{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:07:36Z","timestamp":1791403656047,"version":"4.3.3"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"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:sec><jats:title>Aims<\/jats:title><jats:p>Demonstrate that dexmedetomidine is potentially useful for treatment of psychiatric symptoms caused by acute or chronic stress by using relevant rodent models and doses predicted to achieve sufficient brain levels to activate alpha2-adrenoceptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>In vitro<\/jats:italic> characterization was performed using labeled GTP\u03b3S binding and \u03b2-arrestin recruitment. Free brain levels were measured by using microdialysis probes in rats. <jats:italic>In vivo<\/jats:italic> behavioral characterization of dexmedetomidine was performed both an acute stress model (forced swim test or despair test) and a repeat stress model with repeat dosing (the open space swim test). Dexmedetomidine was assessed using translational models: the CCK-4 induced panic test in Wistar rats and latency to rapid eye movement sleep (REM sleep). Rotarod assessments (Swiss mice) and a cued memory consolidation model (Wistar rats) were used to ensure that effective doses had no overt effects on motor coordination or memory consolidation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Dexmedetomidine is both more potent (&amp;lt;10\u00a0nM EC50) and has higher intrinsic activity than other \u03b12-AR agonists (clonidine, lofexidine or guanfacine). Estimates of free brain levels at efficacious doses are sufficient to activate all 3 \u03b12-ARs. Dexmedetomidine was effective in decreasing immobility (increasing escape behaviors) in the forced swim test after a single acute stress and in the open space swim test after repeat dosing. Effects of dexmedetomidine were completely reversible and no withdrawal effects were observed. Doses used in the open space swim test had no overt effect on the rotarod indicating no impairment of motor coordination. Dexmedetomidine was highly effective in reversing a CCK-4 induced mediated deficit in the elevated plus maze, a translatable model for anxiety and panic. Dexmedetomidine also increased latency to REM sleep and shortened latency to slow wave sleep, positive attributes for a neuropsychiatric drug.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Dexmedetomidine may be a suitable drug for a chronic dosing for a wide range of stress-mediated symptoms, not limited to the acute treatment of agitation. Brain levels are highly predictable based on plasma exposures and are consistent with the known affinity for \u03b12-ARs.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1589075","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T05:51:48Z","timestamp":1751435508000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Dexmedetomidine potently and reversibly regulates stress-mediated behaviors"],"prefix":"10.3389","volume":"16","author":[{"given":"Frank D.","family":"Yocca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh K.","family":"Dhull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhendu","family":"Seth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Chugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishnan","family":"Nandabalan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friso R.","family":"Postma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"De Vivo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.clinph.2017.10.005","article-title":"Dexmedetomidine promotes biomimetic non-rapid eye movement stage 3 sleep in humans: a pilot study","volume":"129","author":"Akeju","year":"2018","journal-title":"Clin. Neurophysiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"4540","DOI":"10.1038\/s41380-023-02057-4","article-title":"Scientific rationale for the use of \u03b12A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders","volume":"28","author":"Arnsten","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"B4","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/s0898-6568(02)00030-x","article-title":"Ligand modulation of [35S]GTPgammaS binding at human alpha(2A), alpha(2B) and alpha(2C) adrenoceptors","volume":"14","author":"Audinot","year":"2002","journal-title":"Cell Signal"},{"key":"B5","doi-asserted-by":"publisher","first-page":"212286","DOI":"10.7573\/dic.212286","article-title":"Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder","volume":"4","author":"Belkin","year":"2015","journal-title":"Drugs Context"},{"key":"B6","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s00441-017-2649-1","article-title":"Locus coeruleus","volume":"373","author":"Benarroch","year":"2018","journal-title":"Cell Tissue Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1016\/s0022-3565(24)37128-9","article-title":"Pharmacokinetic-pharmacodynamic characterization of the cardiovascular, hypnotic, EEG and ventilatory responses to dexmedetomidine in the rat","volume":"283","author":"Bol","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B8","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1001\/archpsyc.1991.01810310021005","article-title":"Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Clinical and behavioral findings","volume":"48","author":"Bradwejn","year":"1991","journal-title":"Arch. Gen. Psychiatry"},{"key":"B9","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1146\/annurev-pharmtox-010919-023348","article-title":"G protein-coupled receptor pharmacology at the single-molecule level","volume":"60","author":"Calebiro","year":"2020","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1001\/archpsyc.1984.01790190025003","article-title":"Noradrenergic function in panic anxiety. Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder","volume":"41","author":"Charney","year":"1984","journal-title":"Arch. Gen. Psychiatry"},{"key":"B11","doi-asserted-by":"publisher","first-page":"22m14447","DOI":"10.4088\/JCP.22m14447","article-title":"Sublingual dexmedetomidine for the treatment of acute agitation in adults with schizophrenia or schizoaffective disorder: a randomized placebo-controlled trial","volume":"83","author":"Citrome","year":"2022","journal-title":"J. Clin. Psychiatry"},{"key":"B12","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1021\/acschemneuro.7b00042","article-title":"The rodent forced swim test measures stress-coping strategy, not depression-like behavior","volume":"8","author":"Commons","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1038\/35000212","article-title":"Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion","volume":"403","author":"Delfs","year":"2000","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s10286-016-0383-5","article-title":"Dexmedetomidine for refractory adrenergic crisis in familial dysautonomia","volume":"27","author":"Dillon","year":"2017","journal-title":"Clin. Auton. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1002\/hbm.20522","article-title":"Functional neuroanatomy of CCK-4-induced panic attacks in healthy volunteers","volume":"30","author":"Eser","year":"2009","journal-title":"Hum. Brain Mapp."},{"key":"B16","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1523\/JNEUROSCI.1035-18.2018","article-title":"\u03b12A-Adrenergic receptor activation decreases parabrachial nucleus excitatory drive onto BNST CRF neurons and reduces their activity in vivo","volume":"39","author":"Fetterly","year":"2019","journal-title":"J. Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"eabn7065","DOI":"10.1126\/science.abn7065","article-title":"Structure-based discovery of nonopioid analgesics acting through the \u03b12A-adrenergic receptor","volume":"377","author":"Fink","year":"2022","journal-title":"Science"},{"key":"B18","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1046\/j.1460-9568.2003.02510.x","article-title":"Alpha2A and alpha2C-adrenoceptor regulation in the brain: alpha2A changes persist after chronic stress","volume":"17","author":"Fl\u00fcgge","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3389\/fnbeh.2018.00043","article-title":"Noradrenergic modulation of fear conditioning and extinction","volume":"12","author":"Giustino","year":"2018","journal-title":"Front. Behav. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1097\/00000542-199504000-00019","article-title":"Desensitization to the behavioral effects of alpha 2-adrenergic agonists in rats","volume":"82","author":"Hayashi","year":"1995","journal-title":"Anesthesiology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1111\/j.1749-6632.1999.tb09368.x","article-title":"Gene substitution\/knockout to delineate the role of alpha 2-adrenoceptor subtypes in mediating central effects of catecholamines and imidazolines","volume":"881","author":"Hein","year":"1999","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1016\/s0006-2952(97)00631-x","article-title":"Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding","volume":"55","author":"Jasper","year":"1998","journal-title":"Biochem. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000007548","article-title":"A randomized clinical trial of dexmedetomidine on delirium, cognitive dysfunction, and sleep after non-ambulatory orthopedic surgery with regional anesthesia","author":"Karageorgos","year":"2025","journal-title":"Anesth. and Analgesia"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3345","DOI":"10.1172\/JCI139642","article-title":"Preventing cytokine storm syndrome in COVID-19 using \u03b1-1 adrenergic receptor antagonists","volume":"130","author":"Konig","year":"2020","journal-title":"J. Clin. Invest"},{"key":"B25","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/S1474-4422(23)00469-6","article-title":"Neuropsychiatric research in 2023: mechanisms of stress and therapies","volume":"23","author":"Lopez","year":"2024","journal-title":"Lancet Neurol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1007\/s11095-022-03246-6","article-title":"Unbound brain-to-plasma partition coefficient, Kp,uu,brain-a game changing parameter for CNS drug discovery and development","volume":"39","author":"Loryan","year":"2022","journal-title":"Pharm. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.neubiorev.2020.07.038","article-title":"The role of norepinephrine in the pathophysiology of schizophrenia","volume":"118","author":"M\u00e4ki-Marttunen","year":"2020","journal-title":"Neurosci. Biobehav Rev."},{"key":"B28","first-page":"136","article-title":"The underlying neurobiology of bipolar disorder","volume":"2","author":"Manji","year":"2003","journal-title":"World Psychiatry"},{"key":"B29","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.neuron.2015.07.002","article-title":"CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety","volume":"87","author":"McCall","year":"2015","journal-title":"Neuron"},{"key":"B30","doi-asserted-by":"publisher","first-page":"2398212820930321","DOI":"10.1177\/2398212820930321","article-title":"The role of the locus coeruleus in the generation of pathological anxiety","volume":"4","author":"Morris","year":"2020","journal-title":"Brain Neurosci. Adv."},{"key":"B31","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.physbeh.2016.08.020","article-title":"A2 noradrenergic neurons regulate forced swim test immobility","volume":"165","author":"Nam","year":"2016","journal-title":"Physiol. Behav."},{"key":"B32","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1126\/science.abb8739","article-title":"Glymphatic failure as a final common pathway to dementia","volume":"370","author":"Nedergaard","year":"2020","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1016\/j.tips.2022.09.007","article-title":"Could dexmedetomidine be repurposed as a glymphatic enhancer?","volume":"43","author":"Persson","year":"2022","journal-title":"Trends Pharmacol. Sci."},{"key":"B34","first-page":"327","article-title":"Behavioral despair in mice: a primary screening test for antidepressants","volume":"229","author":"Porsolt","year":"1977","journal-title":"Arch. Int. Pharmacodyn. Ther."},{"key":"B35","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1001\/jama.2022.0799","article-title":"Effect of sublingual dexmedetomidine vs placebo on acute agitation associated with bipolar disorder: a randomized clinical trial","volume":"327","author":"Preskorn","year":"2022","journal-title":"JAMA"},{"key":"B36","doi-asserted-by":"publisher","first-page":"zsaa167","DOI":"10.1093\/sleep\/zsaa167","article-title":"Dexmedetomidine-induced deep sedation mimics non-rapid eye movement stage 3 sleep: large-scale validation using machine learning","volume":"44","author":"Ramaswamy","year":"2021","journal-title":"Sleep"},{"key":"B37","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/0304-3940(94)90681-5","article-title":"Effects of cholecystokinin tetrapeptide and sulfated cholecystokinin octapeptide in rat models of anxiety","volume":"172","author":"Rex","year":"1994","journal-title":"Neurosci. Lett."},{"key":"B38","article-title":"Cocaine toxicity. 2023 Jun 8","volume-title":"StatPearls treasure island (FL)","author":"Richards","year":"2025"},{"key":"B39","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41386-019-0411-y","article-title":"Sleep, insomnia, and depression","volume":"45","author":"Riemann","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1038\/sj.mp.4000543","article-title":"Genetic alteration of the alpha2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels","volume":"4","author":"Sallinen","year":"1999","journal-title":"Mol. Psychiatry"},{"key":"B41","doi-asserted-by":"publisher","first-page":"3035","DOI":"10.1523\/JNEUROSCI.18-08-03035.1998","article-title":"Adrenergic alpha2C-receptors modulate the acoustic startle reflex, prepulse inhibition, and aggression in mice","volume":"18","author":"Sallinen","year":"1998","journal-title":"J. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1007\/s12640-010-9236-5","article-title":"Regulation of neuronal activation by Alpha2A adrenergic receptor agonist","volume":"20","author":"Savchenko","year":"2011","journal-title":"Neurotox. Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"4875","DOI":"10.1523\/JNEUROSCI.21-13-04875.2001","article-title":"The alpha(2a)-adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety","volume":"21","author":"Schramm","year":"2001","journal-title":"J. Neurosci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"R1051","DOI":"10.1016\/j.cub.2015.09.039","article-title":"Organization of the locus coeruleus-norepinephrine system","volume":"25","author":"Schwarz","year":"2015","journal-title":"Curr. Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"263","DOI":"10.31887\/DCNS.2011.13.2\/jsherin","article-title":"Post-traumatic stress disorder: the neurobiological impact of psychological trauma","volume":"13","author":"Sherin","year":"2011","journal-title":"Dialogues Clin. Neurosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.neuroscience.2009.06.022","article-title":"Alpha2A-adrenergic receptors heterosynaptically regulate glutamatergic transmission in the bed nucleus of the stria terminalis","volume":"163","author":"Shields","year":"2009","journal-title":"Neuroscience"},{"key":"B47","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1002\/0471142301.ns0936s54","article-title":"Open-space forced swim model of depression for mice","volume":"9","author":"Stone","year":"2011","journal-title":"Curr. Protoc. Neurosci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.pbb.2008.07.006","article-title":"Evaluation of the repeated open-space swim model of depression in the mouse","volume":"91","author":"Stone","year":"2008","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B49","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/s0165-0270(03)00068-2","article-title":"Open space swimming test to index antidepressant activity","volume":"126","author":"Sun","year":"2003","journal-title":"J. Neurosci. Methods"},{"key":"B50","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/s0022-3565(25)20276-2","article-title":"Relative efficacy of spinal alpha-2 agonists, dexmedetomidine, clonidine and ST-91, determined in vivo by using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an irreversible antagonist","volume":"258","author":"Takano","year":"1991","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B51","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1007\/BF02245339","article-title":"Behavioral and autonomic responses to intermittent social stress: differential protection by clonidine and metoprolol","volume":"116","author":"Tornatzky","year":"1994","journal-title":"Psychopharmacol. Berl."},{"key":"B52","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1097\/JGP.0b013e3181ab8c61","article-title":"Prazosin for the treatment of behavioral symptoms in patients with alzheimer disease with agitation and aggression","volume":"17","author":"Wang","year":"2009","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"B53","article-title":"Measurement of \u03b2-Arrestin recruitment for GPCR targets. 2017 Nov 20","volume-title":"Assay guidance manual","author":"Wang","year":"2004"},{"key":"B54","doi-asserted-by":"publisher","first-page":"2149","DOI":"10.1523\/JNEUROSCI.3507-16.2017","article-title":"A deletion variant of the \u03b12b-Adrenoceptor modulates the stress-induced shift from Cognitive to Habit memory","volume":"37","author":"Wirz","year":"2017","journal-title":"J. Neurosci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.neubiorev.2018.05.010","article-title":"ADRA2B deletion variant and enhanced cognitive processing of emotional information: a meta-analytical review","volume":"92","author":"Xie","year":"2018","journal-title":"Neurosci. Biobehav Rev."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/pcn.12126","article-title":"Psychiatric symptoms of noradrenergic dysfunction: a pathophysiological view","volume":"68","author":"Yamamoto","year":"2014","journal-title":"Psychiatry Clin. Neurosci."},{"key":"B57","doi-asserted-by":"crossref","DOI":"10.1176\/appi.pn.2022.05.5.10","article-title":"FDA approves igalmi for agitation","volume-title":"Psychiatr. News","author":"Zagorski","year":"2022"},{"key":"B58","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/S0893-133X(01)00266-4","article-title":"Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers","volume":"25","author":"Zwanzger","year":"2001","journal-title":"Neuropsychopharmacology"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1589075\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T05:51:50Z","timestamp":1751435510000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1589075\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,2]]},"references-count":57,"alternative-id":["10.3389\/fphar.2025.1589075"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1589075","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,2]]},"article-number":"1589075"}}