{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:00:03Z","timestamp":1790312403378,"version":"4.1.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Major depressive disorder remains a leading cause of disability worldwide, and current antidepressants are limited by delayed therapeutic onset, incomplete efficacy, and adverse effects. Although\n                    <jats:italic>Rosmarinus officinalis<\/jats:italic>\n                    L. essential oil and its major monoterpenes exhibit antidepressant-like and anxiolytic properties, their molecular mechanisms remain unclear. This study investigated whether the principal rosemary monoterpenes, \u03b1-pinene, camphor, and 1,8-cineole, directly interact with the human serotonin transporter (hSERT) and its functional effects. Molecular docking simulations targeting the orthosteric (S1) and allosteric (S2) binding sites were combined with [\n                    <jats:sup>3<\/jats:sup>\n                    H]-paroxetine binding displacement assays and SERT-mediated uptake experiments based on the fluorescent serotonin analog FFN246 in HEK293 cells expressing YFP-tagged hSERT. Docking analyses predicted plausible binding poses for all three monoterpenes within both the S1 and S2 regions, although with less favorable docking scores than fluoxetine. Radioligand displacement assays provided experimental evidence that all three compounds interact with hSERT, producing concentration-dependent displacement of [\n                    <jats:sup>3<\/jats:sup>\n                    H]-paroxetine, with \u03b1-pinene displaying the highest potency, followed by 1,8-cineole and camphor. Functional assays further showed that all monoterpenes produced significant but incomplete inhibition of transporter-mediated FFN246 uptake, even at high micromolar concentrations, indicating partial rather than complete transporter blockade. Together, these findings identify hSERT as a previously unrecognized molecular target of rosemary monoterpenes, suggesting that these compounds may act as partial inhibitors of serotonin transport. These results provide new molecular insights into the potential mechanism that may contribute to the reported neurobehavioral effects of rosemary, and support further investigation of these compounds in serotonergic signaling and neurotransmission.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1923534","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:27:20Z","timestamp":1790310440000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Interaction of major monoterpenes from Rosmarinus officinalis L. essential oil with the human serotonin transporter: molecular docking, radioligand binding, and functional uptake studies"],"prefix":"10.3389","volume":"17","author":[{"given":"Carolina","family":"Valle","sequence":"first","affiliation":[{"name":"Escuela de Qu\u00edmica y Farmacia, Facultad de Farmacia, Universidad de Valpara\u00edso","place":["Valpara\u00edso, Chile"]},{"name":"Laboratorio de Bioqu\u00edmica y Farmacolog\u00eda Molecular, Departamento de Ciencias Biom\u00e9dicas, Facultad de Ciencias de La Vida, Universidad Vi\u00f1a del Mar","place":["Vi\u00f1a del Mar, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerim","family":"Segura","sequence":"additional","affiliation":[{"name":"Laboratorio de Farmacolog\u00eda Molecular y Qu\u00edmica Medicinal, Departamento de Ciencias Qu\u00edmicas y Recursos Naturales, Facultad de Ingenier\u00eda y Ciencias, Universidad de La Frontera","place":["Temuco, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"C\u00e1rdenas","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica, Facultad de Ciencias, Pontificia Universidad Cat\u00f3lica de Valpara\u00edso","place":["Valpara\u00edso, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson","family":"Osses","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica, Facultad de Ciencias, Pontificia Universidad Cat\u00f3lica de Valpara\u00edso","place":["Valpara\u00edso, Chile"]},{"name":"Center for Interdisciplinary Research in Biomedicine, Biotechnology and Wellbeing (CID3B), Pontificia Universidad Cat\u00f3lica de Valpara\u00edso","place":["Valpara\u00edso, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Mella","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica, Facultad de Ciencias, Universidad de Valpara\u00edso","place":["Valpara\u00edso, Chile"]},{"name":"Center for Research, Development and Innovation of Bioactive Products (CinBio), School of Chemistry and Pharmacy, Faculty of Pharmacy, University of Valpara\u00edso","place":["Valpara\u00edso, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricio","family":"Iturriaga-V\u00e1squez","sequence":"additional","affiliation":[{"name":"Laboratorio de Farmacolog\u00eda Molecular y Qu\u00edmica Medicinal, Departamento de Ciencias Qu\u00edmicas y Recursos Naturales, Facultad de Ingenier\u00eda y Ciencias, Universidad de La Frontera","place":["Temuco, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 A.","family":"Pino","sequence":"additional","affiliation":[{"name":"Laboratorio de Bioqu\u00edmica y Farmacolog\u00eda Molecular, Departamento de Ciencias Biom\u00e9dicas, Facultad de Ciencias de La Vida, Universidad Vi\u00f1a del Mar","place":["Vi\u00f1a del Mar, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Lapier","sequence":"additional","affiliation":[{"name":"Escuela de Qu\u00edmica y Farmacia, Facultad de Farmacia, Universidad de Valpara\u00edso","place":["Valpara\u00edso, Chile"]},{"name":"Center for Research, Development and Innovation of Bioactive Products (CinBio), School of Chemistry and Pharmacy, Faculty of Pharmacy, University of Valpara\u00edso","place":["Valpara\u00edso, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3551","DOI":"10.3390\/nu12113551","article-title":"Effects of continuous intake of rosemary extracts on mental health in working generation healthy Japanese men: post-hoc testing of a randomized controlled trial","volume":"12","author":"Araki","year":"2020","journal-title":"Nutrients"},{"key":"B2","doi-asserted-by":"publisher","first-page":"18524","DOI":"10.1074\/jbc.M112.343681","article-title":"The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters","volume":"287","author":"Bulling","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B3","first-page":"277","article-title":"Investigation of the anxiolytic and antidepressant effects of eucalyptol (1,8-Cineole), a compound from eucalyptus, in the adult Male sprague-dawley rat","volume":"85","author":"Ceremuga","year":"2017","journal-title":"AANA J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1016\/S0140-6736(17)32802-7","article-title":"Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis","volume":"391","author":"Cipriani","year":"2018","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.psc.2016.04.006","article-title":"Sexual dysfunction due to psychotropic medications","volume":"39","author":"Clayton","year":"2016","journal-title":"Psychiatric Clin. N. Am."},{"key":"B6","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/s41594-018-0026-8","article-title":"Structural basis for recognition of diverse antidepressants by the human serotonin transporter","volume":"25","author":"Coleman","year":"2018","journal-title":"Nat. Struct. and Mol. Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1038\/nature17629","article-title":"X-ray structures and mechanism of the human serotonin transporter","volume":"532","author":"Coleman","year":"2016","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41586-019-1135-1","article-title":"Serotonin transporter\u2013ibogaine complexes illuminate mechanisms of inhibition and transport","volume":"569","author":"Coleman","year":"2019","journal-title":"Nature"},{"key":"B9","first-page":"1","article-title":"SSRIs in the treatment of depression: a pharmacological CUL-DE-SAC?","volume-title":"Emerging Neurobiology of Antidepressant Treatments","author":"Cowen","year":"2024"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e5631","DOI":"10.1002\/bmc.5631","article-title":"Study on the opening effect of eucalyptol on the blood\u2013brain barrier and its brain pharmacokinetics","volume":"37","author":"Dao","year":"2023","journal-title":"Biomed. Chromatogr."},{"key":"B11","doi-asserted-by":"publisher","first-page":"9244","DOI":"10.3390\/ijms24119244","article-title":"Antidepressant effects of essential oils: a review of the past decade (2012\u20132022) and molecular docking study of their major chemical components","volume":"24","author":"Fonseca","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.3390\/molecules22112029","article-title":"Dynamic docking: a paradigm shift in computational drug discovery","volume":"22","author":"Gioia","year":"2017","journal-title":"Molecules"},{"key":"B13","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/s41467-023-44637-6","article-title":"Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors","volume":"15","author":"Gradisch","year":"2024","journal-title":"Nat. Commun."},{"key":"B14","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.lfs.2015.02.021","article-title":"Linalool and \u03b2-pinene exert their antidepressant-like activity through the monoaminergic pathway","volume":"128","author":"Guzm\u00e1n-Guti\u00e9rrez","year":"2015","journal-title":"Life Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2680409","DOI":"10.1155\/2016\/2680409","article-title":"The therapeutic potential of rosemary (rosmarinus officinalis) diterpenes for Alzheimer\u2019s disease","volume":"2016","author":"Habtemariam","year":"2016","journal-title":"Evidence-Based Complementary Altern. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1021\/acschemneuro.7b00320","article-title":"Toward serotonin fluorescent false neurotransmitters: development of fluorescent dual serotonin and vesicular monoamine transporter substrates for visualizing serotonin neurons","volume":"9","author":"Henke","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1016\/j.chroma.2011.02.048","article-title":"Analysis of Iranian rosemary essential oil: application of gas chromatography\u2013mass spectrometry combined with chemometrics","volume":"1218","author":"Jalali-Heravi","year":"2011","journal-title":"J. Chromatogr. A"},{"key":"B18","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.etap.2011.03.011","article-title":"Chemical composition and antimicrobial activity of the essential oil of rosemary","volume":"32","author":"Jiang","year":"2011","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1177\/1934578X1501000841","article-title":"Intracerebral distribution of \u03b1-Pinene and the anxiolytic-like effect in mice following inhaled administration of essential oil from Chamaecyparis obtusa","volume":"10","author":"Kasuya","year":"2015","journal-title":"Nat. Product. Commun."},{"key":"B20","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1124\/pr.108.000869","article-title":"SLC6 neurotransmitter transporters: structure, function, and regulation","volume":"63","author":"Kristensen","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"B21","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1016\/j.neuron.2019.02.005","article-title":"Ketamine: a paradigm shift for depression research and treatment","volume":"101","author":"Krystal","year":"2019","journal-title":"Neuron"},{"key":"B22","doi-asserted-by":"publisher","first-page":"280","DOI":"10.3389\/fphar.2017.00280","article-title":"Exploring pharmacological mechanisms of lavender (Lavandula angustifolia) essential oil on central nervous system targets","volume":"8","author":"L\u00f3pez","year":"2017","journal-title":"Front. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1016\/j.pnpbp.2009.03.004","article-title":"Antidepressant-like effect of the extract of rosmarinus officinalis in mice: involvement of the monoaminergic system","volume":"33","author":"Machado","year":"2009","journal-title":"Prog. Neuro-Psychopharmacology Biol. Psychiatry"},{"key":"B24","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/j.foodchem.2012.09.028","article-title":"Antidepressant-like effects of fractions, essential oil, carnosol and betulinic acid isolated from rosmarinus officinalis L","volume":"136","author":"Machado","year":"2013","journal-title":"Food Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","article-title":"Depression","volume":"392","author":"Malhi","year":"2018","journal-title":"Lancet"},{"key":"B26","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1093\/hrp\/7.2.69","article-title":"Selective serotonin-reuptake inhibitors: an update","volume":"7","author":"Masand","year":"1999","journal-title":"Harv. Rev. Psychiatry"},{"key":"B27","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/S2215-0366(21)00395-3","article-title":"Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990\u20132019: a systematic analysis for the global burden of disease study 2019","volume":"9","year":"2022","journal-title":"Lancet Psychiatry"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2734","DOI":"10.3390\/foods10112734","article-title":"Rosemary essential oils as a promising source of bioactive compounds: Chemical composition, thermal properties, biological activity, and gastronomical perspectives","volume":"10","author":"Mici\u0107","year":"2021","journal-title":"Foods"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1177\/0269881118798339","article-title":"Acute ingestion of rosemary water: evidence of cognitive and cerebrovascular effects in healthy adults","volume":"32","author":"Moss","year":"2018","journal-title":"J. Psychopharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.tips.2020.04.006","article-title":"Allosteric modulation of neurotransmitter transporters as a therapeutic strategy","volume":"41","author":"Niello","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"101546","DOI":"10.1016\/j.mtbio.2025.101546","article-title":"The anti-depression effect and mechanism of harmonious rosemary essential oil and its application in microcapsules","volume":"31","author":"Niu","year":"2025","journal-title":"Mater. Today Bio"},{"key":"B32","doi-asserted-by":"publisher","first-page":"812","DOI":"10.17179\/excli2021-3714","article-title":"Recent studies on pinene and its biological and pharmacological activities","volume":"20","author":"Park","year":"2021","journal-title":"EXCLI J."},{"key":"B33","doi-asserted-by":"publisher","first-page":"5063","DOI":"10.1038\/s41467-021-25363-3","article-title":"The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter","volume":"12","author":"Plenge","year":"2021","journal-title":"Nat. Commun."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.22038\/ijbms.2020.45269.10541","article-title":"Therapeutic effects of rosemary (rosmarinus officinalis L.) and its active constituents on nervous system disorders","volume":"23","author":"Rahbardar","year":"2020","journal-title":"Iran. J. Basic Med. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1038\/s41380-025-03201-y","article-title":"Cell membrane cholesterol affects serotonin transporter efflux due to altered transporter oligomerization","volume":"31","author":"Rudin","year":"2026","journal-title":"Mol. Psychiatry"},{"key":"B36","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1080\/08923973.2021.1905658","article-title":"Neuroprotective role of camphor against ciprofloxacin induced depression in rats: modulation of Nrf-2 and TLR4","volume":"43","author":"Salama","year":"2021","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e2304089120","DOI":"10.1073\/pnas.2304089120","article-title":"Dynamic extracellular vestibule of human SERT: unveiling druggable potential with high-affinity allosteric inhibitors","volume":"120","author":"Salomon","year":"2023","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"531","DOI":"10.3797\/scipharm.1209-05","article-title":"Effects of inhaled rosemary oil on subjective feelings and activities of the nervous system","volume":"81","author":"Sayorwan","year":"2013","journal-title":"Sci. Pharm."},{"key":"B39","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"B40","doi-asserted-by":"publisher","first-page":"10924","DOI":"10.1074\/jbc.M109.083154","article-title":"The N terminus of monoamine transporters is a lever required for the action of amphetamines","volume":"285","author":"Sucic","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/nrn1008","article-title":"Plasma membrane monoamine transporters: structure, regulation and function","volume":"4","author":"Torres","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"9071","DOI":"10.1021\/acs.jmedchem.5c03540","article-title":"Alcohols inhibit glucose transporters noncompetitively at a constant membrane concentration according to lipid theory","volume":"69","author":"Uesono","year":"2026","journal-title":"J. Med. Chem."},{"key":"B43","doi-asserted-by":"publisher","first-page":"583211","DOI":"10.3389\/fpsyt.2021.583211","article-title":"A review of the potential use of pinene and linalool as terpene-based medicines for brain health: discovering novel therapeutics in the flavours and fragrances of cannabis","volume":"12","author":"Weston-Green","year":"2021","journal-title":"Front. Psychiatry"},{"key":"B44","doi-asserted-by":"publisher","first-page":"2031","DOI":"10.2147\/PPA.S116823","article-title":"Is it appropriate regarding patient preference to take myrtol standardized enteric-coated soft capsules after a meal rather than at fasted state? A food\u2013drug pharmacokinetic interaction study in healthy Chinese volunteers","volume":"10","author":"Zhao","year":"2016","journal-title":"Patient Prefer Adherence."},{"key":"B45","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.bcp.2011.09.020","article-title":"Consideration of allosterism and interacting proteins in the physiological functions of the serotonin transporter","volume":"83","author":"Zhong","year":"2012","journal-title":"Biochem. Pharmacol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1923534\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:27:26Z","timestamp":1790310446000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1923534\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":45,"alternative-id":["10.3389\/fphar.2026.1923534"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1923534","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"article-number":"1923534"}}