Department of Physiology,
Toho University School of Medicine, Ota-ku,
Tokyo, Japan
-Kita
I, Kubota N, Yanagita S, Motoki C
Intracerebroventricular administration of
corticotropin-releasing factor antagonist
attenuates arousal response accompanied by
yawning behavior in rats. Neurosci.Letter
2008;433(3):205-208
-Kita
I, Yoshida Y, Nishino S. An activation of
parvocellular oxytocinergic neurons in the
paraventricular nucleus in oxytocin-induced
yawning and penile erection. Neurosci Res.
2006;54(4):269-275
-Kita I,
Sato-Suzuki et al.Yawning responses induced
by local hypoxia in the paraventricular nucleus
of the rat.Behavioural Brain Research
2000;117(1-2):119-126
-Kubota
N, Amemiya S, Motoki C, Otsuka T, Nishijima T,
Kita I. Corticotropin-releasing factor
antagonist reduces activation of noradrenalin
and serotonin neurons in the locus coeruleus and
dorsal raphe in the arousal response accompanied
by yawning behavior in rats. Neurosci Res.
2012;72(4):316-323
-Seki Y, Y
Nakatani, et al Light induces cortical
activation and yawning in rat Behav Brain Res
2003;140(1-2):65-73
-Seki Y,
Sato-Suzuki I, et al Yawning/cortical
activation induced by microinjection of
histamine into the paraventricular nucleus of
the rat. Behav Brain Res.
2002;134(1-2):75-82.
-Sato-Suzuki I,
Kita I, Oguri M, Arita H Stereotyped yawning
responses induced by electrical and chemical
stimulation of paraventricular nucleus of the
rat Journal of Neurophysiology,
1998;80(5)2765-2775
Introduction : We have recently
reported that a stereotyped yawning response can
be evoked by electrical and chemical stimulation
of the paraventricular nucleus (PVN) in
anesthetized, spontaneously breathing rats
[12]. A unique aspect of the yawning
response is that a depressor response always
precedes the yawning behavior, characterized by
a single large inspiration with mouth opening.
This phenomenon is of particular interest in
terms of the relationship between attenuation of
cerebral circulation and occurrence of yawning.
It is clinically well known that patients
suffering from brain ischemia frequently yawn.
Another relevant example is the case of
orthostatic hypotension, namely a failure in
regulating cerebral circulation; yawning
frequently occurs in these subjects
[14]. These lines of evidence indicate
that brain hypoxia:ischemia would be one of the
factors causing yawning. Based on these
findings, we hypothesize that local hypoxia
within the PVN may induce yawning. The present
study has been designed to test this hypothesis.
[...]
4. 2. Response to cyanide : This
study provided a new important finding that the
stereotyped yawning response was activated by
local application of cyanide in the PVN. Since
cyanide has been used as a tool for producing
chemical hypoxia [5], the present
results can be explained by the notion that the
PVN is a specific area that is sensitive to
hypoxia. The responsive sites or the sites with
oxygen sensitivity were found in the mp of the
PVN, i.e. the yawning triggering structure
described above. We, therefore, hypothesize that
the stereotyped yawning response is triggered by
local hypoxia in the PVN. Regarding oxygen
sensing cells, peripheral chemoreceptors in the
carotid body have long been recognized
[16]. Recent studies nominated another
oxygen sensing cells in the central nervous
system (CNS). These are found in the rostral
ventrolateral medulla [2,8,15] or the
caudal part of the hypothalamus [6]. The
present study further nominated the PVN as a
similar hypoxia-sensing site within the CNS.
What is the functional role of the oxygen sensor
in the PVN? It has been established that hypoxia
in the ventrolateral medulla, caused by
brainstem ischemia elicits defense reactions
which are characterized by apnea and pressor
response. A distinct functional significance may
be applied to the oxygen sensor in the PVN.
Namely, hypoxia in the PVN, caused by higher
brain ischemia may induce a waking behavior,
which is characterized by yawning and ECoG
arousal.`
4. 3. Mechanism of hypoxia
sensitivity : Accumulating evidence suggests
a linkage among hypoxia: ischemia, L-glutamate
and NO in the mechanism of hypoxic:ischemic
neuronal excitotoxicity [1,9]. Choi
[3] summarized in his recent review that
hypoxia:ischemia leads to stimulation of
L-glutamate (NMDA) receptors, which enhance
calcium influx and further activate NOS in the
brain. In this case, excess NO formation finally
mediates the neurotoxicity. We consider that
analogous neuronal processes might take place
within the PVN where yawning was induced by
cyanide, NO and L-glutamate, as shown in this
study. This idea may be further supported by our
previous study [12] that (1) NOS
positive cells exist in the PVN and (2) yawning
responses were significantly reduced by PVN
treatment with an NOS inhibitor. We propose the
following hypothesis that hypoxia:ischemia in
the higher brain would activate NMDA receptor of
NOScontaining cells within the PVN. NO released
by activation of NOS would then cause the
yawning response.
4. 4. Diffusible NO as a paracrine agent
: In a stereotyped yawning response, the
yawning behaviour (a single large inspiration)
was induced with a time lag of 10 s. The delayed
respiratory response can not be explained by
synaptic transmission but it might be better
explained by the time process required for NO
diffusion within the PVN, namely NO diffusion
from the yawning-triggering structure in the mp
of the PVN to the neurons projecting to the
respiratory portion of the mp (the ventral
border of the mp). As mentioned above, the
neurons projecting to the brainstem
respiratory-related cells are situated in the
ventral border of the PVN. This area is located
apart from the mp where NOS-containing cells are
located. The delay in the respiratory response
might be attributable to the time needed for NO
diffusion from the NO generating cells to the
respiratory efferent cells. It is reasonable to
speculate that if the distance to the
respiratory efferent cells is shortened then the
time required for NO diffusion would be
diminished. This notion is supported by the
present data showing that the time lag is
shortened when advancing the electrode to the
ventral PVN where respiratory efferents are
located.
In conclusion, yawning was induced by
microinjections of L-glutamate and cyanide into
the mp of the PVN. The results suggest that an
oxygen sensor exists within the mp of the PVN
and that yawning may be an arousal behavior
caused by higher brain ischemia.
-Collins
GT, JM Witkin et al Dopamine agonist-induced
yawning in rats: a dopamine d3 receptor mediated
behavior. J Pharmacol Exp Ther
2005;314(1):310-319.
-Collins
GT, Newman AH,Woods JH et al.Yawning and
hypothermia in rats: effects of dopamine D3 and
D2 agonists and antagonists. Psychopharmacology
(Berl).
2007;193(2):159-170
-Collins
GT. et al. Food restriction alters
pramipexole-induced yawning, hypothermia, and
locomotor activity in rats: Evidence for
sensitization of dopamine D2 receptor-mediated
effects. JEPT 2008;325:691-697
-Collins
GT et al. Narrowing in on compulsions:
dopamine receptor functions Exp Clin
Psychopharmacol 2008,16(4):498-502
-Collins
GT et al. Pro-erectile Effects of Dopamine
D2-like Agonists are Mediated by the D3 Receptor
in Rats and Mice JPEP 2009;329(1):210-217
-Collins
GT, Truong YN, et al. Behavioral
sensitization to cocaine in rats: evidence for
temporal differences in dopamine D(3) and D (2)
receptor sensitivity. Psychopharmacology (Berl).
2011;215(4):609-620.
-Hipolide DC; Lobo
LL; De Medeiros R; Neumann B; Tufik S
Treatment with dexamethasone alters yawning
behavior induced by cholinergic but not
dopaminergic agonist. Physiol Behav
1999;65(4-5):829-832
-Hipolide
DC, Tufik S Paradoxical sleep deprivation in
female rats alters drug-induced behaviors
Physiol Behav. 1995;57(6):1139-1143
-Kita
I, Kubota N, Yanagita S, Motoki C
Intracerebroventricular administration of
corticotropin-releasing factor antagonist
attenuates arousal response accompanied by
yawning behavior in rats. Neurosci.Letter
2008;433(3):205-208
-Kita
I, Yoshida Y, Nishino S. An activation of
parvocellular oxytocinergic neurons in the
paraventricular nucleus in oxytocin-induced
yawning and penile erection. Neurosci Res.
2006;54(4):269-275
-Kita I,
Sato-Suzuki et al. Yawning responses induced
by local hypoxia in the paraventricular nucleus
of the rat.Beh Brain Res
2000;117(1-2):119-126
-Kubota
N, Amemiya S, Motoki C, Otsuka T, Nishijima T,
Kita I. Corticotropin-releasing factor
antagonist reduces activation of noradrenalin
and serotonin neurons in the locus coeruleus and
dorsal raphe in the arousal response accompanied
by yawning behavior in rats. Neurosci Res.
2012
-Moyaho A,
Valencia J Grooming and yawning trace
adjustment to unfamiliar environments in
laboratory Sprague-Dawley rats J Comp Psychol
2002;116(3):263-269
-Neumann BG,
Troncone LR, Braz S, Tufik S Modifications
on dopaminergic and cholinergic systems induced
by the water tank technique: analysis through
yawning behavior. Arch Int Pharmacodyn Ther
1990;308:32-38
-Sato-Suzuki I,
Kita I; Oguri M, Arita H Stereotyped yawning
responses induced by electrical and chemical
stimulation of paraventricular nucleus of the
rat Journal of Neurophysiology,
1998;80(5):2765-2775
-Seki Y, Y
Nakatani, et al Light induces cortical
activation and yawning in rat Behav Brain Res
2003;140(1-2):65-73
-Seki Y,
Sato-Suzuki I, et al Yawning/cortical
activation induced by microinjection of
histamine into the paraventricular nucleus of
the rat. Behav Brain Res.
2002;134(1-2):75-82.
-Tufik S et
al Effects of stress on drug induced yawning
Physiol Behav 1995;58(1):1881-1884
