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Histamine as an Alert Signal in the Brain

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The Functional Roles of Histamine Receptors

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 59))

Abstract

Sleep-wake behavior is a well-studied physiology in central histamine studies. Classical histamine H1 receptor antagonists, such as diphenhydramine and chlorpheniramine, promote sleep in animals and humans. Further, neuronal histamine release shows a clear circadian rhythm in parallel with wake behavior. However, the early stages of histamine-associated knockout mouse studies showed relatively small defects in normal sleep-wake control. To reassess the role of histamine in behavioral state control, this review summarizes the progress in sleep-wake studies of histamine-associated genetic mouse models and discusses the significance of histamine for characteristic aspects of wake behavior. Based on analysis of recent mouse models, we propose that neuronal histamine may serve as an alert signal in the brain, when high attention or a strong wake-drive is needed, such as during exploration, self-defense, learning, or to counteract hypersomnolent diseases. Enhanced histaminergic neurotransmission may help performance or sense of signals concerning internal or environmental dangers, like peripheral histamine from mast cells in response to allergic stimuli and inflammatory signals.

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Abbreviations

AAV:

Adeno-associated viral vector

Arc:

Arcuate

CCx:

Cerebral cortex

CNO :

Clozapine N-oxide

EEG:

Electroencephalogram

H1R:

H1 receptor

H2R:

H2 receptor

H3R:

H3 receptor

HDC:

Histidine decarboxylase

Hip:

Hippocampus

hM3Dq:

Human M3 mutant muscarinic Gq-coupled receptor

hM4Di:

Human M4 mutant muscarinic Gi-coupled receptor

HNMT:

Histamine N-methyltransferase

hRPE :

Human retinal pigment epithelium

ILC:

Infralimbic cortex

LS:

Lateral septum

NREM:

Non-rapid eye movement

OX2R :

Orexin receptor 2

REM:

Rapid eye movement

TMN:

Tuberomammillary nucleus

VMH:

Ventromedial hypothalamus

WT:

Wild-type

References

  • Abe H, Honma S, Ohtsu H, Honma K (2004) Circadian rhythms in behavior and clock gene expressions in the brain of mice lacking histidine decarboxylase. Brain Res Mol Brain Res 124(2):178–187

    Article  CAS  PubMed  Google Scholar 

  • Burgess CR, Oishi Y, Mochizuki T, Peever JH, Scammell TE (2013) Amygdala lesions reduce cataplexy in orexin knock-out mice. J Neurosci 33(23):9734–9742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437–451

    Article  CAS  PubMed  Google Scholar 

  • Chu M, Huang ZL, Qu WM, Eguchi N, Yao MH, Urade Y (2004) Extracellular histamine level in the frontal cortex is positively correlated with the amount of wakefulness in rats. Neurosci Res 49(4):417–420

    Article  CAS  PubMed  Google Scholar 

  • Ericson H, Blomqvist A, Köhler C (1991) Origin of neuronal inputs to the region of the tuberomammillary nucleus of the rat brain. J Comp Neurol 311(1):45–64

    Article  CAS  PubMed  Google Scholar 

  • Haas HL, Sergeeva OA, Selbach O (2008) Histamine in the nervous system. Physiol Rev 88(3):1183–1241.

    Article  CAS  PubMed  Google Scholar 

  • Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30(2):345–354

    Article  CAS  PubMed  Google Scholar 

  • Heidbreder CA, Groenewegen HJ (2003) The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci Biobehav Rev 27(6):555–579

    Article  PubMed  Google Scholar 

  • Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T, Urade Y, Hayaishi O (2001) Arousal effect of orexin a depends on activation of the histaminergic system. Proc Natl Acad Sci U S A 98(17):9965–9970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang ZL, Mochizuki T, Qu WM, Hong ZY, Watanabe T, Urade Y, Hayaishi O (2006) Altered sleep-wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice. Proc Natl Acad Sci U S A 103(12):4687–4692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inagaki N, Yamatodani A, Ando-Yamamoto M, Tohyama M, Watanabe T, Wada H (1988) Organization of histaminergic fibers in the rat brain. J Comp Neurol 273:283–300

    Article  CAS  PubMed  Google Scholar 

  • Inoue I, Yanai K, Kitamura D, Taniuchi I, Kobayashi T, Niimura K, Watanabe T, Watanabe T (1996) Impaired locomotor activity and exploratory behavior in mice lacking histamine H1 receptors. Proc Natl Acad Sci U S A 93:13316–13320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishizuka T, Yamatodani A (2012) Integrative role of the histaminergic system in feeding and taste perception. Front Syst Neurosci 6:44

    Article  PubMed  PubMed Central  Google Scholar 

  • Itowi N, Yamatodani A, Mochizuki T, Wada H (1991) Effects of intracerebroventricular histamine injection on circadian activity phase entrainment during rapid illumination changes. Neurosci Lett 123(1):53–56

    Article  CAS  PubMed  Google Scholar 

  • John J, Wu MF, Boehmer LN, Siegel JM (2004) Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 42(4):619–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • John J, Thannickal TC, McGregor R, Ramanathan L, Ohtsu H, Nishino S, Sakai N, Yamanaka A, Stone C, Cornford M, Siegel JM (2013) Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. Ann Neurol 74(6):786–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kárpáti A, Yoshikawa T, Naganuma F, Matsuzawa T, Kitano H, Yamada Y, Yokoyama M, Futatsugi A, Mikoshiba K, Yanai K (2019) Histamine H1 receptor on astrocytes and neurons controls distinct aspects of mouse behaviour. Sci Rep 9(1):16451.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kathmann M, Schlicker E, Marr L, Werthwein S, Stark H, Schunack W (1998) Ciproxifan and chemically related compounds are highly potent and selective histamine H-3-receptor antagonists. Naunyn Schmiedeberg’s Arch Pharmacol 358(6):623–627

    Article  CAS  Google Scholar 

  • Lin JS (2000) Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons. Sleep Med Rev 4(5):471–503

    Article  CAS  PubMed  Google Scholar 

  • Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98(3):365–376

    Article  CAS  PubMed  Google Scholar 

  • Liou SY, Shibata S, Yamakawa K, Ueki S (1983) Inhibitory and excitatory effects of histamine on suprachiasmatic neurons in rat hypothalamic slice preparation. Neurosci Lett 41:109–113

    Article  CAS  PubMed  Google Scholar 

  • Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435(1):6–25

    Article  CAS  PubMed  Google Scholar 

  • Mochizuki T, Yamatodani A, Okakura K, Horii A, Inagaki N, Wada H (1992) Circadian rhythm of histamine release from the hypothalamus of freely moving rats. Physiol Behav 51(2):391–394

    Article  CAS  PubMed  Google Scholar 

  • Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, Scammell TE (2004) Behavioral state instability in orexin knockout mice. J Neurosci 24(28):6291–6300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mochizuki T, Arrigoni E, Marcus JN, Clark EL, Yamamoto M, Honer M, Borroni E, Lowell BB, Elmquist JK, Scammell TE (2011) Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci U S A 108(11):4471–4476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morioka N, Sugimoto T, Tokuhara M, Dohi T, Nakata Y (2010) Noradrenaline induces clock gene Per1 mRNA expression in C6 glioma cells through beta(2)-adrenergic receptor coupled with protein kinase A-cAMP response element binding protein (PKA-CREB) and Src-tyrosine kinase-glycogen synthase kinase-3beta (Src-GSK-3beta). J Pharmacol Sci 113(3):234–245

    Article  CAS  PubMed  Google Scholar 

  • Morioka E, Kanda Y, Koizumi H, Miyamoto T, Ikeda M (2018) Histamine regulates molecular clock oscillations in human retinal pigment epithelial cells via H1 receptors. Front Endocrinol (Lausanne) 9:108

    Article  Google Scholar 

  • Naganuma F, Nakamura T, Yoshikawa T, Iida T, Miura Y, Kárpáti A, Matsuzawa T, Yanai A, Mogi A, Mochizuki T, Okamura N, Yanai K (2017) Histamine N-methyltransferase regulates aggression and the sleep-wake cycle. Sci Rep 7(1):15899.

    Article  PubMed  PubMed Central  Google Scholar 

  • Nishino S, Mignot E (1997) Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol 52(1):27–78

    Article  CAS  PubMed  Google Scholar 

  • Nishino S, Fujiki N, Ripley B, Sakurai E, Kato M, Watanabe T, Mignot E, Yanai K (2001a) Decreased brain histamine content in hypocretin/orexin receptor-2 mutated narcoleptic dogs. Neurosci Lett 313(3):125–128

    Article  CAS  PubMed  Google Scholar 

  • Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers GJ, Vankova J, Okun M, Rogers W, Brooks S, Mignot E (2001b) Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 50(3):381–388

    Article  CAS  PubMed  Google Scholar 

  • Nishino S, Sakurai E, Nevsimalova S, Yoshida Y, Watanabe T, Yanai K, Mignot E (2009) Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep 32(2):175–180

    Article  PubMed  PubMed Central  Google Scholar 

  • Oishi Y, Williams RH, Agostinelli L, Arrigoni E, Fuller PM, Mochizuki T, Saper CB, Scammell TE (2013) Role of the medial prefrontal cortex in cataplexy. J Neurosci 33(23):9743–9751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Panula P, Yang HYT, Costa E (1984) Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci U S A 81:2572–2576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, Watanabe T, Lin JS (2002) Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J Neurosci 22(17):7695–7711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parsons ME, Ganellin CR (2006) Histamine and its receptors. Br J Pharmacol 147:S127–S135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18(23):9996–10015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakurai T (2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8(3):171–181

    Article  CAS  PubMed  Google Scholar 

  • Scammell TE (2003) The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 53(2):154–166

    Article  PubMed  Google Scholar 

  • Scammell TE, Jackson AC, Franks NP, Wisden W, Dauvilliers Y (2019) Histamine: neural circuits and new medications. Sleep 42(1):zsy183

    Article  Google Scholar 

  • Schwartz JC (2011) The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol 163(4):713–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheehan TP, Chambers RA, Russell DS (2004) Regulation of affect by the lateral septum: implications for neuropsychiatry. Brain Res Rev 46(1):71–117

    Article  PubMed  Google Scholar 

  • Sherin JE, Elmquist JK, Torrealba F, Saper CB (1998) Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci 18(12):4705–4721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugimoto T, Morioka N, Sato K, Hisaoka K, Nakata Y (2011) Noradrenergic regulation of period1 expression in spinal astrocytes is involved in protein kinase a, c-Jun N-terminal kinase and extracellular signal-regulated kinase activation mediated by α1- and β2-adrenoceptors. Neuroscience 185:1–13

    Article  CAS  PubMed  Google Scholar 

  • Szakacs Z, Dauvilliers Y, Mikhaylov V, Poverennova I, Krylov S, Jankovic S, Sonka K, Lehert P, Lecomte I, Lecomte JM, Schwartz JC, Grp H-CS (2017) Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 16(3):200–207

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Lin JS, Sakai K (2006) Neuronal activity of histaminergic tuberomammillary neurons during wake-sleep states in the mouse. J Neurosci 26(40):10292–10298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi K, Kayama Y, Lin JS, Sakai K (2010) Locus coeruleus neuronal activity during the sleep-waking cycle in mice. Neuroscience 169(3):1115–1126

    Article  CAS  PubMed  Google Scholar 

  • Threlfell S, Cragg SJ, Kallo I, Turi GF, Coen CW, Greenfield SA (2004) Histamine h3 receptors inhibit serotonin release in substantia nigra pars reticulata. J Neurosci 24(40):8704–8710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thurmond RL, Gelfand EW, Dunford PJ (2008) The role of histamine H-1 and H-4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov 7(1):41–53

    Article  CAS  PubMed  Google Scholar 

  • Tobler I, Deboer T, Fischer M (1997) Sleep and sleep regulation in normal and prion protein-deficient mice. J Neurosci 17(5):1869–1879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valko PO, Gavrilov YV, Yamamoto M, Reddy H, Haybaeck J, Mignot E, Baumann CR, Scammell TE (2013) Increase of histaminergic tuberomammillary neurons in narcolepsy. Ann Neurol 74(6):794–804

    Article  CAS  PubMed  Google Scholar 

  • Venner A, Mochizuki T, De Luca R, Anaclet C, Scammell TE, Saper CB, Arrigoni E, Fuller PM (2019) Reassessing the role of histaminergic tuberomammillary neurons in arousal control. J Neurosci 39(45):8929–8939

    Article  PubMed  PubMed Central  Google Scholar 

  • Walker AK, Park WM, Chuang JC, Perello M, Sakata I, Osborne-Lawrence S, Zigman JM (2013) Characterization of gastric and neuronal histaminergic populations using a transgenic mouse model. PLoS One 8(3):e60276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe T, Taguchi Y, Shiosaka S, Tanaka J, Kubota H, Terano Y, Tohyama M, Wada H (1984) Distribution of the histaminergic neuron system in the central nervous system of rats: a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res 295:13–25

    Article  CAS  PubMed  Google Scholar 

  • Yamada Y, Yoshikawa T, Naganuma F, Kikkawa T, Osumi N, Yanai K (2020) Chronic brain histamine depletion in adult mice induced depression-like behaviours and impaired sleep-wake cycle. Neuropharmacology 175:108179

    Article  CAS  PubMed  Google Scholar 

  • Yu X, Ma Y, Harding EC, Yustos R, Vyssotski AL, Franks NP, Wisden W (2019) Genetic lesioning of histamine neurons increases sleep-wake fragmentation and reveals their contribution to modafinil-induced wakefulness. Sleep 42(5):zsz031

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan

    Takatoshi Mochizuki

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  1. Takatoshi Mochizuki
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Correspondence to Takatoshi Mochizuki .

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Editors and Affiliations

  1. Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan

    Kazuhiko Yanai

  2. Department of Health Science, University of Florence, Firenze, Italy

    Maria Beatrice Passani

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Mochizuki, T. (2021). Histamine as an Alert Signal in the Brain. In: Yanai, K., Passani, M.B. (eds) The Functional Roles of Histamine Receptors. Current Topics in Behavioral Neurosciences, vol 59. Springer, Cham. https://doi.org/10.1007/7854_2021_249

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