Key Points
-
The histaminergic system is implicated in various brain disorders. A mutation in the gene encoding histidine decarboxylase, the histamine synthesizing enzyme, has been identified to be a cause of dominantly inherited Guilles de la Tourette syndrome.
-
In clinical trials, histamine H2 receptor antagonists have shown therapeutic efficacy for schizophrenia. and histamine H3 receptor antagonists have shown promise for combating daytime sleepiness in patients with narcolepsy.
-
In experimental allergic encephalomyelitis, a mouse model of multiple sclerosis, animals lacking histidine decarboxylase (and hence histamine synthesis) or histamine receptors show abnormal development of disease symptoms.
-
Histamine regulates feeding, obesity and the actions of leptin via histamine H1 receptor signalling in the hypothalamus; antipsychotic drugs bind to H1 receptors and cause obesity through this mechanism.
-
Histamine H3 receptor antagonists regulate alcohol self-administration and conditioned place preference in rodents, probably through a modulatory action on dopaminergic signalling. These drugs have already been tested for other disease conditions, so clinical trials on alcoholism could be carried out without extensive early phase studies.
Abstract
Histamine acts as a modulatory neurotransmitter in the mammalian brain. It has an important role in the maintenance of wakefulness, and dysfunction in the histaminergic system has been linked to narcolepsy. Recent evidence suggests that aberrant histamine signalling in the brain may also be a key factor in Gilles de la Tourette syndrome, Parkinson's disease and addictive behaviours. Furthermore, multiple sclerosis (MS) and experimental autoimmune encephalitis, which is an often-used model for MS, are associated with changes in the histaminergic system. This Review explores the possible roles of brain histamine in the mechanisms underlying these diseases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Panula, P., Yang, H. Y. & Costa, E. Histamine-containing neurons in the rat hypothalamus. Proc. Natl Acad. Sci. USA 81, 2572–2576 (1984).
Watanabe, T. et al. 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 (1984).
Haas, H. & Panula, P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nature Rev. Neurosci. 4, 121–130 (2003).
Haas, H. L., Sergeeva, O. A. & Selbach, O. Histamine in the nervous system. Physiol. Rev. 88, 1183–1241 (2008).
Anichtchik, O. V., Rinne, J. O., Kalimo, H. & Panula, P. An altered histaminergic innervation of the substantia nigra in Parkinson's disease. Exp. Neurol. 163, 20–30 (2000).
Ercan-Sencicek, A. G. et al. L-histidine decarboxylase and Tourette's syndrome. N. Engl. J. Med. 362, 1901–1908 (2010). This study identified a mutation in the HDC as a rare and first distinct cause of dominantly inherited GTS.
Saligrama, N., Noubade, R., Case, L. K., Del Rio, R. & Teuscher, C. Combinatorial roles for histamine H1-H2 and H3-H4 receptors in autoimmune inflammatory disease of the central nervous system. Eur. J. Immunol. 42, 1536–1546 (2012).
Tuomisto, L. & Panula, P. in Histaminergic Neurons: Morphology and Function (eds Watanabe, T. & Wada, H.) 177–192 (CRC Press, 1991).
Airaksinen, M. S. et al. Histamine neurons in human hypothalamus: anatomy in normal and Alzheimer diseased brains. Neuroscience 44, 465–481 (1991).
Ericson, H., Watanabe, T. & Kohler, C. Morphological analysis of the tuberomammillary nucleus in the rat brain: delineation of subgroups with antibody against L-histidine decarboxylase as a marker. J. Comp. Neurol. 263, 1–24 (1987). This was the first study to identify functional heterogeneity among the histaminergic neurons projecting to different parts of the brain.
Panula, P. et al. The comparative neuroanatomy and neurochemistry of zebrafish CNS systems of relevance to human neuropsychiatric diseases. Neurobiol. Dis. 40, 46–57 (2010).
Sundvik, M. et al. The histaminergic system regulates wakefulness and orexin/hypocretin neuron development via histamine receptor H1 in zebrafish. FASEB J. 25, 4338–4347 (2011). This was first study to demonstrate that HCRT regulates the development of histaminergic neurons.
Sundvik, M., Chen, Y. C. & Panula, P. Presenilin1 regulates histamine neuron development and behavior in zebrafish, Danio rerio. J. Neurosci. 33, 1589–1597 (2013).
Panula, P., Pirvola, U., Auvinen, S. & Airaksinen, M. S. Histamine-immunoreactive nerve fibers in the rat brain. Neuroscience 28, 585–610 (1989).
Miklos, I. H. & Kovacs, K. J. Functional heterogeneity of the responses of histaminergic neuron subpopulations to various stress challenges. Eur. J. Neurosci. 18, 3069–3079 (2003).
Blandina, P., Munari, L., Provensi, G. & Passani, M. B. Histamine neurons in the tuberomamillary nucleus: a whole center or distinct subpopulations? Front. Syst. Neurosci. 6, 33 (2012).
Giannoni, P. et al. Heterogeneity of histaminergic neurons in the tuberomammillary nucleus of the rat. Eur. J. Neurosci. 29, 2363–2374 (2009).
Arrang, J. M., Garbarg, M. & Schwartz, J. C. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 302, 832–837 (1983).
Arrang, J. M. et al. Highly potent and selective ligands for histamine H3-receptors. Nature 327, 117–123 (1987).
Yamamoto, Y., Mochizuki, T., Okakura-Mochizuki, K., Uno, A. & Yamatodani, A. Thioperamide, a histamine H3 receptor antagonist, increases GABA release from the rat hypothalamus. Methods Find. Exp. Clin. Pharmacol. 19, 289–298 (1997).
Blandina, P. et al. Histamine H3 receptor inhibition of K+-evoked release of acetylcholine from rat cortex in vivo. Inflamm. Res. 45, S54–S55 (1996).
Schlicker, E., Kathmann, M., Detzner, M., Exner, H. J. & Gothert, M. H3 receptor-mediated inhibition of noradrenaline release: an investigation into the involvement of Ca2+ and K+ ions, G protein and adenylate cyclase. Naunyn Schmiedebergs Arch. Pharmacol. 350, 34–41 (1994).
Garcia-Ramirez, M., Aceves, J. & Arias-Montano, J. A. Intranigral injection of the H3 agonist immepip and systemic apomorphine elicit ipsilateral turning behaviour in naive rats, but reduce contralateral turning in hemiparkinsonian rats. Behav. Brain Res. 154, 409–415 (2004).
Arias-Montaño, J. A., Floran, B., Garcia, M., Aceves, J. & Young, J. M. Histamine H3 receptor-mediated inhibition of depolarization-induced, dopamine D1 receptor-dependent release of [3H]-γ-aminobutryic acid from rat striatal slices. Br. J. Pharmacol. 133, 165–171 (2001). One of the first studies to show that H 3 R interferes with dopaminergic regulation of GABA release from striatal neurons, a finding that is relevant for understanding PD, GTS and reward mechanisms.
Ferrada, C. et al. Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function. Neuropharmacology 55, 190–197 (2008).
Connelly, W. M. et al. The histamine H4 receptor is functionally expressed on neurons in the mammalian CNS. Br. J. Pharmacol. 157, 55–63 (2009).
Bongers, G. et al. An 80-amino acid deletion in the third intracellular loop of a naturally occurring human histamine H3 isoform confers pharmacological differences and constitutive activity. J. Pharmacol. Exp. Ther. 323, 888–898 (2007).
Drutel, G. et al. Identification of rat H3 receptor isoforms with different brain expression and signaling properties. Mol. Pharmacol. 59, 1–8 (2001).
Takeshita, Y. et al. Histamine modulates high-voltage-activated calcium channels in neurons dissociated from the rat tuberomammillary nucleus. Neuroscience 87, 797–805 (1998).
Saper, C. B., Scammell, T. E. & Lu, J. Hypothalamic regulation of sleep and circadian rhythms. Nature 437, 1257–1263 (2005).
Takahashi, K., Lin, J. S. & Sakai, K. Neuronal activity of histaminergic tuberomammillary neurons during wake-sleep states in the mouse. J. Neurosci. 26, 10292–10298 (2006).
Lin, J. S., Sakai, K., Vanni-Mercier, G. & Jouvet, M. A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjection of muscimol in freely moving cats. Brain Res. 479, 225–240 (1989). This paper identified that the posterior hypothalamus has a crucial role in the mechanisms of wakefulness and that sleep results from functional blockade of the hypothalamic waking centre.
Zecharia, A. Y. et al. GABAergic inhibition of histaminergic neurons regulates active waking but not the sleep–wake switch or propofol-induced loss of consciousness. J. Neurosci. 32, 13062–13075 (2012).
Lin, J. S., Sakai, K. & Jouvet, M. Evidence for histaminergic arousal mechanisms in the hypothalamus of cat. Neuropharmacology 27, 111–122 (1988).
Sakai, K., Takahashi, K., Anaclet, C. & Lin, J. S. Sleep-waking discharge of ventral tuberomammillary neurons in wild-type and histidine decarboxylase knock-out mice. Front. Behav. Neurosci. 4, 53 (2010).
Xu, C. Q. et al. Histamine innervation and activation of septohippocampal GABAergic neurones: involvement of local ACh release. J. Physiol. 561, 657–670 (2004).
Lin, J. S., Hou, Y., Sakai, K. & Jouvet, M. Histaminergic descending inputs to the mesopontine tegmentum and their role in the control of cortical activation and wakefulness in the cat. J. Neurosci. 16, 1523–1537 (1996).
Kiviranta, T., Tuomisto, L. & Airaksinen, E. M. Diurnal and age-related changes in cerebrospinal fluid tele-methylhistamine levels during infancy and childhood. Pharmacol. Biochem. Behav. 49, 997–1000 (1994).
Zant, J. C., Rozov, S., Wigren, H. K., Panula, P. & Porkka-Heiskanen, T. Histamine release in the basal forebrain mediates cortical activation through cholinergic neurons. J. Neurosci. 32, 13244–13254 (2012).
Ellender, T. J., Huerta-Ocampo, I., Deisseroth, K., Capogna, M. & Bolam, J. P. Differential modulation of excitatory and inhibitory striatal synaptic transmission by histamine. J. Neurosci. 31, 15340–15351 (2011). This was the first study to identify the role of histamine in the striatal circuits that are implicated in GTS and PD.
McCormick, D. A. & Williamson, A. Modulation of neuronal firing mode in cat and guinea pig LGNd by histamine: possible cellular mechanisms of histaminergic control of arousal. J. Neurosci. 11, 3188–3199 (1991).
Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585 (1998).
de Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95, 322–327 (1998).
Peyron, C. et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10015 (1998).
Kaslin, J., Nystedt, J. M., Ostergard, M., Peitsaro, N. & Panula, P. The orexin/hypocretin system in zebrafish is connected to the aminergic and cholinergic systems. J. Neurosci. 24, 2678–2689 (2004).
Anaclet, C. et al. Orexin/hypocretin and histamine: distinct roles in the control of wakefulness demonstrated using knock-out mouse models. J. Neurosci. 29, 14423–14438 (2009).
Eriksson, K. S., Sergeeva, O., Brown, R. E. & Haas, H. L. Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J. Neurosci. 21, 9273–9279 (2001). This was first study to show that HCRT directly regulates histaminergic neurons.
Bayer, L. et al. Orexins (hypocretins) directly excite tuberomammillary neurons. Eur. J. Neurosci. 14, 1571–1575 (2001).
Yamanaka, A. et al. Orexins activate histaminergic neurons via the orexin 2 receptor. Biochem. Biophys. Res. Commun. 290, 1237–1245 (2002).
Huang, Z. L. et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc. Natl Acad. Sci. USA 98, 9965–9970 (2001).
Ishizuka, T., Murotani, T. & Yamatodani, A. Modanifil activates the histaminergic system through the orexinergic neurons. Neurosci. Lett. 483, 193–196 (2010).
Lin, L. et al. Measurement of hypocretin/orexin content in the mouse brain using an enzyme immunoassay: the effect of circadian time, age and genetic background. Peptides 23, 2203–2211 (2002).
Heller, H. C. & Ruby, N. F. Sleep and circadian rhythms in mammalian torpor. Annu. Rev. Physiol. 66, 275–289 (2004).
Sallmen, T. et al. Major changes in the brain histamine system of the ground squirrel Citellus lateralis during hibernation. J. Neurosci. 19, 1824–1835 (1999).
Sallmen, T., Lozada, A. F., Beckman, A. L. & Panula, P. Intrahippocampal histamine delays arousal from hibernation. Brain Res. 966, 317–320 (2003).
Nikmanesh, F. G., Spangenberger, H. & Igelmund, P. Histamine enhances synaptic transmission in hippocampal slices from hibernating and warm-acclimated Turkish hamsters. Neurosci. Lett. 210, 119–120 (1996).
Kukko-Lukjanov, T. K. et al. Histaminergic neurons protect the developing hippocampus from kainic acid-induced neuronal damage in an organotypic coculture system. J. Neurosci. 26, 1088–1097 (2006).
Tamura, Y., Monden, M., Shintani, M., Kawai, A. & Shiomi, H. Neuroprotective effects of hibernation-regulating substances against low-temperature-induced cell death in cultured hamster hippocampal neurons. Brain Res. 1108, 107–116 (2006).
Alvarez, E. O. The role of histamine on cognition. Behav. Brain Res. 199, 183–189 (2009).
Pollard, H., Moreau, J., Arrang, J. M. & Schwartz, J. C. A detailed autoradiographic mapping of histamine H3 receptors in rat brain areas. Neuroscience 52, 169–189 (1993).
Martinez-Mir, M. I. et al. Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates. Brain Res. 526, 322–327 (1990).
de Almeida, M. A. & Izquierdo, I. Memory facilitation by histamine. Arch. Int. Pharmacodyn. Ther. 283, 193–198 (1986).
de Almeida, M. A. & Izquierdo, I. Intracerebroventricular histamine, but not 48/80, causes posttraining memory facilitation in the rat. Arch. Int. Pharmacodyn. Ther. 291, 202–207 (1988).
Dai, H. et al. Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors. Neurosci. Res. 57, 306–313 (2007).
Rizk, A., Curley, J., Robertson, J. & Raber, J. Anxiety and cognition in histamine H3 receptor−/− mice. Eur. J. Neurosci. 19, 1992–1996 (2004).
Dere, E. et al. Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover. Learn. Mem. 10, 510–519 (2003).
Acevedo, S. F., Ohtsu, H., Benice, T. S., Rizk-Jackson, A. & Raber, J. Age-dependent measures of anxiety and cognition in male histidine decarboxylase knockout (Hdc−/−) mice. Brain Res. 1071, 113–123 (2006).
Liu, L. et al. Improved learning and memory of contextual fear conditioning and hippocampal CA1 long-term potentiation in histidine decarboxylase knock-out mice. Hippocampus 17, 634–641 (2007).
Chepkova, A. et al. Histamine receptor expression, hippocampal plasticity and ammonia in histidine decarboxylase knockout mice. Cell. Mol. Neurobiol. 32, 17–25 (2012).
Acevedoa, S. F., Pfankuch, T., Ohtsu, H. & Raber, J. Anxiety and cognition in female histidine decarboxylase knockout (Hdc−/−) mice. Behav. Brain Res. 168, 92–99 (2006).
Horvath, T. L. & Diano, S. The floating blueprint of hypothalamic feeding circuits. Nature Rev. Neurosci. 5, 662–667 (2004).
Saper, C. B., Chou, T. C. & Elmquist, J. K. The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199–211 (2002).
Gillum, M. P. et al. N-acylphosphatidylethanolamine, a gut- derived circulating factor induced by fat ingestion, inhibits food intake. Cell 135, 813–824 (2008).
Dietrich, M. O. & Horvath, T. L. Feeding signals and brain circuitry. Eur. J. Neurosci. 30, 1688–1696 (2009).
Umehara, H. et al. Deprivation of anticipated food under scheduled feeding induces c-Fos expression in the caudal part of the arcuate nucleus of hypothalamus through histamine H1 receptors in rats: potential involvement of E3 subgroup of histaminergic neurons in tuberomammillary nucleus. Brain Res. 1387, 61–70 (2011).
Kroeze, W. K. et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28, 519–526 (2003).
Inzunza, O., Seron-Ferre, M. J., Bravo, H. & Torrealba, F. Tuberomammillary nucleus activation anticipates feeding under a restricted schedule in rats. Neurosci. Lett. 293, 139–142 (2000).
Angeles-Castellanos, M., Aguilar-Roblero, R. & Escobar, C. c-Fos expression in hypothalamic nuclei of food-entrained rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R158–R165 (2004).
Passani, M. B., Blandina, P. & Torrealba, F. The histamine H3 receptor and eating behavior. J. Pharmacol. Exp. Ther. 336, 24–29 (2011).
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
Elmquist, J. K., Bjorbaek, C., Ahima, R. S., Flier, J. S. & Saper, C. B. Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395, 535–547 (1998).
Morimoto, T. et al. Involvement of the histaminergic system in leptin-induced suppression of food intake. Physiol. Behav. 67, 679–683 (1999).
Sakata, T. et al. Modulation of neuronal histamine in control of food intake. Physiol. Behav. 44, 539–543 (1988).
Dhillon, H. et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203 (2006).
Gotoh, K. et al. Glucagon-like peptide-1, corticotropin-releasing hormone, and hypothalamic neuronal histamine interact in the leptin-signaling pathway to regulate feeding behavior. FASEB J. 19, 1131–1133 (2005).
Elmquist, J. K., Ahima, R. S., Elias, C. F., Flier, J. S. & Saper, C. B. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc. Natl Acad. Sci. USA 95, 741–746 (1998).
Sakurai, T. & Mieda, M. Connectomics of orexin-producing neurons: interface of systems of emotion, energy homeostasis and arousal. Trends Pharmacol. Sci. 32, 451–462 (2011).
Ishizuka, T. et al. A role of the histaminergic system for the control of feeding by orexigenic peptides. Physiol. Behav. 89, 295–300 (2006).
Zigman, J. M., Jones, J. E., Lee, C. E., Saper, C. B. & Elmquist, J. K. Expression of ghrelin receptor mRNA in the rat and the mouse brain. J. Comp. Neurol. 494, 528–548 (2006).
Nishino, S. et al. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep 32, 175–180 (2009).
Kanbayashi, T. et al. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep 32, 181–187 (2009).
Lin, J. S. et al. An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: studies in orexin−/− mice and patients. Neurobiol. Dis. 30, 74–83 (2008). This was the first clinical study to show the positive effect of an H 3 R antagonist on excessive daytime sleepiness in patients with narcolepsy.
Peyron, C. et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nature Med. 6, 991–997 (2000).
Scammell, T. E. & Mochizuki, T. Is low histamine a fundamental cause of sleepiness in narcolepsy and idiopathic hypersomnia? Sleep 32, 133–134 (2009).
Sander, K., Kottke, T. & Stark, H. Histamine H3 receptor antagonists go to clinics. Biol. Pharm. Bull. 31, 2163–2181 (2008).
Esbenshade, T. A. et al. The histamine H3 receptor: an attractive target for the treatment of cognitive disorders. Br. J. Pharmacol. 154, 1166–1181 (2008).
Bonaventure, P. et al. Histamine H3 receptor antagonists: from target identification to drug leads. Biochem. Pharmacol. 73, 1084–1096 (2007).
Passani, M. B. & Blandina, P. Histamine receptors in the CNS as targets for therapeutic intervention. Trends Pharmacol. Sci. 32, 242–249 (2011).
Bardgett, M. E., Davis, N. N., Schultheis, P. J. & Griffith, M. S. Ciproxifan, an H3 receptor antagonist, alleviates hyperactivity and cognitive deficits in the APPTg2576 mouse model of Alzheimer's disease. Neurobiol. Learn. Mem. 95, 64–72 (2011).
Varaschin, R. K., Akers, K. G., Rosenberg, M. J., Hamilton, D. A. & Savage, D. D. Effects of the cognition-enhancing agent ABT-239 on fetal ethanol-induced deficits in dentate gyrus synaptic plasticity. J. Pharmacol. Exp. Ther. 334, 191–198 (2010).
Galici, R. et al. JNJ-10181457, a selective non-imidazole histamine H3 receptor antagonist, normalizes acetylcholine neurotransmission and has efficacy in translational rat models of cognition. Neuropharmacology 56, 1131–1137 (2009).
Brioni, J. D., Esbenshade, T. A., Garrison, T. R., Bitner, S. R. & Cowart, M. D. Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer's disease. J. Pharmacol. Exp. Ther. 336, 38–46 (2011).
Welty, N. & Shoblock, J. R. The effects of thioperamide on extracellular levels of glutamate and GABA in the rat prefrontal cortex. Psychopharmacology (Berl.) 207, 433–438 (2009).
Pascoli, V., Boer-Saccomani, C. & Hermant, J. F. H3 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing retrieval. Psychopharmacology (Berl.) 202, 141–152 (2009).
Van Ruitenbeek, P., Vermeeren, A. & Riedel, W. J. Cognitive domains affected by histamine H1-antagonism in humans: a literature review. Brain Res. Rev. 64, 263–282 (2010).
Kuhne, S., Wijtmans, M., Lim, H. D., Leurs, R. & de Esch, I. J. Several down, a few to go: histamine H3 receptor ligands making the final push towards the market? Expert Opin. Investig. Drugs 20, 1629–1648 (2011).
Cho, W. et al. Additive effects of a cholinesterase inhibitor and a histamine inverse agonist on scopolamine deficits in humans. Psychopharmacology (Berl.) 218, 513–524 (2011).
Weisler, R. H., Pandina, G. J., Daly, E. J., Cooper, K. & Gassmann-Mayer, C. Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder. CNS Drugs 26, 421–434 (2012).
Rinne, J. O. et al. Increased brain histamine levels in Parkinson's disease but not in multiple system atrophy. J. Neurochem. 81, 954–960 (2002).
Nakamura, S. et al. Large neurons in the tuberomammillary nucleus in patients with Parkinson's disease and multiple system atrophy. Neurology 46, 1693–1696 (1996).
Nowak, P. et al. Histaminergic activity in a rodent model of Parkinson's disease. Neurotox. Res. 15, 246–251 (2009).
Anichtchik, O. V., Peitsaro, N., Rinne, J. O., Kalimo, H. & Panula, P. Distribution and modulation of histamine H3 receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson's disease. Neurobiol. Dis. 8, 707–716 (2001).
Ryu, J. H., Yanai, K. & Watanabe, T. Marked increase in histamine H3 receptors in the striatum and substantia nigra after 6-hydroxydopamine-induced denervation of dopaminergic neurons: an autoradiographic study. Neurosci. Lett. 178, 19–22 (1994).
Anichtchik, O. V. et al. Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned rats. Eur. J. Neurosci. 12, 3823–3832 (2000).
Nowak, P. et al. Histamine H3 receptor ligands modulate L-dopa-evoked behavioral responses and L-dopa derived extracellular dopamine in dopamine-denervated rat striatum. Neurotox. Res. 13, 231–240 (2008).
Sakumoto, T., Sakai, K., Jouvet, M., Kimura, H. & Maeda, T. 5-HT immunoreactive hypothalamic neurons in rat and cat after 5-HTP administration. Brain Res. Bull. 12, 721–733 (1984).
Yanovsky, Y. et al. L-Dopa activates histaminergic neurons. J. Physiol. 589, 1349–1366 (2011). This study demonstrates the ability of the histaminergic neurons to take up and decarboxylate L-DOPA, a finding relevant for understanding the mechanisms of PD and L-DOPA-induced dyskinesia.
Doreulee, N. et al. Histamine H3 receptors depress synaptic transmission in the corticostriatal pathway. Neuropharmacology 40, 106–113 (2001).
Gomez-Ramirez, J., Johnston, T. H., Visanji, N. P., Fox, S. H. & Brotchie, J. M. Histamine H3 receptor agonists reduce L-dopa-induced chorea, but not dystonia, in the MPTP-lesioned nonhuman primate model of Parkinson's disease. Mov. Disord. 21, 839–846 (2006).
Johnston, T. H., van der Meij, A., Brotchie, J. M. & Fox, S. H. Effect of histamine H2 receptor antagonism on levodopa-induced dyskinesia in the MPTP-macaque model of Parkinson's disease. Mov. Disord. 25, 1379–1390 (2010).
Schwartz, J. C. The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br. J. Pharmacol. 163, 713–721 (2011).
Fernandez, T. V. et al. Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biol. Psychiatry 71, 392–402 (2012).
Kalanithi, P. S. et al. Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome. Proc. Natl Acad. Sci. USA 102, 13307–13312 (2005).
Kataoka, Y. et al. Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome. J. Comp. Neurol. 518, 277–291 (2010).
Turjanski, N. et al. PET studies of the presynaptic and postsynaptic dopaminergic system in Tourette's syndrome. J. Neurol. Neurosurg. Psychiatry 57, 688–692 (1994).
Singer, H. S. et al. Elevated intrasynaptic dopamine release in Tourette's syndrome measured by PET. Am. J. Psychiatry 159, 1329–1336 (2002).
Humbert-Claude, M., Davenas, E., Gbahou, F., Vincent, L. & Arrang, J. M. Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo. Psychopharmacology (Berl.) 220, 225–241 (2012).
Prell, G. D. et al. Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms. Schizophr. Res. 14, 93–104 (1995).
Jin, C. Y., Anichtchik, O. & Panula, P. Altered histamine H3 receptor radioligand binding in post-mortem brain samples from subjects with psychiatric diseases. Br. J. Pharmacol. 157, 118–129 (2009).
Iwabuchi, K. et al. Histamine H1 receptors in schizophrenic patients measured by positron emission tomography. Eur. Neuropsychopharmacol. 15, 185–191 (2005).
Kaminsky, R., Moriarty, T. M., Bodine, J., Wolf, D. E. & Davidson, M. Effect of famotidine on deficit symptoms of schizophrenia. Lancet 335, 1351–1352 (1990).
Rosse, R. B. et al. An open-label study of the therapeutic efficacy of high-dose famotidine adjuvant pharmacotherapy in schizophrenia: preliminary evidence for treatment efficacy. Clin. Neuropharmacol. 19, 341–348 (1996).
Martinez, M. C. Famotidine in the management of schizophrenia. Ann. Pharmacother. 33, 742–747 (1999).
Meskanen, K. et al. Antagonism of histamine H2 receptors as a novel approach to treat schizophrenia: a double-blind, randomized clinical trial. J. Clin. Psychopharmacol. (in the press).
Arrang, J. M. Histamine and schizophrenia. Int. Rev. Neurobiol. 78, 247–287 (2007).
Wagner, U., Segura-Torres, P., Weiler, T. & Huston, J. P. The tuberomammillary nucleus region as a reinforcement inhibiting substrate: facilitation of ipsihypothalamic self-stimulation by unilateral ibotenic acid lesions. Brain Res. 613, 269–274 (1993).
Wagner, U., Weiler, H. T. & Huston, J. P. Amplification of rewarding hypothalamic stimulation following a unilateral lesion in the region of the tuberomammillary nucleus. Neuroscience 52, 927–932 (1993).
Huston, J. P., Wagner, U. & Hasenohrl, R. U. The tuberomammillary nucleus projections in the control of learning, memory and reinforcement processes: evidence for an inhibitory role. Behav. Brain Res. 83, 97–105 (1997).
Brabant, C. et al. The psychostimulant and rewarding effects of cocaine in histidine decarboxylase knockout mice do not support the hypothesis of an inhibitory function of histamine on reward. Psychopharmacology (Berl.) 190, 251–263 (2007).
Lintunen, M. et al. Increased brain histamine in an alcohol-preferring rat line and modulation of ethanol consumption by H3 receptor mechanisms. FASEB J. 15, 1074–1076 (2001).
Nuutinen, S. et al. Evidence for the role of histamine H3 receptor in alcohol consumption and alcohol reward in mice. Neuropsychopharmacology 36, 2030–2040 (2011). In this study, the histamine H 3 R is shown to have a key role in both alcohol consumption and alcohol-induced place preference in several mouse models.
Nuutinen, S., Vanhanen, J., Pigni, M. C. & Panula, P. Effects of histamine H3 receptor ligands on the rewarding, stimulant and motor-impairing effects of ethanol in DBA/2J mice. Neuropharmacology 60, 1193–1199 (2011).
Galici, R. et al. JNJ-39220675, a novel selective histamine H3 receptor antagonist, reduces the abuse-related effects of alcohol in rats. Psychopharmacology (Berl.) 214, 829–841 (2011).
Nuutinen, S., Karlstedt, K., Aitta-Aho, T., Korpi, E. R. & Panula, P. Histamine and H3 receptor-dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice. Psychopharmacology (Berl.) 208, 75–86 (2010).
Alakarppa, K. et al. Effect of alcohol abuse on human brain histamine and tele-methylhistamine. Inflamm. Res. 51, S40–S41 (2002).
Fogel, W. A. et al. Neuronal storage of histamine in the brain and tele-methylimidazoleacetic acid excretion in portocaval shunted rats. J. Neurochem. 80, 375–382 (2002).
Lozeva, V., Tuomisto, L., Tarhanen, J. & Butterworth, R. F. Increased concentrations of histamine and its metabolite, tele-methylhistamine and down-regulation of histamine H3 receptor sites in autopsied brain tissue from cirrhotic patients who died in hepatic coma. J. Hepatol. 39, 522–527 (2003).
Suzuki, T., Takamori, K., Misawa, M. & Onodera, K. Effects of the histaminergic system on the morphine-induced conditioned place preference in mice. Brain Res. 675, 195–202 (1995).
Gong, Y. X., Zhang, W. P., Shou, W. T., Zhong, K. & Chen, Z. Morphine induces conditioned place preference behavior in histidine decarboxylase knockout mice. Neurosci. Lett. 468, 115–119 (2010).
Munzar, P., Nosal, R. & Goldberg, S. R. Potentiation of the discriminative-stimulus effects of methamphetamine by the histamine H3 receptor antagonist thioperamide in rats. Eur. J. Pharmacol. 363, 93–101 (1998).
Munzar, P., Tanda, G., Justinova, Z. & Goldberg, S. R. Histamine H3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release. Neuropsychopharmacology 29, 705–717 (2004).
Brabant, C., Charlier, Y., Quertemont, E. & Tirelli, E. The H3 antagonist thioperamide reveals conditioned preference for a context associated with an inactive small dose of cocaine in C57BL/6J mice. Behav. Brain Res. 160, 161–168 (2005).
Handel, A. E., Giovannoni, G., Ebers, G. C. & Ramagopalan, S. V. Environmental factors and their timing in adult-onset multiple sclerosis. Nature Rev. Neurol. 6, 156–166 (2010).
Tuomisto, L., Kilpelainen, H. & Riekkinen, P. Histamine and histamine-N-methyltransferase in the CSF of patients with multiple sclerosis. Agents Actions 13, 255–257 (1983).
Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Med. 8, 500–508 (2002).
Logothetis, L. et al. A pilot, open label, clinical trial using hydroxyzine in multiple sclerosis. Int. J. Immunopathol. Pharmacol. 18, 771–778 (2005).
Alonso, A., Jick, S. S. & Hernan, M. A. Allergy, histamine 1 receptor blockers, and the risk of multiple sclerosis. Neurology 66, 572–575 (2006).
Dimitriadou, V., Pang, X. & Theoharides, T. C. Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation. Int. J. Immunopharmacol. 22, 673–684 (2000).
Ma, R. Z. et al. Identification of Bphs, an autoimmune disease locus, as histamine receptor H1 . Science 297, 620–623 (2002). The first of several papers from the same research group that identify the role of histamine receptors in EAE, a mouse model of MS.
Passani, M. B. & Ballerini, C. Histamine and neuroinflammation: insights from murine experimental autoimmune encephalomyelitis. Front. Syst. Neurosci. 6, 32 (2012).
Teuscher, C. et al. Attenuation of Th1 effector cell responses and susceptibility to experimental allergic encephalomyelitis in histamine H2 receptor knockout mice is due to dysregulation of cytokine production by antigen-presenting cells. Am. J. Pathol. 164, 883–892 (2004).
Teuscher, C. et al. Central histamine H3 receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS. Proc. Natl Acad. Sci. USA 104, 10146–10151 (2007).
del Rio, R. et al. Histamine H4 receptor optimizes T regulatory cell frequency and facilitates anti-inflammatory responses within the central nervous system. J. Immunol. 188, 541–547 (2012).
Musio, S. et al. A key regulatory role for histamine in experimental autoimmune encephalomyelitis: disease exacerbation in histidine decarboxylase-deficient mice. J. Immunol. 176, 17–26 (2006).
Karlstedt, K., Ahman, M. J., Anichtchik, O. V., Soinila, S. & Panula, P. Expression of the H3 receptor in the developing CNS and brown fat suggests novel roles for histamine. Mol. Cell. Neurosci. 24, 614–622 (2003).
Kinnunen, A., Lintunen, M., Karlstedt, K., Fukui, H. & Panula, P. In situ detection of H1-receptor mRNA and absence of apoptosis in the transient histamine system of the embryonic rat brain. J. Comp. Neurol. 394, 127–137 (1998).
Karlstedt, K., Senkas, A., Ahman, M. & Panula, P. Regional expression of the histamine H2 receptor in adult and developing rat brain. Neuroscience 102, 201–208 (2001).
Prat, A. & Antel, J. Pathogenesis of multiple sclerosis. Curr. Opin. Neurol. 18, 225–230 (2005).
Shimamura, T. et al. Structure of the human histamine H1 receptor complex with doxepin. Nature 475, 65–70 (2011).
de Graaf, C. et al. Crystal structure-based virtual screening for fragment-like ligands of the human histamine H1 receptor. J. Med. Chem. 54, 8195–8206 (2011).
Auvinen, S. & Panula, P. Development of histamine-immunoreactive neurons in the rat brain. J. Comp. Neurol. 276, 289–303 (1988).
Vanhala, A., Yamatodani, A. & Panula, P. Distribution of histamine-, 5-hydroxytryptamine-, and tyrosine hydroxylase-immunoreactive neurons and nerve fibers in developing rat brain. J. Comp. Neurol. 347, 101–114 (1994).
Reiner, P. B., Semba, K., Fibiger, H. C. & McGeer, E. G. Ontogeny of histidine-decarboxylase-immunoreactive neurons in the tuberomammillary nucleus of the rat hypothalamus: time of origin and development of transmitter phenotype. J. Comp. Neurol. 276, 304–311 (1988).
Molina-Hernandez, A. & Velasco, I. Histamine induces neural stem cell proliferation and neuronal differentiation by activation of distinct histamine receptors. J. Neurochem. 106, 706–717 (2008).
Kinnunen, A. & Panula, P. Histamine and tyrosine hydroxylase in developing rat brain. Agents Actions 33, 108–111 (1991).
Vincent, S. R., Hokfelt, T., Skirboll, L. R. & Wu, J. Y. Hypothalamic γ-aminobutyric acid neurons project to the neocortex. Science 220, 1309–1311 (1983).
Trueta, C. & De-Miguel, F. F. Extrasynaptic exocytosis and its mechanisms: a source of molecules mediating volume transmission in the nervous system. Front. Physiol. 3, 319 (2012).
Airaksinen, M. S., Alanen, S., Szabat, E., Visser, T. J. & Panula, P. Multiple neurotransmitters in the tuberomammillary nucleus: comparison of rat, mouse, and guinea pig. J. Comp. Neurol. 323, 103–116 (1992).
Sundvik, M. & Panula, P. The organization of the histaminergic system in adult zebrafish (Danio rerio) brain: neuron number, location and co-transmitters. J. Comp. Neurol. 520, 3827–3845 (2012).
Trottier, S. et al. Co-localization of histamine with GABA but not with galanin in the human tuberomamillary nucleus. Brain Res. 939, 52–64 (2002).
Clapham, J. & Kilpatrick, G. J. Thioperamide, the selective histamine H3 receptor antagonist, attenuates stimulant-induced locomotor activity in the mouse. Eur. J. Pharmacol. 259, 107–114 (1994).
Morisset, S. et al. Acute and chronic effects of methamphetamine on Tele-methylhistamine levels in mouse brain: selective involvement of the D2 and not D3 receptor. J. Pharmacol. Exp. Ther. 300, 621–628 (2002).
Brabant, C., Quertemont, E. & Tirelli, E. Effects of the H3-receptor inverse agonist thioperamide on the psychomotor effects induced by acutely and repeatedly given cocaine in C57BL/6J mice. Pharmacol. Biochem. Behav. 83, 561–569 (2006).
Pillot, C. et al. Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat. J. Neurosci. 22, 7272–7280 (2002). This study shows that neurons of the striatopallidal pathway express H 3 Rs and that ciproxifan can potentiate haloperidol-induced upregulation of proenkephalin expression, suggesting that dopamine D2Rs and H 3 Rs can directly interact with each other.
Brabant, C. et al. Effects of the H3 receptor inverse agonist thioperamide on cocaine-induced locomotion in mice: role of the histaminergic system and potential pharmacokinetic interactions. Psychopharmacology (Berl.) 202, 673–687 (2009).
Bongers, G. et al. The Akt/GSK-3β axis as a new signaling pathway of the histamine H3 receptor. J. Neurochem. 103, 248–258 (2007).
Sanchez-Lemus, E. & Arias-Montano, J. A. Histamine H3 receptor activation inhibits dopamine D1 receptor-induced cAMP accumulation in rat striatal slices. Neurosci. Lett. 364, 179–184 (2004).
Pillot, C., Heron, A., Schwartz, J. C. & Arrang, J. M. Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, modulates the effects of methamphetamine on neuropeptide mRNA expression in rat striatum. Eur. J. Neurosci. 17, 307–314 (2003).
Ferrada, C. et al. Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors. Br. J. Pharmacol. 157, 64–75 (2009). This study identified that H 3 Rs and dopamine D1Rs can heteromerize, an essential finding for understanding striatal functions.
Moreno, E. et al. Dopamine D1-histamine H3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway. J. Biol. Chem. 286, 5846–5854 (2011).
Jin, C. Y. & Panula, P. The laminar histamine receptor system in human prefrontal cortex suggests multiple levels of histaminergic regulation. Neuroscience 132, 137–149 (2005).
Jin, C. Y., Kalimo, H. & Panula, P. The histaminergic system in human thalamus: correlation of innervation to receptor expression. Eur. J. Neurosci. 15, 1125–1138 (2002).
Jin, C., Lintunen, M. & Panula, P. Histamine H1 and H3 receptors in the rat thalamus and their modulation after systemic kainic acid administration. Exp. Neurol. 194, 43–56 (2005).
Panula, P., Airaksinen, M. S., Pirvola, U. & Kotilainen, E. A histamine-containing neuronal system in human brain. Neuroscience 34, 127–132 (1990).
Karlstedt, K., Jin, C. & Panula, P. Expression of histamine receptor Hrh3 and Hrh4 in rat brain endothelial cells. Br. J. Pharmacol. 14 Mar 2013 (doi:10.1111/bph.12173).
Karlstedt, K. et al. Lack of histamine synthesis and down-regulation of H1 and H2 receptor mRNA levels by dexamethasone in cerebral endothelial cells. J. Cereb. Blood Flow Metab. 19, 321–330 (1999).
Thurmond, R. L., Gelfand, E. W. & Dunford, P. J. The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nature Rev. Drug Discov. 7, 41–53 (2008).
Ariyasu, H. et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J. Clin. Endocrinol. Metab. 86, 4753–4758 (2001).
Tschop, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000).
Masaki, T. & Yoshimatsu, H. The hypothalamic H1 receptor: a novel therapeutic target for disrupting diurnal feeding rhythm and obesity. Trends Pharmacol. Sci. 27, 279–284 (2006).
Lintunen, M. et al. Postnatal expression of H1-receptor mRNA in the rat brain: correlation to L-histidine decarboxylase expression and local upregulation in limbic seizures. Eur. J. Neurosci. 10, 2287–2301 (1998).
Masaki, T. et al. Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity. Diabetes 53, 2250–2260 (2004).
Morimoto, T., Yamamoto, Y. & Yamatodani, A. Leptin facilitates histamine release from the hypothalamus in rats. Brain Res. 868, 367–369 (2000).
Ericson, H., Blomqvist, A. & Kohler, C. Brainstem afferents to the tuberomammillary nucleus in the rat brain with special reference to monoaminergic innervation. J. Comp. Neurol. 281, 169–192 (1989).
Acknowledgements
The authors thank H. Haas, R. Leurs, P. Blandina and B. Passani for comments on the manuscript. The authors' research on histamine is supported by COST Action BM 0806 and grants from the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Fund for Alcohol Research, Finska Läkaresällskapet and Magnus Ehrnrooth's Foundation.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
P.P. has received research supplies from Johnson & Johnson and an honorarium for speaking from Abbott Laboratories, and has stock ownership in Delichon Ltd, a biotechnology company, and Orion Pharma, a drug company. S.N. declares no competing financial interests.
Related links
FURTHER INFORMATION
Supplementary information
Supplementary information S1 (table)
Histamine H3 receptor-dependent neurotransmitter release in different brain areas (PDF 93 kb)
Glossary
- Inverse agonists
-
Receptor ligands that have activity at a receptor that is independent of and opposite to the endogenous ligand; most classical receptor antagonists are in fact inverse agonists and true neutral antagonists that have no activity when bound to the receptor are rare.
- Morpholino-oligonucleotide
-
An oligonucleotide that binds to mRNA and inhibits ribosome attachment. It is used to inhibit mRNA translation in zebrafish.
- Cognition
-
This term refers to the mental processes involved in gaining knowledge and comprehension, including attention, learning, short-term memory, working memory and long-term memory.
- Gilles de la Tourette syndrome
-
(GTS). This is a childhood-onset neuropsychiatric disorder with a prevalence close to 1% that is characterized by motor and vocal tics that usually diminish during later life. GTS is often associated one or several comorbidities, including attention-deficit hyperactivity disorder and obsessive-compulsive disorder.
Rights and permissions
About this article
Cite this article
Panula, P., Nuutinen, S. The histaminergic network in the brain: basic organization and role in disease. Nat Rev Neurosci 14, 472–487 (2013). https://doi.org/10.1038/nrn3526
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrn3526
This article is cited by
-
The cancer-immune dialogue in the context of stress
Nature Reviews Immunology (2024)
-
Targeting the Central Histamine H2 Receptor: New Hope for Schizophrenia?
Neuroscience Bulletin (2024)
-
Gut-Brain Axis a Key Player to Control Gut Dysbiosis in Neurological Diseases
Molecular Neurobiology (2023)
-
Chronic H3R activation reduces L-Dopa-induced dyskinesia, normalizes cortical GABA and glutamate levels, and increases striatal dopamine D1R mRNA expression in 6-hydroxydopamine-lesioned male rats
Psychopharmacology (2023)
-
The Roles of Histamine Receptor 1 (hrh1) in Neurotransmitter System Regulation, Behavior, and Neurogenesis in Zebrafish
Molecular Neurobiology (2023)
