{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T03:17:56Z","timestamp":1787887076648,"version":"build-2784847793"},"reference-count":108,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T00:00:00Z","timestamp":1749859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development, and Innovation Office, Hungary","award":["OTKA FK 132454"],"award-info":[{"award-number":["OTKA FK 132454"]}]},{"name":"National Research, Development, and Innovation Office, Hungary","award":["BO\/00750\/22\/5"],"award-info":[{"award-number":["BO\/00750\/22\/5"]}]},{"name":"J\u00e1nos Bolyai Research Scholarship of the Hungarian Academy of Sciences","award":["OTKA FK 132454"],"award-info":[{"award-number":["OTKA FK 132454"]}]},{"name":"J\u00e1nos Bolyai Research Scholarship of the Hungarian Academy of Sciences","award":["BO\/00750\/22\/5"],"award-info":[{"award-number":["BO\/00750\/22\/5"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Dimethyl trisulfide (DMTS) is a naturally occurring polysulfide with known antioxidant and neuroprotective properties. DMTS is a lipophilic transient receptor potential ankyrin 1 (TRPA1) ligand that reaches the central nervous system (CNS). Its role in the CNS, particularly regarding depression-like behaviour, has yet to be explored. This study investigates the influence of DMTS on stress responses and whether this effect is mediated through the TRPA1 ion channel, known for its role in stress adaptation. Using a mouse model involving three-week exposure, we examined the impact of DMTS on depression-like behaviour and anxiety and identified the involved brain regions. Methods: Our methods involved testing both Trpa1-wild-type and gene-knockout mice under CUMS conditions and DMTS treatment. DMTS was administered intraperitoneally at a dose of 30 mg\/kg on days 16 and 20 of the 21-day CUMS protocol\u2014in hourly injections seven times to ensure sustained exposure. Various behavioural assessments\u2014including the open field, marble burying, tail suspension, forced swim, and sucrose preference tests\u2014were performed to evaluate anxiety and depression-like behaviour. Additionally, we measured body weight changes and the relative weights of the thymus and adrenal glands, while serum levels of corticosterone and adrenocorticotropic hormone were quantified via ELISA. FOSB (FBJ murine osteosarcoma viral oncogene homolog B) immunohistochemistry was utilised to assess chronic neuronal activation in stress-relevant brain areas. Results: Results showed that CUMS induces depression-like behaviour, with the response being modulated by the TRPA1 status and that DMTS treatment significantly reduced these effects when TRPA1 channels were functional. DMTS also mitigated thymus involution due to hypothalamic\u2013pituitary\u2013adrenal (HPA) axis dysregulation. Conclusions: Overall, DMTS appears to relieve depressive and anxiety symptoms through TRPA1-mediated pathways, suggesting its potential as a dietary supplement or adjunct therapy for depression and anxiety.<\/jats:p>","DOI":"10.3390\/pharmaceutics17060781","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T14:03:11Z","timestamp":1750082591000},"page":"781","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Anxiolytic and Antidepressant Effects of Organic Polysulfide, Dimethyl Trisulfide Are Partly Mediated by the Transient Receptor Potential Ankyrin 1 Ion Channel in Mice"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7022-1724","authenticated-orcid":false,"given":"Kitti","family":"G\u00f6nt\u00e9r","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School, University of P\u00e9cs, H-7624 P\u00e9cs, Hungary"},{"name":"Department of Pharmacology, Faculty of Pharmacy, University of P\u00e9cs, H-7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3360-2425","authenticated-orcid":false,"given":"Vikt\u00f3ria","family":"Kormos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School, University of P\u00e9cs, H-7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9898-632X","authenticated-orcid":false,"given":"Erika","family":"Pint\u00e9r","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School, University of P\u00e9cs, H-7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8524-7162","authenticated-orcid":false,"given":"G\u00e1bor","family":"Pozsgai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, University of P\u00e9cs, H-7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s40035-021-00239-0","article-title":"Acrolein Scavenger Dimercaprol Offers Neuroprotection in an Animal Model of Parkinson\u2019s Disease: Implication of Acrolein and TRPA1","volume":"10","author":"Shi","year":"2021","journal-title":"Transl. Neurodegener"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E162","DOI":"10.1503\/jpn.210187","article-title":"Peptidergic Neurons of the Edinger\u2013Westphal Nucleus Express TRPA1 Ion Channel That Is Downregulated Both upon Chronic Variable Mild Stress in Male Mice and in Humans Who Died by Suicide","volume":"47","author":"Kormos","year":"2022","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Al-Omari, A., Kecsk\u00e9s, M., Gaszner, B., Bir\u00f3-S\u00fct\u0151, T., Fazekas, B., Berta, G., Kuzma, M., Pint\u00e9r, E., and Kormos, V. (2023). Functionally Active TRPA1 Ion Channel Is Downregulated in Peptidergic Neurons of the Edinger-Westphal Nucleus upon Acute Alcohol Exposure. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1046559"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Konkoly, J., Kormos, V., Gaszner, B., Correia, P., Berta, G., Bir\u00f3-S\u00fct\u0151, T., Zelena, D., and Pint\u00e9r, E. (2022). Transient Receptor Potential Ankyrin 1 Ion Channel Expressed by the Edinger-Westphal Nucleus Contributes to Stress Adaptation in Murine Model of Posttraumatic Stress Disorder. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1059073"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4289","DOI":"10.1111\/bph.12786","article-title":"The Blockade of Transient Receptor Potential Ankirin 1 (TRPA 1) Signalling Mediates Antidepressant- and Anxiolytic-like Actions in Mice","volume":"171","author":"Noroes","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainresbull.2021.07.011","article-title":"TRPA1 Involvement in Depression- and Anxiety-like Behaviors in a Progressive Multiple Sclerosis Model in Mice","volume":"175","author":"Peres","year":"2021","journal-title":"Brain Res. Bull."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1152\/physrev.00005.2019","article-title":"Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease","volume":"100","author":"Talavera","year":"2020","journal-title":"Physiol. Rev."},{"key":"ref_8","first-page":"6546475","article-title":"Intravascular Residence Time Determination for the Cyanide Antidote Dimethyl Trisulfide in Rat by Using Liquid-Liquid Extraction Coupled with High Performance Liquid Chromatography","volume":"2016","author":"Lee","year":"2016","journal-title":"J. Anal. Methods Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1093\/toxsci\/kfx190","article-title":"From the Cover: In Vitro and In Vivo Blood-Brain Barrier Penetration Studies with the Novel Cyanide Antidote Candidate Dimethyl Trisulfide in Mice","volume":"160","author":"Kiss","year":"2017","journal-title":"Toxicol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jchromb.2017.01.010","article-title":"Method Development for Detecting the Novel Cyanide Antidote Dimethyl Trisulfide from Blood and Brain, and Its Interaction with Blood","volume":"1044\u20131045","author":"Kiss","year":"2017","journal-title":"J. Chromatogr. B"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"B\u00e1tai, I.Z., Horv\u00e1th, \u00c1., Pint\u00e9r, E., Helyes, Z., and Pozsgai, G. (2018). Role of Transient Receptor Potential Ankyrin 1 Ion Channel and Somatostatin Sst4 Receptor in the Antinociceptive and Anti-Inflammatory Effects of Sodium Polysulfide and Dimethyl Trisulfide. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00055"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1093\/ijnp\/pyx030","article-title":"Hydrogen Sulfide Inhibits Chronic Unpredictable Mild Stress-Induced Depressive-Like Behavior by Upregulation of Sirt-1: Involvement in Suppression of Hippocampal Endoplasmic Reticulum Stress","volume":"20","author":"Liu","year":"2017","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1007\/s12017-018-8489-7","article-title":"BDNF\/TrkB Pathway Mediates the Antidepressant-Like Role of H2S in CUMS-Exposed Rats by Inhibition of Hippocampal ER Stress","volume":"20","author":"Wei","year":"2018","journal-title":"Neuromol. Med."},{"key":"ref_14","first-page":"E4651","article-title":"Key Bioactive Reaction Products of the NO\/H 2 S Interaction Are S\/N-Hybrid Species, Polysulfides, and Nitroxyl","volume":"112","author":"Kuhnle","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.phrs.2016.09.022","article-title":"Nitrosopersulfide (SSNO\u2212) Targets the Keap-1\/Nrf2 Redox System","volume":"113","author":"Pullmann","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1089\/ars.2012.5041","article-title":"Polysulfides Link H 2 S to Protein Thiol Oxidation","volume":"19","author":"Greiner","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Yang, G., and Wu, L. (2017). Trend in H2S Biology and Medicine Research\u2014A Bibliometric Analysis. Molecules, 22.","DOI":"10.3390\/molecules22122087"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.niox.2017.01.012","article-title":"Analgesic Effect of Dimethyl Trisulfide in Mice Is Mediated by TRPA1 and Sst 4 Receptors","volume":"65","author":"Pozsgai","year":"2017","journal-title":"Nitric Oxide"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dombi, \u00c1., S\u00e1nta, C., B\u00e1tai, I.Z., Kormos, V., Kecsk\u00e9s, A., T\u00e9kus, V., Poh\u00f3czky, K., B\u00f6lcskei, K., Pint\u00e9r, E., and Pozsgai, G. (2021). Dimethyl Trisulfide Diminishes Traumatic Neuropathic Pain Acting on TRPA1 Receptors in Mice. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073363"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1096\/fj.12-226415","article-title":"Polysulfides Are Possible H 2 S-derived Signaling Molecules in Rat Brain","volume":"27","author":"Kimura","year":"2013","journal-title":"FASEB J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"221","DOI":"10.2147\/NDT.S198774","article-title":"Management of Treatment-Resistant Depression: Challenges and Strategies","volume":"16","author":"Voineskos","year":"2020","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"G\u00f6nt\u00e9r, K., Dombi, \u00c1., Kormos, V., Pint\u00e9r, E., and Pozsgai, G. (2024). Examination of the Effect of Dimethyl Trisulfide in Acute Stress Mouse Model with the Potential Involvement of the TRPA1 Ion Channel. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202406.0434.v1"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"88","DOI":"10.5662\/wjm.v5.i2.88","article-title":"Past, Present and Future of Cyanide Antagonism Research: From the Early Remedies to the Current Therapies","volume":"5","author":"Petrikovics","year":"2015","journal-title":"World J. Methodol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1177\/0748233715622713","article-title":"Dimethyl Trisulfide: A Novel Cyanide Countermeasure","volume":"32","author":"Rockwood","year":"2016","journal-title":"Toxicol. Ind. Health"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.chroma.2019.01.058","article-title":"Analysis of Potential Cyanide Antidote, Dimethyl Trisulfide, in Whole Blood by Dynamic Headspace Gas Chromatography\u2013Mass Spectroscopy","volume":"1591","author":"Bhadra","year":"2019","journal-title":"J. Chromatogr. A"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.neuroscience.2016.06.004","article-title":"Reduced Response to Chronic Mild Stress in PACAP Mutant Mice Is Associated with Blunted FosB Expression in Limbic Forebrain and Brainstem Centers","volume":"330","author":"Kormos","year":"2016","journal-title":"Neuroscience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.jad.2021.02.005","article-title":"H2S-Mediated Aerobic Exercise Antagonizes the Hippocampal Inflammatory Response in CUMS-Depressed Mice","volume":"283","author":"Liu","year":"2021","journal-title":"J. Affect. Disord."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1097\/FBP.0b013e3283654258","article-title":"Antidepressant-like and Anxiolytic-like Effects of Hydrogen Sulfide in Behavioral Models of Depression and Anxiety","volume":"24","author":"Chen","year":"2013","journal-title":"Behav. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.jneumeth.2014.06.012","article-title":"Marble Burying as a Test of the Delayed Anxiogenic Effects of Acute Immobilisation Stress in Mice","volume":"233","author":"Kedia","year":"2014","journal-title":"J. Neurosci. Methods"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/0091-3057(91)90590-X","article-title":"Evaluation of Marble-Burying Behavior as a Model of Anxiety","volume":"38","author":"Handley","year":"1991","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/2040-2392-5-15","article-title":"Rating Scale Measures Are Associated with Noldus EthoVision-XT Video Tracking of Behaviors of Children on the Autism Spectrum","volume":"5","author":"Cohen","year":"2014","journal-title":"Mol. Autism"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"104911","DOI":"10.1016\/j.neures.2025.104911","article-title":"Long-Lasting Expression of FosB\/\u0394FosB Immunoreactivity Following Acute Stress in the Paraventricular and Supraoptic Nuclei of the Rat Hypothalamus","volume":"217","author":"Uchida","year":"2025","journal-title":"Neurosci. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1093\/biomet\/52.3-4.591","article-title":"An Analysis of Variance Test for Normality (Complete Samples)","volume":"53","author":"Shapiro","year":"1965","journal-title":"Biometrika"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ynstr.2016.08.002","article-title":"The Chronic Mild Stress (CMS) Model of Depression: History, Evaluation and Usage","volume":"6","author":"Willner","year":"2017","journal-title":"Neurobiol. Stress."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.bbr.2014.07.015","article-title":"Chronic Social Stress Does Not Affect Behavioural Habituation in Male CD1 Mice","volume":"273","author":"Boleij","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"R250","DOI":"10.1152\/ajpregu.00361.2014","article-title":"Chronic and Acute Effects of Stress on Energy Balance: Are There Appropriate Animal Models?","volume":"308","author":"Harris","year":"2015","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.euroneuro.2015.04.026","article-title":"Evidence against a Critical Role of CB1 Receptors in Adaptation of the Hypothalamic\u2013Pituitary\u2013Adrenal Axis and Other Consequences of Daily Repeated Stress","volume":"25","author":"Rabasa","year":"2015","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neuroscience.2017.04.019","article-title":"Construct and Face Validity of a New Model for the Three-Hit Theory of Depression Using PACAP Mutant Mice on CD1 Background","volume":"354","author":"Farkas","year":"2017","journal-title":"Neuroscience"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1126\/science.273.5281.1561","article-title":"Appetite-Suppressing Effects of Urocortin, a CRF-Related Neuropeptide","volume":"273","author":"Spina","year":"1996","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Landini, L., Souza Monteiro De Araujo, D., Titiz, M., Geppetti, P., Nassini, R., and De Logu, F. (2022). TRPA1 Role in Inflammatory Disorders: What Is Known So Far?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094529"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Naert, R., L\u00f3pez-Requena, A., and Talavera, K. (2021). TRPA1 Expression and Pathophysiology in Immune Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111460"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Szab\u00f3, K., Kem\u00e9ny, \u00c1., Bal\u00e1zs, N., Khanfar, E., S\u00e1ndor, Z., Boldizs\u00e1r, F., Gyulai, R., Najbauer, J., Pint\u00e9r, E., and Berki, T. (2022). Presence of TRPA1 Modifies CD4+\/CD8+ T Lymphocyte Ratio and Activation. Pharmaceuticals, 15.","DOI":"10.3390\/ph15010057"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Szab\u00f3, K., Makkai, G., Konkoly, J., Kormos, V., Gaszner, B., Berki, T., and Pint\u00e9r, E. (2024). TRPA1 Covalent Ligand JT010 Modifies T Lymphocyte Activation. Biomolecules, 14.","DOI":"10.3390\/biom14060632"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1046\/j.1365-2826.2000.00441.x","article-title":"Evidence That Hydrogen Sulphide Can Modulate Hypothalamo-Pituitary-Adrenal Axis Function: In Vitro and In Vivo Studies in the Rat","volume":"12","author":"Russo","year":"2000","journal-title":"J. Neuroendocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.lfs.2019.04.020","article-title":"Protective Effect of Diallyl Sulfide against Lead-Mediated Oxidative Damage, Apoptosis and down-Regulation of CYP19 Gene Expression in Rat Testes","volume":"226","author":"Hassan","year":"2019","journal-title":"Life Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"264","DOI":"10.7150\/ijbs.38143","article-title":"Hydrogen Sulfide Plays an Important Protective Role through Influencing Endoplasmic Reticulum Stress in Diseases","volume":"16","author":"Wang","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Sodhi, R.K., Singh, R., Bansal, Y., Bishnoi, M., Parhar, I., Kuhad, A., and Soga, T. (2021). Intersections in Neuropsychiatric and Metabolic Disorders: Possible Role of TRPA1 Channels. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.771575"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1046\/j.1472-8206.2003.00160.x","article-title":"Monoamine Metabolism Changes Following the Mouse Forced Swimming Test but Not the Tail Suspension Test","volume":"17","author":"Renard","year":"2003","journal-title":"Fundamemntal Clin. Pharma"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jchemneu.2015.07.002","article-title":"The Centrally Projecting Edinger\u2013Westphal Nucleus\u2014I: Efferents in the Rat Brain","volume":"68","author":"Haemmerle","year":"2015","journal-title":"J. Chem. Neuroanat."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.neuroscience.2016.10.072","article-title":"Serotonin and Urocortin 1 in the Dorsal Raphe and Edinger\u2013Westphal Nuclei after Early Life Stress in Serotonin Transporter Knockout Rats","volume":"340","author":"Robroch","year":"2017","journal-title":"Neuroscience"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.biopsych.2009.02.014","article-title":"Stress-Induced Redistribution of Corticotropin-Releasing Factor Receptor Subtypes in the Dorsal Raphe Nucleus","volume":"66","author":"Waselus","year":"2009","journal-title":"Biol. Psychiatry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1002\/da.22490","article-title":"Treatment for Anhedonia: A Neuroscience Driven Approach: 2015 ADAA Scientific Research Symposium: Treatment for Anhedonia","volume":"33","author":"Craske","year":"2016","journal-title":"Depress. Anxiety"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Yakovleva, O., Bogatova, K., Mukhtarova, R., Yakovlev, A., Shakhmatova, V., Gerasimova, E., Ziyatdinova, G., Hermann, A., and Sitdikova, G. (2020). Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress. Biomolecules, 10.","DOI":"10.3390\/biom10070995"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1080\/14737175.2019.1668270","article-title":"Hydrogen Sulfide: A Target to Modulate Oxidative Stress and Neuroplasticity for the Treatment of Pathological Anxiety","volume":"20","author":"Chen","year":"2020","journal-title":"Expert. Rev. Neurother."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.janxdis.2010.01.006","article-title":"Testing a Hierarchical Model of Anxiety and Depression in Adolescents: A Tri-Level Model","volume":"24","author":"Prenoveau","year":"2010","journal-title":"J. Anxiety Disord."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2174\/1570159X14666160202121111","article-title":"Synaptic Plasticity, Metaplasticity and Depression","volume":"15","author":"Vose","year":"2017","journal-title":"Curr. Neuropharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.2147\/IJGM.S413176","article-title":"Regulatory Molecules of Synaptic Plasticity in Anxiety Disorder","volume":"16","author":"Sha","year":"2023","journal-title":"Int. J. Gen. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nm.4050","article-title":"Synaptic Plasticity and Depression: New Insights from Stress and Rapid-Acting Antidepressants","volume":"22","author":"Duman","year":"2016","journal-title":"Nat. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ejphar.2014.10.034","article-title":"\u2206FosB: A Transcriptional Regulator of Stress and Antidepressant Responses","volume":"753","author":"Nestler","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/S0006-8993(98)01191-3","article-title":"\u0394FosB: A molecular mediator of long-term neural and behavioral plasticity","volume":"835","author":"Nestler","year":"1999","journal-title":"Brain Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"10594","DOI":"10.1523\/JNEUROSCI.2542-04.2004","article-title":"Induction of \u0394FosB in Reward-Related Brain Structures after Chronic Stress","volume":"24","author":"Perrotti","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Sterrenburg, L., Gaszner, B., Boerrigter, J., Santbergen, L., Bramini, M., Elliott, E., Chen, A., Peeters, B.W.M.M., Roubos, E.W., and Kozicz, T. (2011). Chronic Stress Induces Sex-Specific Alterations in Methylation and Expression of Corticotropin-Releasing Factor Gene in the Rat. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028128"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.neuropharm.2015.07.005","article-title":"Differential Induction of FosB Isoforms throughout the Brain by Fluoxetine and Chronic Stress","volume":"99","author":"Vialou","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Virk, H.S., Rekas, M.Z., Biddle, M.S., Wright, A.K.A., Sousa, J., Weston, C.A., Chachi, L., Roach, K.M., and Bradding, P. (2019). Validation of Antibodies for the Specific Detection of Human TRPA1. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-55133-7"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.neuroscience.2010.09.031","article-title":"Transient Receptor Potential V1 Regulates Activation and Modulation of Transient Receptor Potential A1 by Ca2+","volume":"171","author":"Patil","year":"2010","journal-title":"Neuroscience"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1369\/00221554241251904","article-title":"Correlation of TRPA1 RNAscope and Agonist Responses","volume":"72","author":"Ciotu","year":"2024","journal-title":"J. Histochem. Cytochem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.neuroscience.2007.12.050","article-title":"Gender-Related Urocortin 1 and Brain-Derived Neurotrophic Factor Expression in the Adult Human Midbrain of Suicide Victims with Major Depression","volume":"152","author":"Kozicz","year":"2008","journal-title":"Neuroscience"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.brainresbull.2006.12.009","article-title":"Differential Effects of Exposure to Low-Light or High-Light Open-Field on Anxiety-Related Behaviors: Relationship to c-Fos Expression in Serotonergic and Non-Serotonergic Neurons in the Dorsal Raphe Nucleus","volume":"72","author":"Bouwknecht","year":"2007","journal-title":"Brain Res. Bull."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/mp.2009.134","article-title":"The Missing Link; the Significance of Urocortin 1\/Urocortin 2 in the Modulation of the Dorsal Raphe Serotoninergic System","volume":"15","author":"Kozicz","year":"2010","journal-title":"Mol. Psychiatry"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"19020","DOI":"10.1073\/pnas.1013761107","article-title":"A Triple Urocortin Knockout Mouse Model Reveals an Essential Role for Urocortins in Stress Recovery","volume":"107","author":"Tsoory","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/(SICI)1096-9861(19991220)415:3<285::AID-CNE1>3.0.CO;2-0","article-title":"Urocortin Expression in Rat Brain: Evidence Against a Pervasive Relationship of Urocortin-Containing Projections with Targets Bearing Type 2 CRF Receptors","volume":"415","author":"Bittencourt","year":"1999","journal-title":"J. Comp. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ygcen.2007.04.005","article-title":"On the Role of Urocortin 1 in the Non-Preganglionic Edinger\u2013Westphal Nucleus in Stress Adaptation","volume":"153","author":"Kozicz","year":"2007","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1177\/0269881113492900","article-title":"5-HT1A and 5-HT2A Receptor Control of a Panic-like Defensive Response in the Rat Dorsomedial Hypothalamic Nucleus","volume":"27","author":"Yamashita","year":"2013","journal-title":"J. Psychopharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Zuniga, A., and Ryabinin, A.E. (2020). Involvement of Centrally Projecting Edinger\u2013Westphal Nucleus Neuropeptides in Actions of Addictive Drugs. Brain Sci., 10.","DOI":"10.3390\/brainsci10020067"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.neubiorev.2015.08.005","article-title":"Placing the Paraventricular Nucleus of the Thalamus within the Brain Circuits That Control Behavior","volume":"56","author":"Kirouac","year":"2015","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1038\/s41593-021-00912-7","article-title":"Divergent Projections of the Paraventricular Nucleus of the Thalamus Mediate the Selection of Passive and Active Defensive Behaviors","volume":"24","author":"Ma","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/npp.2010.213","article-title":"The Modulatory Role of the Lateral Septum on Neuroendocrine and Behavioral Stress Responses","volume":"36","author":"Singewald","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.psyneuen.2008.12.013","article-title":"Chronic Stress Increases Pituitary Adenylate Cyclase-Activating Peptide (PACAP) and Brain-Derived Neurotrophic Factor (BDNF) mRNA Expression in the Bed Nucleus of the Stria Terminalis (BNST): Roles for PACAP in Anxiety-like Behavior","volume":"34","author":"Hammack","year":"2009","journal-title":"Psychoneuroendocrinology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/0006-8993(93)90665-A","article-title":"Regulation of the Hypothalamic Pituitary Adrenal Axis during Chronic Stress: Responses to Repeated Intraperitoneal Hypertonic Saline Injection","volume":"630","author":"Kiss","year":"1993","journal-title":"Brain Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1111\/j.1460-9568.2004.03568.x","article-title":"Chronic Stress Attenuates GABAergic Inhibition and Alters Gene Expression of Parvocellular Neurons in Rat Hypothalamus","volume":"20","author":"Verkuyl","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/cne.20445","article-title":"Organization and Regulation of Paraventricular Nucleus Glutamate Signaling Systems: N-methyl-D-aspartate Receptors","volume":"484","author":"Ziegler","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1002\/cne.22142","article-title":"Chronic Stress-induced Neurotransmitter Plasticity in the PVN","volume":"517","author":"Flak","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2174\/1570159X11311020002","article-title":"Mechanisms in the Bed Nucleus of the Stria Terminalis Involved in Control of Autonomic and Neuroendocrine Functions: A Review","volume":"11","author":"Crestani","year":"2013","journal-title":"Curr. Neuropharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.yfrne.2003.07.001","article-title":"Central Mechanisms of Stress Integration: Hierarchical Circuitry Controlling Hypothalamo\u2013Pituitary\u2013Adrenocortical Responsiveness","volume":"24","author":"Herman","year":"2003","journal-title":"Front. Neuroendocrinol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/S0006-8993(97)01011-1","article-title":"Effects of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) on Corticotropin-Releasing Hormone (CRH) Gene Expression in the Rat Hypothalamic Paraventricular Nucleus","volume":"773","author":"Grinevich","year":"1997","journal-title":"Brain Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1210\/en.2007-0883","article-title":"The Anteroventral Bed Nucleus of the Stria Terminalis Differentially Regulates Hypothalamic-Pituitary-Adrenocortical Axis Responses to Acute and Chronic Stress","volume":"149","author":"Choi","year":"2008","journal-title":"Endocrinology"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Deji, C., Yan, P., Ji, Y., Yan, X., Feng, Y., Liu, J., Liu, Y., Wei, S., Zhu, Y., and Lai, J. (2022). The Basolateral Amygdala to Ventral Hippocampus Circuit Controls Anxiety-Like Behaviors Induced by Morphine Withdrawal. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.894886"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Kov\u00e1cs, L.\u00c1., F\u00fcredi, N., Ujv\u00e1ri, B., Golgol, A., and Gaszner, B. (2022). Age-Dependent FOSB\/\u0394FOSB Response to Acute and Chronic Stress in the Extended Amygdala, Hypothalamic Paraventricular, Habenular, Centrally-Projecting Edinger-Westphal, and Dorsal Raphe Nuclei in Male Rats. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.862098"},{"key":"ref_89","first-page":"868","article-title":"Role of Hydrogen Sulfide and Polysulfides in Neurological Diseases: Focus on Protein S-Persulfidation","volume":"19","author":"Sun","year":"2021","journal-title":"Curr. Neuropharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.neuint.2013.09.003","article-title":"Physiological Role of Hydrogen Sulfide and Polysulfide in the Central Nervous System","volume":"63","author":"Kimura","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1021\/cn500185g","article-title":"Hydrogen Sulfide: A Neuromodulator and Neuroprotectant in the Central Nervous System","volume":"5","author":"Zhang","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Kimura, H. (2021). Hydrogen Sulfide (H2S) and Polysulfide (H2Sn) Signaling: The First 25 Years. Biomolecules, 11.","DOI":"10.3390\/biom11060896"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1021\/acs.chemrestox.7b00181","article-title":"Reaction of Dimethyl Trisulfide with Hemoglobin","volume":"30","author":"Dong","year":"2017","journal-title":"Chem. Res. Toxicol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.chroma.2016.07.046","article-title":"Determination of Dimethyl Trisulfide in Rabbit Blood Using Stir Bar Sorptive Extraction Gas Chromatography-Mass Spectrometry","volume":"1461","author":"Manandhar","year":"2016","journal-title":"J. Chromatogr. A"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1080\/15376516.2019.1585504","article-title":"Antidotal Efficacies of the Cyanide Antidote Candidate Dimethyl Trisulfide Alone and in Combination with Cobinamide Derivatives","volume":"29","author":"Petrikovics","year":"2019","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"27171","DOI":"10.1021\/acsomega.0c03208","article-title":"Evaluation of the Long-Term Storage Stability of the Cyanide Antidote: Dimethyl Trisulfide and Degradation Product Identification","volume":"5","author":"Warnakula","year":"2020","journal-title":"ACS Omega"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1126\/science.1108609","article-title":"Impaired Thermosensation in Mice Lacking TRPV3, a Heat and Camphor Sensor in the Skin","volume":"307","author":"Moqrich","year":"2005","journal-title":"Science"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neubiorev.2020.01.011","article-title":"The Contagion of Social Defeat Stress: Insights from Rodent Studies","volume":"111","author":"Carnevali","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e216","DOI":"10.1038\/tp.2012.144","article-title":"Peripuberty Stress Leads to Abnormal Aggression, Altered Amygdala and Orbitofrontal Reactivity and Increased Prefrontal MAOA Gene Expression","volume":"3","author":"Poirier","year":"2013","journal-title":"Transl. Psychiatry"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Konkoly, J., Kormos, V., Gaszner, B., S\u00e1ndor, Z., Kecsk\u00e9s, A., Alomari, A., Szil\u00e1gyi, A., Szil\u00e1gyi, B., Zelena, D., and Pint\u00e9r, E. (2021). The Role of TRPA1 Channels in the Central Processing of Odours Contributing to the Behavioural Responses of Mice. Pharmaceuticals, 14.","DOI":"10.3390\/ph14121336"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Olah, E., Rumbus, Z., Kormos, V., Tekus, V., Pakai, E., Wilson, H.V., Fekete, K., Solymar, M., Kelava, L., and Keringer, P. (2021). The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice. Pharmaceuticals, 14.","DOI":"10.3390\/ph14100992"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Cano, G., Hernan, S.L., and Sved, A.F. (2021). Centrally Projecting Edinger-Westphal Nucleus in the Control of Sympathetic Outflow and Energy Homeostasis. Brain Sci., 11.","DOI":"10.3390\/brainsci11081005"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.neuroscience.2009.06.046","article-title":"Estrogen Receptor Beta Regulates the Expression of Tryptophan-Hydroxylase 2 mRNA within Serotonergic Neurons of the Rat Dorsal Raphe Nuclei","volume":"163","author":"Donner","year":"2009","journal-title":"Neuroscience"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.brainres.2014.07.041","article-title":"Effects of Sex Steroids and Estrogen Receptor Agonists on the Expression of Estrogen Receptor Alpha in the Principal Division of the Bed Nucleus of the Stria Terminalis of Female Rats","volume":"1582","author":"Leite","year":"2014","journal-title":"Brain Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.tins.2021.10.010","article-title":"Neurobiology of the Lateral Septum: Regulation of Social Behavior","volume":"45","author":"Menon","year":"2022","journal-title":"Trends Neurosci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.neures.2004.02.011","article-title":"Expression of Estrogen Receptors (\u03b1, \u03b2) and Androgen Receptor in Serotonin Neurons of the Rat and Mouse Dorsal Raphe Nuclei; Sex and Species Differences","volume":"49","author":"Sheng","year":"2004","journal-title":"Neurosci. Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0006-8993(03)02594-0","article-title":"Preautonomic Neurons in the Paraventricular Nucleus of the Hypothalamus Contain Estrogen Receptor \u03b2","volume":"975","author":"Stern","year":"2003","journal-title":"Brain Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1016\/j.psyneuen.2013.04.011","article-title":"Estrogen Receptor GPR30 Exerts Anxiolytic Effects by Maintaining the Balance between GABAergic and Glutamatergic Transmission in the Basolateral Amygdala of Ovariectomized Mice after Stress","volume":"38","author":"Tian","year":"2013","journal-title":"Psychoneuroendocrinology"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/6\/781\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:52:11Z","timestamp":1760032331000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/6\/781"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,14]]},"references-count":108,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["pharmaceutics17060781"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17060781","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,14]]}}}