Enhancement of hippocampal synaptic AMPA receptor function by the antidepressant tianeptine and by opioid peptides.
7 affiliations
- 1Division of Neuroscience, School of Medicine, University of Dundee, Dundee DD1 5HL, United Kingdom.
- 2Institute of Polymers, Composites and Biomaterials-Consiglio Nazionale delle Ricerche, Naples 80125, Italy.
- 3Federal Center of Brain Research and Neurotechnologies, Moscow 117513, Russia.
- 4Laboratory of Neurobiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia.
- 5Faculty of Medicine, Macau University of Science and Technology, Macau SAR 999078, China.
- 6Macau Institute for AI in Medicine, Macau University of Science and Technology, Macau SAR 999078, China.
- 7Max Planck Institute for Medical Research, Heidelberg D-69120, Germany.
Abstract
Management of major depressive disorder (MDD) with conventional therapeutics that enhance monoaminergic neurotransmission requires prolonged treatment prior to clinical benefit and a substantial proportion of patients show little or no improvement. Identifying alternative molecular targets is required to develop efficacious, rapid acting antidepressants. In this regard, tianeptine, an established but atypical clinical antidepressant, is of interest. Tianeptine does not directly influence monoamine levels; in rodents it has a relatively rapid onset of antidepressant-like efficacy and, unusually for an antidepressant, exhibits procognitive properties. Here, voltage-clamp recordings from mouse hippocampal CA1 pyramidal neurons demonstrated tianeptine enhanced the amplitude of neurally evoked excitatory postsynaptic currents mediated by glutamate activation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The effect required intracellular polyamines and expression of the GluA1 subunit. These observations suggest that tianeptine relieves the channel block by endogenous polyamines of synaptic GluA1 containing AMPARs (GluA1-AMPARs). The tianeptine effect was abolished by postsynaptic inhibition of G-protein signaling, was reduced in mice lacking either the µ- or the δ-opioid receptor, and inhibited by selective antagonists of these receptors, collectively demonstrating that the facilitation of excitatory transmission was indirectly mediated by activation of opioid receptors. Importantly, enhancement of GluA1-AMPAR function was mimicked by opioid peptide and nonpeptide agonists selective for µ- or δ-receptors. These observations improve understanding of how the antidepressant tianeptine enhances glutamatergic transmission but more generally suggest that endogenous and exogenous opioids act in a similar manner, which may contribute to their behavioral effects.
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BibTeX
@article{mariano2026enhancement,
title = {{Enhancement of hippocampal synaptic AMPA receptor function by the antidepressant tianeptine and by opioid peptides.}},
author = {Anna Mariano and Andrei Rozov and Grant D Phillips and Sam Singleton and Daniel Baptista-Hon and Fliza Valiullina-Rakhmatullina and Rolf Sprengel and Rosamund Langston and Stephen J Martin and Tim G Hales and Jeremy J Lambert},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2521987123},
url = {https://europepmc.org/article/MED/42842414},
note = {CC BY},
}
RIS
TY - JOUR
TI - Enhancement of hippocampal synaptic AMPA receptor function by the antidepressant tianeptine and by opioid peptides.
AU - Anna Mariano
AU - Andrei Rozov
AU - Grant D Phillips
AU - Sam Singleton
AU - Daniel Baptista-Hon
AU - Fliza Valiullina-Rakhmatullina
AU - Rolf Sprengel
AU - Rosamund Langston
AU - Stephen J Martin
AU - Tim G Hales
AU - Jeremy J Lambert
PY - 2026
DA - 2026/10/07
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2521987123
UR - https://europepmc.org/article/MED/42842414
AB - Management of major depressive disorder (MDD) with conventional therapeutics that enhance monoaminergic neurotransmission requires prolonged treatment prior to clinical benefit and a substantial proportion of patients show little or no improvement. Identifying alternative molecular targets is required to develop efficacious, rapid acting antidepressants. In this regard, tianeptine, an established but atypical clinical antidepressant, is of interest. Tianeptine does not directly influence monoamine levels; in rodents it has a relatively rapid onset of antidepressant-like efficacy and, unusually for an antidepressant, exhibits procognitive properties. Here, voltage-clamp recordings from mouse hippocampal CA1 pyramidal neurons demonstrated tianeptine enhanced the amplitude of neurally evoked excitatory postsynaptic currents mediated by glutamate activation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The effect required intracellular polyamines and expression of the GluA1 subunit. These observations suggest that tianeptine relieves the channel block by endogenous polyamines of synaptic GluA1 containing AMPARs (GluA1-AMPARs). The tianeptine effect was abolished by postsynaptic inhibition of G-protein signaling, was reduced in mice lacking either the µ- or the δ-opioid receptor, and inhibited by selective antagonists of these receptors, collectively demonstrating that the facilitation of excitatory transmission was indirectly mediated by activation of opioid receptors. Importantly, enhancement of GluA1-AMPAR function was mimicked by opioid peptide and nonpeptide agonists selective for µ- or δ-receptors. These observations improve understanding of how the antidepressant tianeptine enhances glutamatergic transmission but more generally suggest that endogenous and exogenous opioids act in a similar manner, which may contribute to their behavioral effects.
SN - 0027-8424
SN - 1091-6490
ER -