The physiology of brain histamine

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Abstract

Histamine-releasing neurons are located exclusively in the TM of the hypothalamus, from where they project to practically all brain regions, with ventral areas (hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation. The intrinsic electrophysiological properties of TM neurons (slow spontaneous firing, broad action potentials, deep afterhyperpolarisations, etc.) are extremely similar to other aminergic neurons. Their firing rate varies across the sleep-wake cycle, being highest during waking and lowest during rapid-eye movement sleep. In contrast to other aminergic neurons somatodendritic autoreceptors (H3) do not activate an inwardly rectifying potassium channel but instead control firing by inhibiting voltage-dependent calcium channels. Histamine release is enhanced under extreme conditions such as dehydration or hypoglycemia or by a variety of stressors. Histamine activates four types of receptors. H1 receptors are mainly postsynaptically located and are coupled positively to phospholipase C. High densities are found especially in the hypothalamus and other limbic regions. Activation of these receptors causes large depolarisations via blockade of a leak potassium conductance, activation of a non-specific cation channel or activation of a sodium–calcium exchanger. H2 receptors are also mainly postsynaptically located and are coupled positively to adenylyl cyclase. High densities are found in hippocampus, amygdala and basal ganglia. Activation of these receptors also leads to mainly excitatory effects through blockade of calcium-dependent potassium channels and modulation of the hyperpolarisation-activated cation channel. H3 receptors are exclusively presynaptically located and are negatively coupled to adenylyl cyclase. High densities are found in the basal ganglia. These receptors mediated presynaptic inhibition of histamine release and the release of other neurotransmitters, most likely via inhibition of presynaptic calcium channels. Finally, histamine modulates the glutamate NMDA receptor via an action at the polyamine binding site. The central histamine system is involved in many central nervous system functions: arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. A role for the neuronal histamine system as a danger response system is proposed.

Introduction

Every moment of every day our brains are bombarded by information arising from the environment and transduced by our senses. Our brains are not, however, passive receptacles for this information impinging upon us. We instantly impose our own subjective order, values and beliefs on this information depending on our memories and our bodily/psychological needs at that time. How do our brains create the subjective context for this information? The answer to this question likely involves the four aminergic systems present in the mammalian central nervous system, i.e. the serotonergic, dopaminergic, noradrenergic and histaminergic systems. All four of these systems consist of small groups of neurons, which have projection patterns encompassing practically the whole brain and spinal cord, allowing them to globally modulate neuronal function. Furthermore, these neurons have similar intrinsic electrophysiological properties and their receptors utilise similar effector mechanisms. Specificity of action is achieved by the different afferent input they receive and by the specific localisation of receptor subtypes in target regions. Whilst the dopaminergic, noradrenergic and serotonergic systems have been extensively investigated, the histaminergic system has received less attention, although it is likely to be of comparable importance. This review summarises our current state of knowledge of the central histaminergic system, with particular emphasis on its physiology. For more detailed discussions of anatomy, biochemistry, pharmacology and pathophysiology of this system, the interested reader is encouraged to consult recent reviews focusing more on those aspects (Prell and Green, 1986, Hough, 1988, Schwartz et al., 1991, Onodera et al., 1994, Hill et al., 1997)

Section snippets

Histamine metabolism, turnover

The presence of histamine can be demonstrated in two major pools in the brain — in neurons and in mast cells (Garbarg et al., 1976). Mast cells are relatively scarce in the brain, in comparison to other tissues, and their function is at present unclear. Marked differences in density of mast cells occur according to species and sex studied and according to physiological state (Dropp, 1979, Theoharides, 1990). Significant numbers can be observed in the thalamus and hypophysis but in most other

Anatomy

Whilst early lesion, biochemical and electrophysiological studies indicated the presence of a neuronal histaminergic system (Kuhar et al., 1971, Haas et al., 1973, Dismukes and Snyder, 1974, Garbarg et al., 1974, Haas, 1974, Snyder et al., 1974, Garbarg et al., 1976, Schwartz et al., 1976, Haas and Wolf, 1977, Garbarg et al., 1978), it was only with the development of antibodies against histamine and HDC that the localisation and projection patterns of histamine neurons could be established (

Electrophysiology of the TM region

Histaminergic TM neurons display characteristics very similar to other aminergic cell groups (Fig. 2) such as the dopaminergic neurons in the substantia nigra or ventral tegmental area (Grace and Bunney, 1983, Grace and Onn, 1989). They fire spontaneously in a slow (0–3 Hz) regular, pacemaker fashion, have broad action potentials (1.8 ms mid-amplitude duration) and deep (15–20 mV), long-lasting afterhyperpolarisations (Reiner and McGeer, 1987, Haas and Reiner, 1988). TM neuron firing varies

Histamine H1 receptors

Central histamine H1 receptors are the main site responsible for the sedative effects of antihistamines. The gene for the human histamine H1 receptor is located on chromosome 3 (Le Coniat et al., 1994) and encodes a member of the large, 7-transmembrane-spanning, G-protein-associated receptor family. Intracellularly, the receptor is associated with the Gq/11 GTP-hydrolysing protein which, when activated by histamine binding to the receptor, stimulates the activity of phospholipase C (Leurs et

Effects of histamine on target regions

Electrophysiological effects of histamine have been found in many regions of the central nervous system including the cerebral cortex, thalamus, hippocampus, striatum, hypothalamus, cerebellum, brain stem and spinal cord (Haas and Wolf, 1977, Haas et al., 1991, Haas, 1992). In this section we concentrate, however, on those areas for which a number of reports are available.

Effect of histamine on synaptic plasticity

Studies of the effect of histamine on synaptic plasticity are in their infancy. However, histamine has the potential to modulate or cause plastic change by a variety of mechanisms. The histamine H1 receptor is linked to increases of intracellular calcium levels and to PKC, both of which have been shown to be important in the induction and early stages of synaptic plasticity (Bliss and Collingridge, 1993). The histamine H2 receptor is a potent stimulator of the cAMP pathway which is necessary

Arousal

The original impetus for the suggestion that histamine is involved in arousal mechanisms came from observations of the sedative effects of a number of antihistamines (H1 antagonists), used in the treatment of inflammatory reactions. These drugs readily cross the blood–brain barrier and block H1 receptors in the brain (White and Rumbold, 1988). Further investigation has supported the idea of a central histaminergic arousal system. This evidence can be divided into four parts:

  • 1.

    Electrophysiological

Conclusions/future directions

The central histamine system has been well conserved during evolution. What is the selective advantage to an organism of possessing such a system? The data reviewed in this article are suggestive of a role for brain histamine as a danger response signal. The release or turnover of neuronal histamine is enhanced by a wide variety of aversive or potentially dangerous stimuli: dehydration (Section 8.2.1), hypoglycemia (Section 8.2.2), changes in blood pressure (Section 8.2.4), sensory conflict

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (Grant DFG HA 1525/1-3). We would like to thank Professor Ulrich Knigge for critical comments on the manuscript.

References (439)

  • P.C. Braga et al.

    Electrophysiological correlates for antinociceptive effects of histamine after intracerebral administration to the rat

    Neuropharmacology

    (1992)
  • R.E. Brown et al.

    Histaminergic modulation of synaptic plasticity in area CA1 of rat hippocampal slices

    Neuropharmacology

    (1995)
  • J. Bugajski et al.

    Central histaminergic stimulation of pituitary — adrenocortical response in the rat

    Life Sci.

    (1983)
  • G. Buzsaki

    Two-stage model of memory trace formation: a role for ‘noisy’ brain states

    Neuroscience

    (1989)
  • R.M. Chemelli et al.

    Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation

    Cell

    (1999)
  • E.A. Clark et al.

    Sensitivity of histamine H3 receptor agonist-stimulated [35S]GTP gamma[S] binding to pertussis toxin

    Eur. J. Pharmacol.

    (1996)
  • W.G. Clark et al.

    Changes in body temperature after administration of amino acids, peptides, dopamine, neuroleptics and related agents: II

    Neurosci. Biobehav. Rev.

    (1985)
  • F.M. Correa et al.

    Increase in histamine concentrations in discrete hypothalamic nuclei of spontaneously hypertensive rats

    Brain Res.

    (1981)
  • F.M. Correa et al.

    High histamine levels in specific hypothalamic nuclei of Brattleboro rats lacking vasopressin

    Brain Res.

    (1983)
  • N.K. Cote et al.

    Histamine phase shifts the circadian clock in a manner similar to light

    Brain Res.

    (1993)
  • P. Cumming et al.

    Subclasses of histamine H3 antagonist binding sites in rat brain

    Brain Res.

    (1994)
  • P. Cumming et al.

    Cerebral histamine levels are unaffected by MPTP administration in the mouse

    Eur. J. Pharmacol.

    (1989)
  • P. Cumming et al.

    Distribution of histamine H3 binding in forebrain of mouse and guinea pig

    Brain Res.

    (1994)
  • T. Darland et al.

    Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more

    Trends Neurosci.

    (1998)
  • K. Dismukes et al.

    Histamine turnover in rat brain

    Brain Res.

    (1974)
  • H.C. Dringenberg et al.

    Involvement of direct and indirect pathways in electrocorticographic activation

    Neurosci. Biobehav. Rev.

    (1998)
  • S.J. Eaton et al.

    Histamine synthesis inhibition reduces light-induced phase shifts of circadian rhythms

    Brain Res.

    (1995)
  • S.J. Eaton et al.

    Circadian rhythm photic phase shifts are not altered by histamine receptor antagonists

    Brain Res. Bull.

    (1996)
  • L. Finch et al.

    Involvement of hypothalamic histamine-receptors in the central cardiovascular actions of histamine

    Neuropharmacology

    (1977)
  • A.E. Fleckenstein et al.

    Evidence that histamine-stimulated prolactin secretion is not mediated by an inhibition of tuberoinfundibular dopaminergic neurons

    Life Sci.

    (1992)
  • A.E. Fleckenstein et al.

    Activation of noradrenergic neurons projecting to the diencephalon following central administration of histamine is mediated by H1 receptors

    Brain Res.

    (1994)
  • A.E. Fleckenstein et al.

    Effects of histamine on 5-hydroxytryptaminergic neuronal activity in the rat hypothalamus

    Eur. J. Pharmacol.

    (1994)
  • N. Adachi et al.

    Changes in the metabolism of histamine and monoamines after occlusion of the middle cerebral artery in rats

    J. Neurochem.

    (1991)
  • N. Adachi et al.

    Direct evidence for increased continuous histamine release in the striatum of conscious freely moving rats produced by middle cerebral artery occlusion

    J. Cereb. Blood Flow Metab.

    (1992)
  • M.S. Airaksinen et al.

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

    J. Comp. Neurol.

    (1988)
  • V.F. Akins et al.

    Brain histamine regulates pressor responses to peripheral hyperosmolality

    Am. J. Physiol.

    (1990)
  • V.F. Akins et al.

    Central nervous system histamine regulates peripheral sympathetic activity

    Am. J. Physiol.

    (1991)
  • V.F. Akins et al.

    Hypothalamic histamine release, neuroendocrine and cardiovascular responses during tuberomammillary nucleus stimulation in the conscious rat

    Neuroendocrinology

    (1993)
  • E.O. Alvarez et al.

    Effects of localized histamine microinjections into the hippocampal formation on the retrieval of a one-way active avoidance response in rats

    J. Neural Transm. Gen. Sect.

    (1995)
  • E.O. Alvarez et al.

    Hippocampal histamine receptors: possible role on the mechanisms of memory in the rat, II

    J. Neural Transm.

    (1996)
  • X.A. Alvarez et al.

    Effects of neurotoxic lesions in the posterior hypothalamic region on psychomotor activity and learning

    Agents Actions

    (1994)
  • J.-M. Arrang et al.

    Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor

    Nature

    (1983)
  • J.-M. Arrang et al.

    H3-receptor control histamine release in human brain

    J. Neurochem.

    (1988)
  • J.M. Arrang et al.

    Characterization of histamine H3 receptors regulating acetylcholine release in rat entorhinal cortex

    Br. J. Pharmacol.

    (1995)
  • F.W. Bach et al.

    The inhibition of stress-induced beta-endorphin secretion by histamine receptor antagonists [letter]

    Anesthesiology

    (1987)
  • K.E. Barke et al.

    Simultaneous measurement of opiate-induced histamine release in the periaqueductal gray and opiate antinociception: an in vivo microdialysis study

    J. Pharmacol. Exp. Ther.

    (1993)
  • M. Baudry et al.

    H1 and H2 receptors in the histamine-induced accumulation of cyclic AMP in guinea pig brain slices

    Nature

    (1975)
  • S.L. Bealer

    Histamine releases norepinephrine in the paraventricular nucleus/anterior hypothalamus of the conscious rat

    J. Pharmacol. Exp. Ther.

    (1993)
  • S.L. Bealer et al.

    Paraventricular nucleus histamine increases blood pressure by adrenoreceptor stimulation of vasopressin release

    Am. J. Physiol.

    (1995)
  • J.M. Bekkers

    Enhancement by histamine of NMDA-mediated synaptic transmission in the hippocampus

    Science

    (1993)
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