Although physiological significance is
uncertain, yawning behavior has received a great
deal of attention. From accumulated behavioral
studies, including our previous experimental
results, it has been shown that physostigmine,
an anticholinesterase agent, and pilocarpine, a
muscarinic receptor agonist, induce yawning
behavior that is blocked by muscarinic receptor
antagonists, but not by dopamine receptor
antagonists. On the other hand, the yawning
induced by dopamine D2 receptor agonists, such
as bromocriptine and talipexole, is antagonized
by both dopaminergic and muscarinic receptor
antagonists.
On the basis of these findings, the yawning
induced by cholinesterase inhibitors and
muscarinic receptor agonists appears to involve
cholinergic activation, and that in response to
dopamine receptor agonists seems to require both
dopaminergic and cholinergic activation. Thus,
the cholinergic activation followed by unknown
yawn-inducing neuronal mechanisms seems to be
essential in eliciting yawning behavior.
In addition, yawning behavior seems to
involve other neuronal mechanisms. Because the
yawning responses to both dopaminergic and
cholinergic receptor agonists arc increased by
beta-adrenoceptor blockers and adrenaline
synthesis inhibitors, the occurrence of yawning
evoked by dopaminergic and cholinergic
activation seems to be downregulated by the
activity of central adrenergic neurons via
stimulation of beta-adrenoceptors.
On the other hand, central administration of
certain peptides, such as
a-melanocyte-stimulating hormone a-MSH and
adrenocorticotropic hormone (ACTH), is also
capable of inducing a peculiar syndrome
characterized by recurrent episodes of yawning,
stretching, body shaking, and penile erection.
Oxytocin has also been reported to elicit
yawning behavior that is inhibited by muscarmic
receptor antagonists but not by dopamine
receptor antagonists.
The prescrit experiments were therefore
performed to investigate whether
beta-adrenoceptor activity is involved in
regulation of the yawning induced by the
neuropeptides oxytocin and a-MSH in
rats.[...]
DISCUSSION
Previous studies have shown that a
muscarinic receptor agonist, pilocarpine,
induces yawning behavior, in rats. Muscarinic
receptors have been designated as either 1 or M2
receptors, depending on whether they have high
or low affinity for pirenzepine, although such
classification is as yet tentative. In the
present study, RS-86, a centrally acting potent
muscarinic M1 receptor agonist, administered SC
produced yawning in rats, as reported previously
by Gower,
suggesting that the muscarinic receptors
participating in the induction of yawning may be
M1 receptors.
From such dose-response studies on systemic
administration of RS-86, 100 µg/rat was
selected for ICV administration in the present
study. On the other hand, central administration
of nanogram amounts of oxytocin was reported to
produce yawning in rats. For ICV administration
of the peptides, oxytocin was given at doses of
50 and 100 ng/rat according to the previous
reports by Argiolas
et al., and a-MSH was administered at 20
µg/rat from the results of our previous
experiments. In the present study, oxytocin and
a-MSH injected ICV evoked yawning behavior, but
the potency of oxytocin seemed to be less
effective in causing yawning compared with the
previous report by Argiolas et al. We have no
adequate explanation for this difference in
effect at prescrit, but it may be due, at least
in part, to differences in species and/or
strains used in both studies.
Previous experiments have shown that the
yawning responses to dopaminergic agonists were
increased by administration of beta-adrenoceptor
antagonists such as pindolol and propranolol.
The yawning responses to cholinergic agents such
as physostigmine, pilocarpine, and tacrine were
also increased by treatment with the
a-adrenoceptor antagonist, pindolol Moreover,
the potentiation was elicited by central
beta-adrenoceptor blockers such as propranolol
and others, which reach the brain through the
blood-brain barrier, but not by peripheral
a-adrenoceptor blockers (carteolol and
atenolol), indicating that potentiation by
beta-blockers occurs in the brain. The yawning
induced by RS-86 administered SC and ICV was
potentiated by treatment with the
beta-adrenoceptor blocker pindolol in the
present study. In addition, the occurrence of
yawning behaviors produced by the neuropeptides
oxytocin and a-MSH given ICV was markedly
potentiated by treatment with pindolol.
It bas been reported that oxytocin-induced
yawning is inhibited by
[d(CH2)5Tyr(Me)2,Orn8]-vasotocin, an
oxytocin receptor antagonist. In the present
study, the yawning produced by oxytocin
administered in combination with pindolol was
also blocked by d(CH2)5Tyr(Me)2,Orn8]
-vasotocin, whereas that by a-MSH or RS-86 plus
pindolol was unaffected, suggesting that the
yawning responses are elicited via different
receptor mechanisms. The yawning evoked by ACTH,
an a-MSH-related peptide, was also reported to
be unaffected by oxytocin receptor
antagonists.
The yawning induced by muscarinic receptor
agonists was reported to be blocked by
muscarinic receptor antagonists, but was
unaffected by dopamine receptor antagonists. In
the prescrit study, the yawning behavior
elicited by RS-86, a muscarinic M1 receptor
agonist, administered in combination with
pindolol was inhibited by scopolamine, a
muscarinic receptor antagonist, but not by
spiperone, a dopamine D2 receptor
antagonist.
The yawning produced by oxytocin after
pindolol was also antagonized by scopolamine,
without being affected by spiperone. These
results seem to be in agreement with the
previous proposal that the expression of yawning
induced by dopaminergic agonists involves
dopamine-oxytocin, but not oxytocin-dopamine,
linkage. The yawning evoked by an a-MSH-related
peptide, ACTH, which was unaffected by oxytocin
receptor antagonists, was also reported to be
prevented by cholinergic receptor
antagonists.
Our previous results also indicated that
none of the responses to a-MSH, yawning,
stretching, and body shaking, are associated
with changes in the activities of the
nigrostriatal, mesolimbic, tuberoinfundibular,
or tuberohypophyseal dopaminergic neurons, and
that a-MSH-induced yawning is decreased by
administration of cholinergic receptor
antagonists. In the present study, the yawning
evoked by a-MSH administered after pindolol was
antagonized by scopolamine, but not by
spiperone. From such findings, the oxytocin- and
a-MSH-induced yawning responses appear to
involve cholinergic, but not dopaminergic,
activation, although further investigation is
warranted to identify the neuronal circuit
between the peptidergic-cholinergic-linked
neuronal system involved in causing yawning
behavior. It is also suggested that the
activation of a muscarinic receptor constitutes
the expression of yawning as a common mechanism.
Moreover, the present results also indicate that
beta-adrenoceptors seern to be involved in the
yawn-inducing neuronal mechanism linked to
cholinergic neurons and thereby play an
inhibitory role in modulation of occurrence of
the behavior.
Body shaking was reported previously after
administration of various drugs such as a-MSH,
thyrotropin-releasing hormone and
5-hydroxytryptophan, and after electrical
stimulation of the hippocampus in rats. The
present study also confirmed that ICV
administration of a-MSH induced body
shaking.
The present results suggest that the
neuropeptides oxytocin and a-MSH and the
muscarinic M1 receptor agonists produce yawning
via activation of cholinergic mechanisms, and
that beta-adrenoceptors are involved in
regulation of the yawning induced by the
neuropeptides.
-Fugikawa
M; Yamada K; Nagashima M; Furukawa T
Involvement of beta-adrenoreceptors in
regulation of the yawning induced by
neuropeptides; oxytocin and alpha-melanocytes
stimuling hormone in rats. Pharmacol Biochem
Behav 1995; 50; 339-343
-Furukawa
T Yawning behavior for preclinical drug
evaluation Meth Find Exp Clin Phamacol 1996; 18;
2; 141-155
-Kimura H;
Yamada K; Nagashima M; Matsumoto S Role of
adrenergic neuronal activity in the yawning
induced by tacrine and NIK-247 in rats.Pharmacol
Biochem Behav 1992; 43; 4; 985-91
-Kimura
H; Yamada K; Nagashima M; Furukawa T
Involvement of catecholamine receptor activities
in modulating the incidence of yawning in
rats.Pharmacol Biochem Behav 1996; 53(; 4;
1017-21
Ogura
H, Kosasa T, Kuriya Y, Yamanishi Y Central
and peripheral activity of cholinesterase
inhibitors as revealed by yawning and
fasciculation in rats. Eur J Pharmacol. 2001;
415; 2-3; 157-64
-Serra
G , Collu M and Gessa GL Yawning is elicited
by D2 dopamine agonists but is blocked by D1
antagonist Psychopharmacology 1987; 91;
330-337
-Serra G,
Gessa GL Hypophysectomy prevents yawning and
penile erection but not hypomotility induced by
apomorphine Pharmacology Biochemistry &
Behavior 1983; 19; 917-919
-Serra G
et al Cycloheximide prevents apomporphine
induced yawning, penile erection and genital
grooming in rats European Journal of
Pharmacology1983; 86; 279-282
-Kostrzewa RM
and R Brus Is dopamine-agonist induced
yawning behavior a D3 mediated event? Life Sci
1991; 48; 26; 129
-Ushijima I,
Mizuki Y, Yamada M Multifocal sites of
action involved in dopaminergic-cholinergic
neuronal interactions in yawning
Psychopharmacology (Berl) 1988; 95; 34-7
-Ushijima
I et al, Muscarinic and nicotinic effects on
yawning and tongue protruding in the rat
Pharmacol Biochem Behavior 1984; 21;
297-300
-Ushijima
et al modification of apomorphine,
physiostigmine and pilocarpine induced yawning
after long term treatment with neuroleptic or
cholinergic agents Arch Int Pharmacodyn 1984;
271; 180-188
-Ushijima
I et al Characteristics of yawning behavior
induced by apomorphine, physostigmine and
pilocarpine Arch Int Pharmacodyn 1985; 273;
196-201
-Ushijima,
I., Y. Mizuki, et al. Behavioral effects of
dilazep on cholinergic, dopaminergic, and
purinergic systems in the rat. Pharmacol Biochem
Behav 1992;43(3): 673-676.
-Yamada K,
Furukawa T Direct evidence for involvement
of dopaminergic inhibition and cholinergic
activation in yawning Psychopharmacology 1980;
67; 39-43
-Yamada K,
Furukawa T The yawning elicited by
alpha-melanocyte-stimulating hormone involves
serotonergic -dopaminergic - cholinergic neuron
link in rats Naunyn-Schmiedeberg's Arch
Pharmacol 1981; 316; 155 -160
-Yamada K et
al Involvement of septal and striatal
dopamine D2 receptors in yawning behavior in
rats Psychopharmacology 1986; 90; 9-13
-Yamada K
et al Possible involvement of differing
classes of dopamine d2 receptors in yawning and
stereotypy in rats Psychopharmacology 1990; 100;
141-144
-Yamada K,
Furukawa T Behavioral studies on central
dopaminergic neurons. especially jumping,
stretching, body shaking and yawning behavior J
PharmacoBio dynamics 1980; 3; S16-S18
