH. JH, KMN, and RH wrote the manuscript. CL, EAP, SGG, and JAJ conducted the time course studies. FA and BLK performed the habenula-specific experiments, AZH developed the CVORS paradigm, JP contributed mouse lines and helped with experimental design, and RH and KMN were supervising PIs.

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Correspondence to René Hen or Katherine M. Nautiyal.

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Competing interests

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.

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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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