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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 \u03b1-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 \u00b5- or the \u03b4-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 \u00b5- or \u03b4-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.<\/jats:p>","DOI":"10.1073\/pnas.2521987123","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:35:51Z","timestamp":1791390951000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Enhancement of hippocampal synaptic AMPA receptor function by the antidepressant tianeptine and by opioid peptides"],"prefix":"10.1073","volume":"123","author":[{"given":"Anna","family":"Mariano","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03h2bxq36","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Neuroscience, School of Medicine, University of Dundee","place":["Dundee, United 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