{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:49:25Z","timestamp":1790099365385,"version":"4.0.1"},"reference-count":26,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Ketamine and magnesium sulfate are commonly used perioperatively to prevent shivering, a frequent and clinically relevant complication of spinal and general anesthesia. Although their hypothermic effects are well documented, the neurotransmitter mechanisms underlying these effects remain insufficiently understood. This study examines whether serotonergic, adrenergic (\u03b12), and GABAergic (GABAA) systems contribute to hypothermia induced by ketamine and a ketamine\u2013magnesium sulfate combination. Methods: Body temperature was measured in Wistar rats after administration of ketamine (10 mg\/kg) or the ketamine (5 mg\/kg)\u2013magnesium sulfate (5 mg\/kg) combination. To assess neurotransmitter involvement, animals received yohimbine (\u03b12 antagonist), methysergide (non-selective 5-HT antagonist), or bicuculline (GABAA antagonist) prior to ketamine or the drug combination. Data were analyzed using two-way repeated measures ANOVA followed by Tukey\u2019s post hoc test. Results: Yohimbine at 0.5 and 1 mg\/kg significantly potentiated ketamine-induced hypothermia, while only 3 mg\/kg enhanced the effect of the ketamine\u2013magnesium sulfate combination. Methysergide had a bidirectional influence: 1 mg\/kg methysergide deepened ketamine-induced hypothermia, whereas 0.5 mg\/kg methysergide attenuated the hypothermic effect of the ketamine\u2013magnesium sulfate combination. Bicuculline (1\u20132 mg\/kg) did not alter the hypothermic responses to ketamine or the combination. Conclusions: These findings indicate that ketamine- and ketamine\u2013magnesium sulfate-induced hypothermia is primarily modulated by serotonergic and adrenergic mechanisms, whereas GABAA receptor-dependent pathways do not appear to play a major role under the experimental conditions used. These results provide new mechanistic insights into NMDA antagonist\u2013related thermoregulation and may help inform anesthetic strategies for shivering prevention and maintenance of perioperative thermal stability.<\/jats:p>","DOI":"10.3390\/brainsci16020189","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T17:20:14Z","timestamp":1770225614000},"page":"189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neurotransmitter Mechanisms of Ketamine and Ketamine\u2013Magnesium Sulfate-Induced Hypothermia: Evidence for Serotonergic and Adrenergic Involvement Without GABAA Contributions"],"prefix":"10.3390","volume":"16","author":[{"given":"Katarina","family":"Savi\u0107 Vujovi\u0107","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Vu\u010dkovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Samard\u017ei\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7012-6766","authenticated-orcid":false,"given":"Branislava","family":"Medi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9680-0840","authenticated-orcid":false,"given":"Dragana","family":"Srebro","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9862-592X","authenticated-orcid":false,"given":"Ana","family":"Joti\u0107","sequence":"additional","affiliation":[{"name":"Clinic for Otorhinolaryngology and Maxillofacial Surgery, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1515-1824","authenticated-orcid":false,"given":"Ivana","family":"\u0106irkovi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.23736\/S0375-9393.18.12478-3","article-title":"Shivering Prevention and Treatment During Cesarean Delivery Under Neuraxial Anesthesia: A Systematic Review","volume":"84","author":"Liu","year":"2018","journal-title":"Minerva Anestesiol."},{"key":"ref_2","first-page":"395","article-title":"Prevention of Shivering During Spinal Anesthesia: Comparison Between Tramadol, Ketamine and Ondansetron","volume":"56","author":"Lakhe","year":"2017","journal-title":"J. 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