An In Vivo Definition of Brain Histamine Dynamics Reveals Critical Neuromodulatory Roles for This Elusive Messenger

An In Vivo Definition of Brain Histamine Dynamics Reveals Critical Neuromodulatory Roles for This Elusive Messenger | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article An In Vivo Definition of Brain Histamine Dynamics Reveals Critical Neuromodulatory Roles for This Elusive Messenger Shane Berger, Beatrice Baumberger, S Samaranayake, M Hersey, Sergio Mena, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1462510/v3 This work is licensed under a CC BY 4.0 License Status: Posted Version 3 posted You are reading this latest preprint version Show more versions Abstract Histamine is well known for mediating peripheral inflammation, but histamine is also found in high concentrations in the brain where amongst other roles, this amine is thought to be neuromodulator. Neuromodulation is critical for brain function, yet histamine dynamics are very difficult to measure and thus several fundamental aspects of the mechanisms that control the extracellular and modulatory behavior of this messenger remain undefined. In this work we undertake the first in-depth characterization of in vivo histamine dynamics in real time using fast-scan cyclic voltammetry at carbon fiber microelectrodes. We measure electrically evoked histamine in the mouse hypothalamus and find that histamine release is sensitive to pharmacological manipulation at the level of synthesis, packaging, autoreceptor control of release, and metabolism. We find two breakthrough aspects of histamine modulation. First, there are differences in H 3 receptor regulation of histamine between sexes showing that histamine release in female mice is more much tightly regulated than in male mice under H 3 or inflammatory drug challenge. We hypothesize that this finding may contribute to hormone-mediated neuroprotection mechanisms in female mice. Second, we find that a high dose of a commonly available antihistamine, the H 1 receptor inverse agonist diphenhydramine, rapidly decreases serotonin levels. This high dose is considered overdose; however, this finding highlights the sheer significance of better consideration of the modulatory nuances of histamine on serotonin. We, thus, present the first in depth in vivo characterization of fast histamine dynamics and highlight two breakthrough regulatory aspects of this elusive modulator. The implications of our study are new avenues to better understand and treat histamine related disorders of the brain (such as neuroinflammation), emphasizing that sex and modulation (of serotonin) are critical factors to consider when studying/designing new histamine targeting therapeutics. inflammation neuroprotection antihistamine serotonin Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Cite Share Download PDF Status: Posted Version 3 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1462510","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":94507463,"identity":"3a1c6a7c-15de-4a78-ab51-c84abdc46700","order_by":0,"name":"Shane Berger","email":"","orcid":"","institution":"University of South Carolina","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shane","middleName":"","lastName":"Berger","suffix":""},{"id":94507464,"identity":"2c5f0023-4e61-4aff-9e22-ba21abc6dea0","order_by":1,"name":"Beatrice Baumberger","email":"","orcid":"","institution":"Imperial College 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Hashemi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYDACCQYGZiDFw88M5fJBxBMIa5FshnLZiNXCYHAAKkBQi7l08+PPBRXbZIyPc6c9+LjHQp6NgfnhB8a2NJxaLOccM5OeceY2j9lh3u2GM55JGLYxsBlLMLbl4NRicCPBjJm3DaxlmzTPAaBiBgYzBsa2Cjxa0j9/5v13m8e4GajlzwEJ+zYG9m8EtOQYSPM23OYxYAZqYTggkdjGwAOyBbfDLGfklEnzHLvNIwHyS88BieQ2Zp5iiYRzuL1vLpG++TNPzW17/v6z2x78OFBn28/evvHDh7Jk3A5DYkNjBBRNCTg1YNUyCkbBKBgFowANAAA24Et3NrBGBAAAAABJRU5ErkJggg==","orcid":"","institution":"Imperial College London","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Parastoo","middleName":"","lastName":"Hashemi","suffix":""}],"badges":[],"createdAt":"2022-03-17 14:37:49","currentVersionCode":3,"declarations":{"humanSubjects":false,"vertebrateSubjects":true,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":true,"coiExplicitlySet":false},"doi":"10.21203/rs.3.rs-1462510/v3","doiUrl":"https://doi.org/10.21203/rs.3.rs-1462510/v3","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":19746362,"identity":"2ea982c9-c847-4daf-9fb4-07583f46c7bb","added_by":"auto","created_at":"2022-03-29 17:50:14","extension":"tiff","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":195415,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 1 (A)\u003c/strong\u003e Representative color plot shows in the mouse TMN upon MFB stimulation. Inset in the top right corner is the characteristic CV with peaks occurring around 0.2 V for histamine and 0.7 V for serotonin oxidation. The concentration \u003cem\u003evs.\u003c/em\u003e time traces for the release of histamine and inhibition of serotonin is shown for \u003cstrong\u003e(B)\u003c/strong\u003e male (blue) and female (red) mice. Electrical stimulation (2 s) is represented by the grey bars. \u003cstrong\u003e(C) \u003c/strong\u003eTabulated values of metrics of experimental data in male and female mice.\u0026nbsp;\u003cstrong\u003e(D)\u003c/strong\u003e\u0026nbsp;placement of the CFMS in all experiments in this paper in the lateral hypothalamus. \u003cstrong\u003e(E)\u003c/strong\u003e Evoked histamine release and serotonin inhibition for female mice in estrous (n=23), metestrus (n=16), diestrus (n=10), and proestrus (n=10). The shaded grey bar represents the 2 s electrical stimulation.\u003cstrong\u003e (F)\u003c/strong\u003e Tabulated values of metrics of experimental data in female mice in different stages of the estrous cycle.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Figure1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-1462510/v3/aaabfd1b3707656524467a45.tiff"},{"id":19746359,"identity":"1370563d-ce3f-4568-96f5-d34ce78ff052","added_by":"auto","created_at":"2022-03-29 17:50:14","extension":"tiff","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":160888,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 2 (A-D)\u003c/strong\u003e Averaged concentration versus time traces for control (blue) and post-drug (green) evoked histamine.\u0026nbsp;The drug and mouse’s sex are listed. For α-fluoromethylhistidine male and female traces were averaged \u003cstrong\u003e(E) \u003c/strong\u003eSchematic representation of basic histamine metabolism,\u0026nbsp;abbreviations are:\u003cstrong\u003e \u003c/strong\u003ebHT, blood histidine; cHT, cytosolic histidine; HTpool, the histidine pool; cHA, cytosolic histamine; vHA, vesicular histamine; eHA, extracellular histamine, gHA, glial cell histamine; bHA, the concentration of bound autoreceptors; G and G∗, the inactive and active G-protein subunit; T and T∗, the inactive and active RGS protein; HTL, the histidine transporter; HTDC, histidine decarboxylase; HNMT, histamine methyltransferase; HAT, the putative HA transporter; H3, histamine autoreceptor.v\u003c/p\u003e","description":"","filename":"Figure2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-1462510/v3/c8f646a652d3231ab427bc12.tiff"},{"id":19746363,"identity":"6915d19c-4660-4efb-9fe4-e9592ff65e42","added_by":"auto","created_at":"2022-03-29 17:50:14","extension":"tiff","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":110696,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 3 (A-B) \u003c/strong\u003eThe drug and mouse’s sex are listed. Concentration versus time traces for control (blue) and post-drug (green) evoked histamine. The mathematical model results are in black dotted lines. \u003cstrong\u003e(C)\u003c/strong\u003e [HA] vs time profiles of evoked histamine for control (n=5, blue), 60 min following immepip (n=5, orange), and 40 min following thioperamide after 60 min immepip (n=4, green). Max amplitude of evoked histamine for control (blue), 60 min immepip (orange), and 40 min following thioperamide after initial 60 min immepip (green). Significance between two points was taken as p \u0026lt; 0.05 \u003cstrong\u003e(D) \u003c/strong\u003eMale vs female % difference (\u003cem\u003evs.\u003c/em\u003e control) in evoked histamine release with time after LPS injection.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Figure3.tiff","url":"https://assets-eu.researchsquare.com/files/rs-1462510/v3/fc15db35029216010bcec95e.tiff"},{"id":19746360,"identity":"ecf11a2f-a6e0-4f7c-aa40-d8cf813032f5","added_by":"auto","created_at":"2022-03-29 17:50:14","extension":"tiff","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":139036,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 4\u003c/strong\u003e \u003cstrong\u003e(A and B)\u003c/strong\u003e The drug and mouse’s sex are listed. Concentration versus time traces for control (blue) and post-drug (green) evoked histamine, and control (purple) and post-drug (orange) inhibited serotonin. The light blue bar and the shaded grey bar represent the 2 s electrical stimulation. The mathematical model results are in black dotted lines. \u003cstrong\u003e(C)\u003c/strong\u003e Extracellular ambient serotonin levels in the CA2 region of the hippocampus measured once a minute after a large DPH dose (gray bar). \u003cstrong\u003e(D) \u003c/strong\u003eSchematic diagram of histamine transmission\u003cem\u003e via \u003c/em\u003ethe H\u003csub\u003e1\u003c/sub\u003eR. Abbreviations: bHT, blood histidine; cHT, cytosolic histidine; HTpool, the histidine pool; cHA, cytosolic histamine; vHA, vesicular histamine; eHA, extracellular histamine; HTL; HTDC, histidine decarboxylase; HNMT, histamine methyltransferase; HAT, the HA transporter; H1, H\u003csub\u003e1\u003c/sub\u003eR; S, inhibitory retrograde messenger.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"FIgure4.tiff","url":"https://assets-eu.researchsquare.com/files/rs-1462510/v3/4e0a1692cfa1b9ef7938e77c.tiff"},{"id":19746361,"identity":"4c184fd8-ba97-4133-927d-677a6c0a6acd","added_by":"auto","created_at":"2022-03-29 17:50:14","extension":"tiff","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":102623,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 5 \u003c/strong\u003e- A comic strip illustration of DPH effects on histamine and serotonin.\u003c/p\u003e","description":"","filename":"cartoon1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-1462510/v3/6370604ef5ca828853b49e02.tiff"},{"id":20153733,"identity":"d90d4ed9-16d0-484b-bdd7-9c831e93269f","added_by":"auto","created_at":"2022-04-09 19:55:59","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2742052,"visible":true,"origin":"","legend":"","description":"","filename":"HApaperfinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1462510/v3_covered.pdf"},{"id":19746364,"identity":"246f3f93-3a01-46f2-b548-854d9f3137df","added_by":"auto","created_at":"2022-03-29 17:50:25","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2733355,"visible":true,"origin":"","legend":"","description":"","filename":"HApaperHashemi.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1462510/v3_covered.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAn \u003cem\u003eIn Vivo\u003c/em\u003e Definition of Brain Histamine Dynamics Reveals Critical Neuromodulatory Roles for This Elusive Messenger\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-1462510/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of South Carolina","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"inflammation, neuroprotection, antihistamine, serotonin","lastPublishedDoi":"10.21203/rs.3.rs-1462510/v3","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1462510/v3","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHistamine is well known for mediating peripheral inflammation, but histamine is also found in high concentrations in the brain where amongst other roles, this amine is thought to be neuromodulator. Neuromodulation is critical for brain function, yet histamine dynamics are very difficult to measure and thus several fundamental aspects of the mechanisms that control the extracellular and modulatory behavior of this messenger remain undefined. In this work we undertake the first in-depth characterization of \u003cem\u003ein vivo \u003c/em\u003ehistamine dynamics in real time using fast-scan cyclic voltammetry at carbon fiber microelectrodes. We measure electrically evoked histamine in the mouse hypothalamus and find that histamine release is sensitive to pharmacological manipulation at the level of synthesis, packaging, autoreceptor control of release, and metabolism. We find two breakthrough aspects of histamine modulation. First, there are differences in H\u003csub\u003e3\u003c/sub\u003e receptor regulation of histamine between sexes showing that histamine release in female mice is more much tightly regulated than in male mice under H\u003csub\u003e3\u003c/sub\u003e or inflammatory drug challenge. We hypothesize that this finding may contribute to hormone-mediated neuroprotection mechanisms in female mice. Second, we find that a high dose of a commonly available antihistamine, the H\u003csub\u003e1\u003c/sub\u003e receptor inverse agonist diphenhydramine, rapidly decreases serotonin levels. This high dose is considered overdose; however, this finding highlights the sheer significance of better consideration of the modulatory nuances of histamine on serotonin.\u003c/p\u003e\u003cp\u003eWe, thus, present the first in depth \u003cem\u003ein vivo\u003c/em\u003e characterization of fast histamine dynamics and highlight two breakthrough regulatory aspects of this elusive modulator. The implications of our study are new avenues to better understand and treat histamine related disorders of the brain (such as neuroinflammation), emphasizing that sex and modulation (of serotonin) are critical factors to consider when studying/designing new histamine targeting therapeutics.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","manuscriptTitle":"An In Vivo Definition of Brain Histamine Dynamics Reveals Critical Neuromodulatory Roles for This Elusive Messenger","msid":"","msnumber":"","nonDraftVersions":[{"code":3,"date":"2022-03-29 17:50:12","doi":"10.21203/rs.3.rs-1462510/v3","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2022-03-29 14:36:45","doi":"10.21203/rs.3.rs-1462510/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2022-03-21 15:53:01","doi":"10.21203/rs.3.rs-1462510/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6914af26-301c-4a8a-93a8-150fa24d4b88","owner":[],"postedDate":"March 29th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-03-21T15:53:01+00:00","versionOfRecord":[],"versionCreatedAt":"2022-03-29 17:50:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v3","identity":"rs-1462510","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1462510","identity":"rs-1462510","version":["v3"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}