The histaminergic system in the brain: structural characteristics and changes in hibernation

doi:10.1016/S0891-0618(99)00052-6

Journal of Chemical Neuroanatomy

Volume 18, Issues 1–2, February 2000, Pages 65-74

https://doi.org/10.1016/S0891-0618(99)00052-6 Get rights and content

Abstract

Histaminergic neurons in adult vertebrate brain are confined to the posterior hypothalamic area, where they are comprised of scattered groups of neurons referred to as the tuberomammillary nucleus. Histamine regulates hormonal functions, sleep, food intake, thermoregulation and locomotor activity, for example. In the zebrafish, Danio rerio, histamine was detected only in the brain, where also the histamine synthesizing enzyme l-histidine decarboxylase (HDC) was expressed. It is possible that histamine has first evolved as a neurotransmitter in the central nervous system. We established sensitive quantitative in situ hybridization methods for histamine H₁ and H₂ receptors and HDC, to study the modulation of brain histaminergic system under pathophysiological conditions. A transient increase in H₁ receptor expression was seen in the dentate gyrus and striatum after a single injection of kainic acid, a glutamate analog. H₁ antagonists are known to increase duration of convulsions, and increased brain histamine is associated with reduced convulsions in animal models of epilepsy. No HDC mRNA was detected in brain vessels by in situ hybridization, which suggests lack of histamine synthesis by brain endothelial cells. This was verified by lack of HDC mRNA in a rat brain endothelial cell line, RBE4 cells. Both H₁ and H₂ receptor mRNA was found in this cell line, and the expression of both receptors was downregulated by dexamethasone. The findings are in agreement with the concept that histamine regulates blood–brain barrier permeability through H₁ and H₂ receptor mediated mechanisms. Hibernation is characterized by a drastic reduction of central functions. The activity of most transmitter systems is maintained at a very low level. Surprisingly, histamine levels and turnover were clearly elevated in hibernating ground squirrels, and the density of histamine-containing fibers was higher than in euthermic animals. It is possible that histamine actively maintains the low activity of other transmitters during the hibernation state.

Section snippets

Structural organisation of histamine system in vertebrates

Histamine has been detected in three different cellular compartments of the central nervous system: in hypothalamic tuberomammillary neurons and their processes (Panula et al., 1984, Steinbusch and Mulder, 1984, Watanabe et al., 1984, Fig. 4A and B), perivascular mast cells (Fig. 4C), and isolated cerebral microvessels (for review, see Edvinsson et al., 1993).

Histaminergic neurons are located in the posterior hypothalamic tuberomammillary nucleus in all mammals studied so far (Panula et al.,

Brain histamine regulates general functions through widespread receptors

Several reviews have dealt with the basic functions of the brain histamine system (Panula, 1987, Schwartz et al., 1991, Wada et al., 1991). Histamine is involved in hormonal regulation, food intake, thermoregulation, locomotor activity and sleep. However, information on changes in key parameters of the whole histaminergic system in pathophysiological conditions is limited. It would be valuable to build working hypotheses on the role of histamine in other brain functions and to establish its

Brain histamine regulates excitability and seizures

H₁ receptor antagonists induce convulsions in healthy humans (Wyngaarden and Seevers, 1951, Schwartz and Patterson, 1978, Mueller, 1983) and may increase epileptic discharges in patients suffering from epilepsia (Shimoda et al., 1960, Yokoyama et al., 1992). H₁ receptor binding is also increased in the epileptic foci of patients with seizures (Iinuma et al., 1993). The high density of H₁ receptor binding sites in some temporal lobe structures including the hippocampus (Palacios et al., 1981)

Histaminergic regulation of capillary permeability

Intracerebral histamine is also a known regulator of cerebral blood flow (Edvinsson et al., 1993) and endothelial permeability (Dux and Joó, 1982). A relatively high content of histamine (Robinson-White and Beaven, 1982), but low activity of HDC and histamine-N-methyltransferase are characteristic of microvessel-enriched fractions isolated from guinea pig brain (Karnushina et al., 1980). Histamine is also found in blood vessel preparations isolated from the bovine brain (Jarrott et al., 1979).

Histamine may be a key regulator of hibernation

Hibernation is characterized by a dramatic reduction of several key functions, including body temperature and metabolism. This state is neuronally controlled through the hypothalamus, septum, hippocampus and brain stem reticular formation (Heller, 1979, Beckman and Stanton, 1982), but the mechanisms underlying the regulatory processes are not known. During the non-hibernating state, the brain activity of hibernators resembles that of non-hibernating species, but during the hibernating state, it

Acknowledgements

Original studies were supported by the Academy of Finland, the Erna and Viktor Hasselblad Foundation and the Signal Transduction Program of the Abo Akademi University.

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The histaminergic system in the brain: structural characteristics and changes in hibernation

Abstract

Section snippets

Structural organisation of histamine system in vertebrates

Brain histamine regulates general functions through widespread receptors

Brain histamine regulates excitability and seizures

Histaminergic regulation of capillary permeability

Histamine may be a key regulator of hibernation

Acknowledgements

Neuroscience

Brain Res.

J. Chem. Neuroanat.

Neurosci. Lett.

Lancet

Brain. Res.

Neurochem. Int.

Pharmacol. Ther.

J. Neurol. Sci.

Neuroscience

Brain Res.

Neuroscience

Epilepsy Res.

Eur. J. Pharmacol.

Neuropharmacology

Trends Neurosci.

Brain Res.

J. Biol. Chem.

The histaminergic system in the guinea pig central nervous system: an immunocytochemical mapping study using an antiserum against histamine

J. Comp. Neurol.

Histaminergic system of the tree shrew brain

J. Comp. Neurol.

Comparative neuroanatomy of the histaminergic system in the brain of the frog Xenopus laevis

J. Comp. Neurol.

Histamine neurons in human hypothalamus: anatomy in normal and Alzheimer diseased brains

Neuroscience

Properties of the CNS during the state of hibernation

Effect of steroid therapy on ischaemic brain oedema and blood to brain sodium transport

Acta Neurochir.

Effect of steroids on oedema and and sodium uptake of the brain during focal ischaemia in rats

Stroke

Distribution of histaminergic neurons in the brain of the lamprey Lampetra fluviatilis as revealed by histamine-immunohistochemistry

J. Comp. Neurol.

Function of steroid receptor system in the central nervous system

Clin. Neuropharmac.

Steroid treatment in acute ischemic stroke. A comparative retrospective study of 556 cases

Eur. Neurol.

Nitric oxide and endothelin secretion by brain microvessel endothelial cells: regulation by cyclic nucleotides

J. Cell. Physiol.

Effects of histamine on brain capillaries: fine structural and immunohistochemical studies after intracarotid infusion

Exp. Brain Res.

Histamine

Evidence for non-mast cell histamine in the vascular wall

Blood Vessels

Development of the histaminergic neurons and expression of histidine decarboxylase mRNA in the zebrafish brain in the absence of all peripheral histaminergic systems

Eur. J. Neurosci.

Histaminergic H1 antagonists modulate seizure pattern induced by electroschock in mice

Br. J. Psychopharmac.

Molecular cloning of a gene encoding the histamine H2 receptor

Proc. Natl. Acad. Sci. USA

Regulation of histamine H1 receptor coupling by dexamethasone in human cultured airway smooth muscle

Br. J. Pharmacol.

Hibernation: neural aspects

Ann. Rev. Physiol.

Histamine receptors of the microvascular endothelium revealed in situ with a histamine–ferritin conjugate: characteristic high-affinity binding sites in venules

J. Cell. Biol.

Histaminergic H₁ antagonists modulate seizure pattern induced by electroschock in mice

Molecular cloning of a gene encoding the histamine H₂ receptor

Regulation of histamine H₁ receptor coupling by dexamethasone in human cultured airway smooth muscle