Section of Physiology,
Department of Basic Sciences, Faculty of
Veterinary Medicine, Urmia University, Iran
Abstract:
In this study, the effects of
intraperitoneal (ip) injection of physostigmine,
subcutaneous (sc) injection of atropine, and
intracerebroventricular (icv) injections of
histamine, chlorpheniramine (H1-receptor
antagonist), and ranitidine (H2-receptor
antagonist) in separate and combined treatments
were investigated during yawning in rats.
Physostigmine at a dose of 0.25 mg/kg produced
the highest number of yawns. Atropine, used
alone, was without effect, but physostigmine
(0.25 mg/kg, ip)-induced yawning was blocked by
pretreatment with atropine (1 mg/kg, sc).
Histamine at the doses of 10, 20 and 40 g
produced yawning. Chlorpheniramine and
ranitidine, used alone, had no effect, whereas
pretreatments with chlorpheniramine and
ranitidine at the same dose of 80 g prevented
histamine (40 g, icv)-induced yawning. The
suppressive effect of chlorpheniramine was more
than that of ranitidine. Histamine (10 and 40 g,
icv) enhanced, whereas chlorpheniramine and
ranitidine at the same dose of 80 ?g suppressed,
physostigmine (0.25 mg/kg, ip)-induced yawning.
Atropine (1 mg/kg, sc) not only suppressed
histamine-induced yawning, but also enhanced the
inhibitory effect of chlorpheniramine, but not
of ranitidine on yawning induced by
histamine.
These results indicate that muscarinic
receptors mediate yawning induced by
physostigmine. Histamine central H1, and to a
lesser extent H2 receptors, may be involved in
histamine-induced yawning. Cholinergic
muscarinic receptors, as well as histaminergic
H1 and to a lesser extent H2 receptors, may also
be involved in the interaction between brain
acetylcholine and histamine.
Introduction
Yawning, as a common physiological event,
occurs with a low frequency in humans and
animals and is under coordinated control of
several neurotransmitters and neuropeptides such
as dopamine, excitatory amino acids, serotonin,
nitric oxide, noradrenaline, -aminobutyric acid
(GABA), adrenocorticotropic hormone-related
peptides, prolactin, urotensin, oxytocine and
opioid peptides at the central nervous system
level [2]. Several lines of
pharmacological evidence suggest that
acetylcholine is involved in the expression of
the yawning. This evidence includes, for
example, findings that cholinomimetic drugs
(e.g., physostigmine and pilocarpine) induce
yawning in rats and muscarinic receptor
antagonists that cross the blood-brain barrier,
such as atropine and scopolamine, but not the
nicotinic receptor antagonist, mecamylamine,
prevent yawning induced by dopamine D 2 receptor
antagonists [15, 19, 23, 40].
On the other hand, additional evidence
suggests that the brain histamine may also be
involved in the induction of yawning. It was
found that microinjection of histamine into the
paraventricular nucleus (PVN) of the brain
produced yawning in the pentobarbital sodium
anesthetized rats [33]. In the study of
Seki et al. [33], the involvement of
histamine H 1 receptors in histamine-induced
yawning was clarified. In addition, Seki et al.
[32] reported a suppressive effect of
prylamine (H 1-receptor antagonist) in the
light-induced yawning response in rats. Brain
histamine, through its H 1, H2 and H3 receptors,
influences the release and function of other
neurotransmitters as well as neuropeptides such
as dopamine, GABA, serotonin, acetylcholine,
oxytocin and orexins [8, 17, 25].
In the higher functions of the brain such as
arousal, learning and memory the interaction
between histaminergic and cholinergic systems
has been documented [6]. Moreover, it
has been reported that brain histamine, through
its central H 1, but not H2 receptors mediates
neostigmine-induced hyperglycemia in rats
[20]. In addition, it was reported that
central histamineinduced hyperglycemia was
suppressed by icv injection of atropine
[21]. Therefore, the present study was
designed to investigate the interaction between
physostigmine and brain histamine during yawning
in rats. To clarify the involvement of
histaminergic and cholinergic receptors in
yawning, the effects of histamine H 1 and H2
receptor antagonists, chlorpheniramine and
ranitidine, respectively, and atropine (a
muscarinic antagonist) were also examined.
Discussion
The results of the present study show that
physostigmine at the low (0.625 mg/kg) and high
(1 mg/kg) doses was without effect, whereas at
the doses of 0.125, 0.25 and 0.5 mg/kg, with the
highest response at the dose of 0.25 mg/kg,
physostigmine produced yawning. Physostigmine is
a major alkaloid found in the seeds of the
fabaceous plant Physostigma venenosum, and it is
a powerful and reversible acetylcholine esterase
inhibitor that effectively increases the
concentration of acetylcholine in the sites of
cholinergic transmission [43].
Physostigmine, as a cholinomimetic agent, at the
dose range of 0.05&endash;1 mg/kg has been
frequently used in the study of the involvement
of the cholinergic system in behavioral and
physiological events. Most research has reported
that physostigmine at the doses of
0.1&endash;0.3 mg/kg, especially at the dose of
0.2 mg/kg, produces an increased yawning
response [15, 24, 36, 41, 42].
Physostigmine at higher doses (0.5&endash;2
mg/kg) produces tremor, fasciculation,
salivation, tongue protruding, hypothermia and
defecation [7, 22, 23, 29, 36, 37]. In
the present study, atropine prevented
physostigmine-induced yawning. This finding is
in agreement with those from other
investigations [7, 15, 34]. It would
appear that physostigmine-induced yawning and
the inhibitory effect of atropine on the yawning
induced by physostigmine may occur at a central
level. Distigmine, a peripherally acting
cholinesterase inhibitor, did not produce any
yawning, whereas E2030 and donepezil, with
marked preferential central cholinergic
activities, relative to peripheral activities,
produced more yawning and scopolamine, a
centrally acting antimuscarinic drug, inhibited
E2030-iduced yawning [23].
The results presented here indicate that icv
injection of histamine produced yawning.
Histamine H 1 and H 2 blockers, chlorpheniramine
and ranitidine, respectively, produced no
yawning response in the absence of histamine,
but in the presence of histamine,
chlorpheniramine and to a lesser extent
ranitidine prevented histamine-induced yawning.
This indicates that both histamine central H 1
and H2 receptors are involved in yawning induced
by brain histamine. The cell bodies of the
histaminergic neuron system are concentrated in
the tuberomammillary nucleus of the hypothalamus
and send out axons to innervate the entire
central nervous system [17, 31]. The
areas known to be involved in the induction of
yawning (e.g., hippocampus, PVN, pituitary
gland, nigrostriatal system, locus cereleus,
nucleus of solitary tract, the dorsal motor
nucleus of the vagus nerve, ventrolateral
medulla and spinal cord) [2, 30], are
also innervated by the brain histamine system
[31].
It has been found that microinjection of
histamine into the medial, but not into the
lateral and caudal parts of the PVN produces a
yawning response in anesthetized rats
[33]. It was reported that after
microinjection of trifluoromethyl toluidide
dimaleate, an H 1-receptor agonist, into the
PVN, yawning was produced, while pyrilamine (H
1-receptor antagonist) prevented
histamine-induced yawning [33]. In
addition, dimaprit, an H 2-receptor agonist,
produced yawning after microinjection into the
PVN, but cimetidine (H 2-receptor antagonist)
did not prevent histamine-induced yawning
[33]. Icv injection of pyrilamine
blocked the yawning induced by light
stimulation, suggesting a role for brain
histamine H 1 receptors in modulating
light-induced yawning [32]. In this
regard, Gower et al. [16] reported that
the H 1-receptor antagonist,
dexchlorpheniramine, inhibited
apomorphine-induced yawning. Moreover, Ferrari
and Baggio [14] found that cimetidine
but not ranitidine, injected ip antagonized the
yawning induced by apomorphine. In our study,
the route of ranitidine injection, the yawning
inducing agent, and the conscious level of the
animal may affect the results obtained from
ranitidine.
However, further studies are required to
identify the histamine H 2-receptor action on
the yawning response. Yawning is a complex
arousal defense reflex located in the reticular
brainstem with a peripheral and central arch,
whose aim is to reverse brain hypoxia
[38]. On the other hand, the involvement
of the brain histamine in the arousal regulation
has been documented [8]. Seki et al.
[33] reported an arousal shift in the
electrocorticogram after microinjection of
histamine into the PVN. Therefore, it seems that
the histamine-induced yawning observed in the
present study may be associated with the action
of histamine on the area involved in the
activation of yawning/arousal mechanisms.
The results of the present study indicate
that brain histamine produced an additive effect
on physostigmine-induced yawning, and histamine
H 1 and H2 blockers suppressed the yawning
induced by physostigmine. On the other hand,
atropine suppressed histamine-induced yawning
and enhanced the suppressive effects of
chlopheniramine but not for ranitidine on the
yawning induced by histamine. These data
therefore indicate that brain histamine, through
its H 1 and H 2 receptors, might have an
excitatory effect on acetylcholine function, and
that cholinergic muscarinic receptors might
interact with central H 1 but not H 2
histaminergic stimulation of yawning.
Microinjection of histamine into the basolateral
amygdala increased the escape latency in
acquisition and avoidance tasks
[1].
The basolateral amygdala receives abundant
cholinergic innervation from the nucleus basalis
mangocellularis [10]. Moreover, in the
ventral striatal neurons, histamine increased
while -fluoromethylhistidine, a suicide
inhibitor of histidine decarboxylase, decreased
the release of acetylcholine [27]. By
whole-cell current-clamp recording, it was shown
that histamine excited the septohippocampal
cholinergic neurons [39]. It was
reported that in the ventral striatal neurons,
thiazolylethylamine (TEA, H 1-receptor agonist)
and dimaprit (H2-receptor agonist) enhanced the
release of acetylcholine, while blockade of
histamine H 1 and H2-receptors with triprolidine
(H 1-receptor antagonist) and impromidine (H
2-receptor antagonist) produced opposite effects
[28]. On the other hand, cholinergic
nucleus basalis neurons projecting to the cortex
were excited by histamine mostly via H 1 but
also via H2 receptors [18]. In addition,
blockade of medial septum-diagonal band H 2
receptors with cimetidine was found to
antagonize the release of acetylcholine produced
by H 3 receptor antagonist, whereas
triprolidine, an H 1 receptor antagonist was
without effect [5].
Betahistine, as a partial histamine H 1
receptor agonist, was reported to increase
acetylcholine from the cortex of freely moving
rats [12]. It has been reported that
mepyramine and cimetidine failed to alter
acetylcholine spontaneous release from the
cortex: however, H 1 but not H2 receptor
antagonists antagonized the releases of
acetylcholine elicited by histamine
[11]. In freely moving rats, intraseptal
administrations of thioperamide and ciproxifan,
H 3 receptor antagonists increased the release
of acetylcholine from the hippocampus and
cimetidine inhibited the effects of thioperamide
and ciproxifan [3, 4].
Central pretreatments with pyrilamine and
atropine suppressed central histamineinduced
hyperglycemia and suggested that histamine H 1
receptors and muscarinic cholinergic neurons are
involved in histamine-induced hyperglycemia
[21]. Bugajski and G1dek, [9]
have suggested that cholinergic muscarinic
receptors interact with central H 1 and H 2
histaminergic stimulation during the increased
pituitary-adrenocortical response in stressed
rats. The discrepancies between findings of H 2
receptors involvement in acetylcholine release
and function may be associated with the fact
that histamine, via H 2 receptors, inhibits
activity of dopaminergic and GABAergic neurons,
thus indirectly modulating the release of
acetylcholine. Moreover, histamine also slightly
increases acetylcholine release through H 2
receptors, possibly located on cholinergic
neurons [27, 28].
In conclusion, the results of the present
study suggest that the central histaminergic and
cholinergic systems interact with each other in
the modulation of yawning. Cholinergic
muscarinic receptors as well as histaminergic H
1, and and to a lesser extent H2 receptors, are
involved in the interaction between brain
acetylcholine and histamine.
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