{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T16:44:47Z","timestamp":1780418687526,"version":"3.54.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T00:00:00Z","timestamp":1732147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19H03339 22K19477 24K22082"],"award-info":[{"award-number":["19H03339 22K19477 24K22082"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJSP2124"],"award-info":[{"award-number":["JPMJSP2124"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>The lateral habenula (LHb) has been implicated in stress coping and autonomic control. The LHb regulates the midbrain system of monoamine neurotransmitters such as dopamine, serotonin, and noradrenaline. However, how the LHb regulates autonomic cardiovascular control in stressful situations is unclear. In this study, we examined the participation of the midbrain dopaminergic system in the cardiovascular response elicited by activation of the LHb. We used urethane-anesthetized Wistar male rats. We performed electrical stimulation of the LHb to observe changes in heart rate and blood pressure. Stimulation of the LHb caused bradycardia and a pressor response. Application of a nonselective dopamine receptor antagonist attenuated both the heart rate and the blood pressure changes induced by the LHb. We also tested the effects of blockade of dopamine receptor subtypes in the LHb-induced cardiovascular responses. Application of selective dopamine D<jats:sub>1<\/jats:sub>\/D<jats:sub>5<\/jats:sub>, D<jats:sub>2<\/jats:sub>\/D<jats:sub>3<\/jats:sub>, or D<jats:sub>4<\/jats:sub> receptor antagonists attenuated the LHb-induced pressor response but did not change the HR response. Furthermore, we examined the effect of inactivation of the ventral tegmental area (VTA) on the cardiovascular response induced by LHb stimulation. Inactivation of the VTA turned bradycardia into tachycardia caused by the LHb stimulation and attenuated the pressor response. Our results indicated that regulation of the dopaminergic system by the LHb mediates the generation of the autonomic cardiovascular response. Dopamine D<jats:sub>1<\/jats:sub>-like and D<jats:sub>2<\/jats:sub>-like receptors mediate the sympathoexcitation resulting from the activation of the LHb. The VTA is one of the dopaminergic origins related to the cardiovascular response originating from LHb activation.<\/jats:p>","DOI":"10.3389\/fphys.2024.1496726","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T06:25:08Z","timestamp":1732170308000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["The dopaminergic system mediates the lateral habenula-induced autonomic cardiovascular responses"],"prefix":"10.3389","volume":"15","author":[{"given":"Yuma","family":"Sato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadachika","family":"Koganezawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e12990","DOI":"10.1111\/adb.12990","article-title":"Alcohol dependence activates ventral tegmental area projections to central amygdala in male mice and rats","volume":"26","author":"Avegno","year":"2021","journal-title":"Addict. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2545","DOI":"10.1002\/cne.23080","article-title":"Individual neurons in the rat lateral habenular complex project mostly to the dopaminergic ventral tegmental area or to the serotonergic raphe nuclei","volume":"520","author":"Bernard","year":"2012","journal-title":"J. Comp. Neurol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/S0006-8993(99)02112-5","article-title":"Evidence that dopaminergic axons provide a dense innervation of specific neuronal subpopulations in the rat basolateral amygdala","volume":"850","author":"Brinley-Reed","year":"1999","journal-title":"Brain Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"4894","DOI":"10.1073\/pnas.0811507106","article-title":"Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli","volume":"106","author":"Brischoux","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1161\/01.res.56.3.359","article-title":"Electrophysiological study of cardiovascular neurons in the rostral ventrolateral medulla in rats","volume":"56","author":"Brown","year":"1985","journal-title":"Circ. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"107392","DOI":"10.1016\/j.pharmthera.2019.07.003","article-title":"Dopamine outside the brain: the eye, cardiovascular system and endocrine pancreas","volume":"203","author":"Bucolo","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"B7","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1523\/JNEUROSCI.06-03-00613.1986","article-title":"Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat","volume":"6","author":"Christoph","year":"1986","journal-title":"J. Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1046\/j.1440-1681.2002.03640.x","article-title":"Central mechanisms underlying short- and long-term regulation of the cardiovascular system","volume":"29","author":"Dampney","year":"2002","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"S270","DOI":"10.1016\/j.biopsych.2017.02.1076","article-title":"667. The in vivo electrophysiological effects of cariprazine on the rat midbrain dopaminergic system","volume":"81","author":"Delcourte","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"B10","doi-asserted-by":"publisher","first-page":"655617","DOI":"10.3389\/fnins.2021.655617","article-title":"Lateral habenula regulates cardiovascular autonomic responses via the serotonergic system in rats","volume":"15","author":"Doan","year":"2021","journal-title":"Front. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"5154","DOI":"10.1111\/ejn.15803","article-title":"Functional brain-wide network mapping during acute stress exposure in rats: interaction between the lateral habenula and cortical, amygdalar, hypothalamic and monoaminergic regions","volume":"56","author":"Durieux","year":"2022","journal-title":"Eur. J. Neurosci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.physbeh.2004.08.004","article-title":"Acute and chronic stress influence blood pressure variability in mice","volume":"83","author":"Farah","year":"2004","journal-title":"Physiol. Behav."},{"key":"B13","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1002\/(SICI)1098-2396(199812)30:4<362::AID-SYN3>3.0.CO;2-W","article-title":"Alpha1-adrenergic, D1, and D2 receptors interactions in the prefrontal cortex: implications for the modality of action of different types of neuroleptics","volume":"30","author":"Gioanni","year":"1998","journal-title":"Synapse"},{"key":"B14","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/nrn2866","article-title":"The habenula: from stress evasion to value-based decision-making","volume":"11","author":"Hikosaka","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e32855","DOI":"10.1371\/journal.pone.0032855","article-title":"Blood pressure variations real-time reflect the conditioned fear learning and memory","volume":"7","author":"Hsu","year":"2012","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1523\/JNEUROSCI.1703-13.2014","article-title":"Similar roles of substantia nigra and ventral tegmental dopamine neurons in reward and aversion","volume":"34","author":"Ilango","year":"2014","journal-title":"J. Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1002\/j.1875-9114.1991.tb02628.x","article-title":"Clozapine","volume":"11","author":"Jann","year":"2012","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"B18","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1002\/cne.21891","article-title":"The mesopontine rostromedial tegmental nucleus: a structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta","volume":"513","author":"Jhou","year":"2009","journal-title":"J. Comp. Neurol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/0306-4522(93)90188-l","article-title":"Up-regulation of dopamine receptors in the brain of the spontaneously hypertensive rat: an autoradiographic analysis","volume":"52","author":"Kirouac","year":"1993","journal-title":"Neuroscience"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e12831","DOI":"10.14814\/phy2.12831","article-title":"Role played by periaqueductal gray neurons in parasympathetically mediated fear bradycardia in conscious rats","volume":"4","author":"Koba","year":"2016","journal-title":"Physiol. Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1097\/HRP.0000000000000065","article-title":"Fear and the defense cascade: clinical implications and management","volume":"23","author":"Kozlowska","year":"2015","journal-title":"Harv Rev. Psychiatry"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1152\/jn.00843.2004","article-title":"Dopamine modulates excitability of basolateral amygdala neurons in vitro","volume":"93","author":"Kroner","year":"2005","journal-title":"J. Neurophysiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1016\/j.neubiorev.2007.01.004","article-title":"A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition","volume":"31","author":"Lecourtier","year":"2007","journal-title":"Neurosci. Biobehav Rev."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1038\/nature05860","article-title":"Lateral habenula as a source of negative reward signals in dopamine neurons","volume":"447","author":"Matsumoto","year":"2007","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/nn.2233","article-title":"Representation of negative motivational value in the primate lateral habenula","volume":"12","author":"Matsumoto","year":"2009","journal-title":"Nat. Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/0006-8993(83)91125-3","article-title":"(-)-Sulpiride activates the firing rate and tyrosine hydroxylase activity of dopaminergic neurons in unanesthetized rats","volume":"264","author":"Mereu","year":"1983","journal-title":"Brain Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.tins.2017.06.001","article-title":"The lateral habenula and adaptive behaviors","volume":"40","author":"Mizumori","year":"2017","journal-title":"Trends Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1111\/j.1460-9568.2010.07457.x","article-title":"Dopamine attenuates evoked inhibitory synaptic currents in central amygdala neurons","volume":"32","author":"Naylor","year":"2010","journal-title":"Eur. J. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1111\/j.1460-9568.2009.06924.x","article-title":"Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area","volume":"30","author":"Omelchenko","year":"2009","journal-title":"Eur. J. Neurosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e12297","DOI":"10.14814\/phy2.12297","article-title":"Activation of the habenula complex evokes autonomic physiological responses similar to those associated with emotional stress","volume":"3","author":"Ootsuka","year":"2015","journal-title":"Physiol. Rep."},{"key":"B31","volume-title":"The rat brain in stereotaxic coordinates","author":"Paxinos","year":"1986"},{"key":"B32","doi-asserted-by":"publisher","first-page":"139","DOI":"10.3390\/biomedicines9020139","article-title":"The role of the renal dopaminergic system and oxidative stress in the pathogenesis of hypertension","volume":"9","author":"Qaddumi","year":"2021","journal-title":"Biomedicines"},{"key":"B33","doi-asserted-by":"publisher","first-page":"20160206","DOI":"10.1098\/rstb.2016.0206","article-title":"Freeze for action: neurobiological mechanisms in animal and human freezing","volume":"372","author":"Roelofs","year":"2017","journal-title":"Philos. Trans. R. Soc. Lond B Biol. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1038\/s41583-022-00608-2","article-title":"Freezing revisited: coordinated autonomic and central optimization of threat coping","volume":"23","author":"Roelofs","year":"2022","journal-title":"Nat. Rev. Neurosci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1007\/s00429-020-02069-8","article-title":"Untangling the dorsal diencephalic conduction system: a review of structure and function of the stria medullaris, habenula and fasciculus retroflexus","volume":"225","author":"Roman","year":"2020","journal-title":"Brain Struct. Funct."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1007\/s00018-010-0293-y","article-title":"The dopamine D4 receptor: biochemical and signalling properties","volume":"67","author":"Rondou","year":"2010","journal-title":"Cell Mol. Life Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1007\/s00210-013-0841-8","article-title":"Predominant role of the dopamine D3 receptor subtype for mediating the quinpirole-induced inhibition of the vasopressor sympathetic outflow in pithed rats","volume":"386","author":"Ruiz-Salinas","year":"2013","journal-title":"Naunyn Schmiedeb. Arch. Pharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1152\/physrev.00002.2003","article-title":"The amygdaloid complex: anatomy and physiology","volume":"83","author":"Sah","year":"2003","journal-title":"Physiol. Rev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1111\/j.1440-1681.2005.04210.x","article-title":"Role of the central nucleus of the amygdala in the control of blood pressure: descending pathways to medullary cardiovascular nuclei","volume":"32","author":"Saha","year":"2005","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.lfs.2008.05.014","article-title":"Clozapine interacts with the glycine site of the NMDA receptor: electrophysiological studies of dopamine neurons in the rat ventral tegmental area","volume":"83","author":"Schwieler","year":"2008","journal-title":"Life Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"9367","DOI":"10.1523\/JNEUROSCI.17-23-09367.1997","article-title":"Interaction of GABA and excitatory amino acids in the basolateral amygdala: role in cardiovascular regulation","volume":"17","author":"Soltis","year":"1997","journal-title":"J. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1002\/cne.902290211","article-title":"Projections to the cardioinhibitory region of the nucleus ambiguus of rat","volume":"229","author":"Stuesse","year":"1984","journal-title":"J. Comp. Neurol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.neuroimage.2019.01.062","article-title":"Functional neuroanatomical review of the ventral tegmental area","volume":"191","author":"Trutti","year":"2019","journal-title":"Neuroimage"},{"key":"B44","doi-asserted-by":"publisher","first-page":"955","DOI":"10.6061\/clinics\/2012(08)16","article-title":"Auditory stimulation and cardiac autonomic regulation","volume":"67","author":"Valenti","year":"2012","journal-title":"Clin. (Sao Paulo)"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0482-20.2021","article-title":"Lateral habenula mediates defensive responses only when threat and safety memories are in conflict","volume":"8","author":"Velazquez-Hernandez","year":"2021","journal-title":"eNeuro"},{"key":"B46","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1007\/s12576-017-0523-2","article-title":"Bidirectional cardiovascular responses evoked by microstimulation of the amygdala in rats","volume":"68","author":"Yamanaka","year":"2018","journal-title":"J. Physiol. Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/npp.2011.245","article-title":"Blockade of dopamine d4 receptors attenuates reinstatement of extinguished nicotine-seeking behavior in rats","volume":"37","author":"Yan","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.1038\/s41467-023-38180-7","article-title":"Neural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice","volume":"14","author":"Yang","year":"2023","journal-title":"Nat. Commun."},{"key":"B49","doi-asserted-by":"publisher","first-page":"R1114","DOI":"10.1152\/ajpregu.00831.2009","article-title":"Differential control of renal and lumbar sympathetic nerve activity during freezing behavior in conscious rats","volume":"299","author":"Yoshimoto","year":"2010","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/0304-3940(96)12631-8","article-title":"Effect of conditioned fear stress on dopamine release in the rat prefrontal cortex","volume":"209","author":"Yoshioka","year":"1996","journal-title":"Neurosci. Lett."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2024.1496726\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T06:25:13Z","timestamp":1732170313000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2024.1496726\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,21]]},"references-count":50,"alternative-id":["10.3389\/fphys.2024.1496726"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2024.1496726","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,21]]},"article-number":"1496726"}}