Acta Otolaryngol (Stockh) 1997; Suppl 526: 43-46

Physiopathology of H, -Receptors and Pharmacology of Betahistine

P. B. VAN CAUWENBERGE and S. E. G. DE MOOR
From the Depnrtmenr of OtorhinoIrrynRoloR~~~
University Hospirril of Ghenr. Ghent, Belgium

Van Cauwenberge PB, De Moor SEG. Plzy.~ioprrtl~olog~~

qfH,-receptors rind pharmncologj, of hetuhistine. Acta Otolaryngol
(Stockh) 1997: Suppl 526: 43-46.
This article reviews published research on the physiology of histamine H,-receptors. The function of this inhibitory
autoreceptor. its localisation and influence on histaminergic neurones as well as histamine-controlled processes are
presented together with the role of H,-receptors in the vestibular system. In addition to a summary of the properties of
the main H;-agonists and -antagonists. the pharmacology of betahistine and its place in the treatment of vertigo are
discussed. Key words: H,-receptor. histamine, hetuliistine, imnpromidine. thioperamide. histnminergic neurones. vestihulur
svstem
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INTRODUCTION
Histamine plays an important physiological role in
the human vestibular system, as it does in other
organs. It is a rather simple molecule that performs
the functions of a local hormone as well as a neuro-
transmitter.
The first antihistaminic compounds to be discov-
ered were the diphenhydramines which initially were
For personal use only.
H , -receptors
H,-receptors are associated with an adenylate cyclase
system which uses cyclic adenosine monophosphate
as a second messenger (4). The central functions of
H,-receptors are not well characterised although anti-
nociception and prolactin secretion are two of the
identified roles (3). Both H I - and H,-receptors are
found on the postsynaptic membrane.

used only for the treatment of allergies. However,

they had no effect on other histamine-related pro-
cesses such as increased gastric secretion and cardiac
stimulation. We now know that the reason for this
anomaly is the existence of three different types of
histamine receptors.
HISTAMINE RECEPTORS
In the 1960s, the presence of two types of histamine
receptors ( H I and H2) was proposed and selective
ligands-agonists and antagonists-were identified.
The H I-antagonists (e.g. chlorpheniramine) are used
in allergic conditions while H,-antagonists (e.g. cime-
tidine, ranitidine) are important anti-ulcer agents.
Although H i -antagonists were known to have a
marked sedative effect on the central nervous system
(CNS) it was not until the 1980s that histamine was
shown to act as a central neurotransmitter (1).
H , -receptors
H , -receptors are stimulated by histamine but very
close structural analogues of histamine may have
diminished affinity for the receptor. These receptors
are linked to a phosphatidylinositol pathway which
mobilises calcium ions via a second messenger (2).
The physiological role of H,-receptors in the CNS is
only partially understood: receptor blockade pro-
duces sedation and even sleep, whereas centrally ap-
plied histamine induces arousal that can be anta-
gonised by H I - but not by H,-antagonists (3).
H3-receptors
The first discovery of presynaptic H,-receptors in rat
brain was made in 1983 by Arrang et al. (1).
In general, presynaptic receptors are involved in
the release of other neurotransmitters and, by impli-
cation, the propagation of a nerve impulse. A presy-
naptic receptor which influences the release of a
neurotransmitter from the terminal is called an au-
toreceptor. At high concentrations, further release
of the neurotransmitter is inhibited by negative
feedback on the autoreceptor. Presynaptic autorecep-
tors are therefore considered to be important in
the fine regulation of neurotransmitter release. His-
tamine is known to inhibit its own release, indicating
the existence of a presynaptic inhibitory autoreceptor
(5).
The results of autoradiographic and membrane
binding studies have shown that the distribution of
H,-receptors is heterogeneous; furthermore, the re-
ceptors are not restricted only to histaminergic neu-
rones (6, 7).
H,-receptors have been identified in human brain
in a density greater than that found in the periphery
(8). They also have a physiological role in controlling
peripheral circulation and the motility of the gas-
trointestinal tract. In the lungs, low concentrations of
histamine can reduce neurotransmitter release from
cholinergic nerves. The latter potency is due to the
greater affinity of histamine for H, - than H I-recep-
tors (3, 6).

( 1997 Scandinavian University Press ISSN 0365-5237

 44 P. B . Vrrn Ccrumvrnher,~rund S. E. G. De Moor
Stimulation of C N S H,-receptors reduced the syn-
thesis and release of histamine from histaminergic
neurones, while blockade of H I- and/or H2-receptors
did not significantly change histamine turnover in the
brain (5).
Some close analogues of histamine which display
reduced activity at H , - and H,-receptors do, how-
ever, have a potent effect on H,-receptors (3). Al-
though the natural agonist of the H,-receptor is
histamine, the R-isomer of alpha-methylhistamine is
fifteen times more potent than histamine yet has
about the same effect on H , - and H,-receptors (9,
10).
lmpromidine is a strong H,-receptor agonist (48
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times more potent than histamine) as well as a potent
H,-receptor antagonist. Thioperamide is a competi-
tive antagonist of H,-receptors and betahistine is a
weak HI-agonist with moderate antagonist activity
on H,-receptors.
The role of H,-receptors in the C N S is still specula-
tive. Centrally acting histamine agonists and antago-
nists affect histamine-controlled functions. Histamine
has been demonstrated to affect hormone secretions,
energy production, sleep and waking, and regulation
For personal use only.
of the cerebral circulation. Thioperamide increases
the turnover of histamine in rat brain (10).
HISTAMINERGIC NEURONES
The cell bodies of histaminergic neurones are concen-
trated in a very small area of the brain: the tubero-
mammillary nucleus of the posterior hypothalamus
(7). These neurones receive afferent input from fibres
originating in the prefrontal cortex and the medial
preoptic area, as well as those containing neuropep-
tide Y, substance P. adrenaline and noradrenaline.
Histaminergic neurones reach almost all parts of the
brain but the distribution is heterogeneous. There is a
high density in the thalamus and hypothalamus. an
intermediate density in the telencephalon. and the
lowest concentration is found in the brainstem and
cerebellum (7).
Histaminergic neurones exhibit well-developed
dendrites and express several neuroactive substances
and enzymes including histamine, histidine decar-
boxylase, glutamate decarboxylase, adenosine deami-
nase, monoamine oxidase B, galanin and substance
P (11).
There is evidence that histaminergic neurones affect
a variety of brain activities simultaneously. F o r in-
stance. they constitute a single neuronal group with-
out any topological division; they send fibre
collaterals to almost all parts of the brain; they have
few synaptic contacts with neurones because their
varicose fibres run in parallel with neurones. astro-
cytes and blood vessels suggesting that the released
histamine diffuses into the brain; and they co-express
other neuroactive substances (7, 9).
C E N T R A L E F F E C T S OF H I S T A M I N E A N D
BETAHISTINE
His t urnine
Histamine is both a local hormone and a neurotrans-
mitter. In support of its effect on the arousal state
( 1 2). depletion of histamine ( b y alpha-methylhis-
tamine) increased the amount of slow-wave-sleep and
decreased wakefulness ( 12). Furthermore. thiop-
eramide-induced neuronal histamine release de-
creased slow-wave sleep and enhanced wakefulness.
The involvement of neuronal histamine in arousal
control was also demonstrated by a histaniine-in-
duced decrease in glycogen levels of the cerebral
cortex in vitro.
Intravenous injection of histamine causes vasodila-
tion in the microcirculation. As the cerebral vessels
are very sensitive to the vasodilatory action of his-
tamine, the result is a rise in intracranial and cerebral
pulse pressures. In the past, the vasodilating proper-
ties of histarnine were frequently used for the treat-
ment of vertigo and inner ear disorders as they were
thought to have a vascular pathology ( I 3).
Betmliistinr
Betahistine ( N-alpha-methyl-2-pyridylethylamine)
has structural a n d pharmacological properties similar
t o those of histamine. It has weak H,-agonistic activ-
ity, virtually n o effect on H,-receptors, and is a
potent H,-receptor antagonist (14).
Experimentally, betahistine produced cerebral and
peripheral vasodilation with an increase in blood flow
within the vertebrobasilar arterial system of up to
54% following intravenous administration ( 1 5). In
addition, some investigators found a n improvement
in the microcirculation of the internal auditory. coch-
lear and vestibular systems including the capillaries.
arterioles and arteriovenous arcades of the stria vas-
cularis and spiral ligament (16, 17).
The circulatory effects of betahistine have also
been demonstrated in humans. For example, be-
tahistine increased regional cerebral blood flow in
patients with cerebrovascular disease (18) and signifi-
cantly improved mental function in elderly patients
(19).
The advantage of betahistine over histamine in the
therapy of vertigo is its easier administration. More-
over. unlike histamine, betahistine is effective when
administered orally. and the therapeutic margin is
wider.
 Hisruniitie titid crytigo
There is a striking paradox in that both hlocknde ( o f
H I-receptors) and .stitiiul(rtioti of histamine receptors
( H I- and/or H,-receptors) result in a n anti-vertigo
effect. Thus, while histamine has a therapeutic effect
mediated by H , - a n d H,-receptor stimulation, the
H I-receptor antagonists. flunarizine and cinnarizine,
also improve vertigo. Nevertheless, it is possible that
the latter agents niay act by other mechanisms (e.g.
blockade of calcium) and may not even cross the
blood-brain-barrier.
If it is accepted that HI-receptor blockade is an
effective approach for the treatment of vertigo, then
betahistine (weak H I-agonism) must act by another
Acta Otolaryngol Downloaded from informahealthcare.com by RMIT University on 08/18/14
mechanism. namely H,-receptor antagonism. As the
H,-receptor is an inhibitory autoreceptor, betahistine
inhibits the auto-feedback mechanism, thus prolong-
ing the effect of any histamine that is released. The
most important anti-vertigo effect of histamine is
thought to be its action on the cerebral and internal
auditory blood flow.
Hisrtrniitir iti the tiirrlirrl wstihulirr. t i i i c h s
Histamine has been shown to depolarise three types
For personal use only.
of medial vestibular neurones in vitro, and increase
their spontaneous firing (20); this effect is mediated
by postsynaptic H,-receptors and capable of inhibi-
tion by H,-antagonists. Furthermore, one study has
demonstrated that H,-receptors are involved in his-
tamine-induced firing of neurones in the medial
vestibular nucleus (21). H,-receptor activation proba-
bly down-regulates the vestibular neurones by de-
creasing histamine release.
Local perfusion of the medial vestibular nucleus
with the H,-antagonist, cimetidine, and the H,-ago-
nist, N-alpha-niethylhistanlilie, caused oculomotor
and postural disturbances which mimicked a lesion of
the horizontal canal nerve ( 2 1 ). lntraperitoneal perfu-
sion with thioperaniide in guinea-pigs resulted in a
reversible. dose- and frequency-dependent vestibulo-
plegic effect since it strongly depressed the horizontal
vestibular-ocular reflex ( H V O R ) gain. The effect was
H,-receptor mediated as it could be blocked by N-al-
pha-methylhistamine. Interestingly, betahistine has
also been shown to depress HVOR gain (22).
BtJtahistit i r (11 it1 cochlrtr r. blood f to 1I'
,
The effects of betahistine on cochlear blood flow
(CBF) in the rat were seen at much lower doses than
those needed to produce systemic effects (23). This
indicated that specific receptors were present in the
cochlear blood vessels. Thioperamide had no effect
on CBF and even antagonised the effect of be-
tahistine ( 2 3 ) ; the latter finding niay be due to a
secondary property of thioperaniide. In contrast, N-
alpha-methylhistamine did not block the positive ef-
fect of betahistine on C B F (23) although it is possible
that the H,-agonist is not able to reach the site of
action.
Another interpretation of these findings is that
betahistine acts on different receptors. For instance, it
has been demonstrated that atropine blocks the
effect of betahistine on CBF, thus implicating a
cholinergic component (23). As promethazine did not
inhibit the activity of betahistine it was concluded
that no H , -receptors were involved, but this premise
may be insecure because promethazine also affects
muscarinic, dopaminergic and alpha I -adrenergic re-
ceptors. Further experiments are needed to clarify the
effects of H,-agonists and -antagonists on cochlear
blood flow.
CONCLUSIONS
Histamine and histamine receptors are important me-
diators in the mammalian vestibular system. During
the last two decades our understanding of the thera-
peutic effect of histamine-receptor agonists and an-
tagonists in vertigo has greatly improved.
It seems that the anti-vertigo effect of H I-receptor
antagonists cannot be attributed to blockade of H I -
receptors; instead they may be effective by virtue of
their calcium antagonism and thus ameliorate vomit-
ing.
Because H,-receptors are involved in the firing of
nerves in the medial vestibular nucleus, the develop-
ment of an H,-agonist capable of penetrating the
brain yet lacking any stimulation of gastric acid
secretion would be a major advance.
H,-antagonists constitute a n appropriate treatment
for vertigo since they enhance cerebral and vestibular
circulation by auto-inhibition of histamine release.
They have the advantage of increasing alertness. The
anti-vertigo effect of betahistine is probably due to
the drug's mixed H I-agonist and H,-antagonist ac-
t iot i s.
Further studies with more potent H,-antagonists
are warranted because of the interesting therapeutic
potential they offer.
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Address for correspondence:
P. B. Van Cauwenberge
Department of Otorhinolaryngology
University Hospital of Ghent
De Pintelaan 185
B-9000 Ghent
Belgium