Yawning is under the control of several
neurotransmitters and neuropeptides. While
its neuropharmacology is complex and not yet
fully understood, it could have useful
applications.
DOPAMINE
In rats, dopamine receptor agonists--such
as apomorphine and bromocriptine--are able to
induce yawning, often together with penile
erection in rats. This response is induced by
selective D2 receptor agonists but not by
type D1. Extremely low doses of a dopamine
receptor agonist (quinpirole), that has 100
fold greater affinity for D3 than D2
receptors, induced yawning behaviour in
absence of other effects. Therefore the
authors have suggested that yawning may be a
D3 mediated process. Logically, dopamine
receptor antagonists like classical
neuroleptics block these responses. The
implication of dopamine presynaptic
autoreceptor agonists has been amply
discussed. For instance, Morelli demonstrated
that a dopamine receptor agonist with high D1
receptor affinity was able to significantly
reduce yawning evoked by apomorphine. Since
dopamine autoreceptors are type D2, a D1
receptor antagonist is not expected to
interact with them. Furthermore, Stalhe et
al. demonstrated that apomorphine can induce
hypomotility and yawning even when
amphetamine elevated the extracellular level
of dopamine.They showed, moreover, that
apomorphine-induced yawning does not follow
autoreceptor-induced reductions in
neurotransmitter metabolism in the striatum .
Lynch et al. obtained the same result in the
mesolimbic region . These results suggest
that D2 post synaptic receptors are involved
in induced yawning, but that presynaptic
autoreceptors, or D1 receptors are not. Proof
of a possible involvement of D3 receptors
must await further investigation. The site of
action of dopamine receptor agonists is the
paraventricular nucleus of the hypothalamus.
This hypothalamus nucleus contains
dopaminergic nerve endings;
immunocytochemical studies have showed that
dopaminergic synapses impinge on the cell
bodies of oxytocinergic neurones in this
nucleus. Moreover, oxytocin receptor
antagonists prevent apomorphine induced
yawning. These results suggest that dopamine
receptor agonists induce yawning by
activating oxytocinergic neurones. In healthy
humans, we demonstrated that low doses of
apomorphine also induce
yawning, and various pathologies mainly
related to dopaminergic system dysfunction
show variations of spontaneous yawning
frequency. Typical neuroleptics that have a
dopamine receptor antagonist action, such as
haloperidol, prevent apomorphine induced
yawning. Concerning atypical neuroleptics,
while certain authors have concluded that
they do not prevent apomorphine-induced
yawning, others have ascertained the
contrary. In a double-blind placebo
controlled study conducted in 1995, we
investigated the effect of a pretreatment
with amisulpiride (a D2-D3 blocker) on
apomorphine induced yawning in healthy
volunteers. Amisulpiride (300mg), which has
been shown to improve negative symptoms in
schizophrenic patients with predominant
negative signs, and was therefore suggested
to block dopamine presynaptic D2 receptors
did not block apomorphine induced yawning.
Several explanations might be proposed, among
them are the following : yawning is not
related to either D2 presynaptic receptor
stimulation, or D3 receptor stimulation.
OXYTOCIN
Oxytocin, a neuropeptid of the
neurohypophysis, is mainly implicated in
parturition and lactation. In fact, it is
also present in the hypothalamus and is able
to induce penile induction and yawning when
injected in the central nervous system and
especially in the paraventricular nucleus of
the hypothalamus, in rats. This
oxytocin-induced yawning is abolished by both
atropine and scopolamine, which are
antimuscarinic drugs, but not by dopamine D2
receptor antagonists such as neuroleptics. We
can thus speculate that dopamine receptor
agonists induce yawning by releasing
oxytocin, which subsequently activates
cholinergic transmission in another brain
area. Experimental studies suggest that, in
the paraventricular nucleus of the
hypothalamus, oxytocin induces yawning by
activating its own transmission. One of the
oxytocinergic pathways, activated by oxytocin
itself, which projects to extrahypothalamic
areas and whose activation induces yawning,
might be a hypothalamo-hippocampus pathway.
However, oxytocin also projects endings to
the pons and to the medulla oblongata.
NITRIC OXIDE
Nitric Oxide (NO) is produced from
arginine by Nitric Oxide Synthetase (NOS), a
calciumÐcalmodulin dependent enzyme. Many
compounds that induce yawning such as
dopamine receptor agonist, NMDA, oxytocin
increase NOS activity and thus NO production.
Yawning induced by dopamine receptor
agonists, NMDA, oxytocin is prevented by
calcium channel blockade (w-conotoxin), a NOS
inhibitor and oxytocin receptor antagonist. A
NO-releasing compound injected in the medial
part of the paraventricular nucleus of the
hypothalamus (PVN) induces the stereotypical
yawning response. The paraventricular nucleus
of the hypothalamus is one of the brain areas
richest in NOS activity. In the PVN,
parvocellular and magnocellular neurons
contain NOS. Parvocellular cells in the PVN
send descending axons to the lower brainstem
. These results suggest that dopamine D2
receptor agonists, NMDA, Oxytocin induce
yawning by increasing intracellular calcium,
which in turn activates NO synthesis, in the
parvocellular cells of the paraventricular
nucleus of the hypothalamus. These
parvocellular neurons would project to
respiratory, cardiovascular, motor and
arousal systems in the lower brain stem.
yawning induced by dopamine receptor
agonist, ACTH, MSH, oxytocin. These results
suggest that yawning induced by these four
drugs is mediated by cholinergic activation.
In fact, M1 type muscarinic receptors are
involved in this reaction. Cholinergic
transmission has therefore been suggested
being the final step of the neuronal pathway
involved in yawning. The site of the brain
where acetylcholine receptor agonists induce
yawning may well be the hippocampus; indeed
mesoseptal dopaminergic neurons play a role
in the control of the hippocampal cholinergic
neurons. Moreover MSH, when inducing yawning,
increases acethylcholin turnover rate in the
hippocampus of the rat. However, in humans,
Skorzewska did not find a significant
correlation between yawning and a muscarinic
receptor antagonist injection.
ACTH and MSH
The central administration of
adrenocorticotropin hormone (ACTH) or
melanocyte stimulating hormone
(MSH) induced recurrent episodes of
yawning and stretching in different animal
species. Beta adrenoceptor agonist
(salbutamol) and muscarinic M1 receptor
antagonist inhibit yawning produced by these
wo neuropeptides, but not by dopaminergic
activation or inhibition. Hence, ACTH and MSH
produce yawning via activation of a
cholinergic mechanism. Recent studies have
led to the cloning of the ACTH- MSH receptor
genes. They are present in several brain
areas including the hypothalamus, the
midbrain and the brainstem. One of these
sites is probably involved in the
yawning-stretching syndrome. ACTH and ?MSH
induced yawning and stretching (when injected
into the hypothalamus periventricular region
of the third ventricule) is prevented by a
selective melanocortine 4 (MC4) receptor
antagonist. A MC1 receptor selective agonist
was able to induce yawning and stretching.
ACTH-MSH induced yawning is prevented by
calcium channel blockade and by nitric oxide
synthetase inhibitor, suggesting that these
neuropeptids probably exert their effect via
nitric oxide activation. In humans, Melaton
II, a non selective melanocortin receptor
agonist, induces erections, increase of
sexual desire, nausea and stretching-yawning
behaviour.
SEROTONINE
Post-synaptic serotoninergic 5HT1a
receptor agonists have an inhibitory effect
on yawning induced by dopamine receptor
agonists. Inhibitory serotoninergic receptors
seem to be located on the terminal
dopaminergic neuron on the striatum.
Depletion of serotonin potentiates dopamine
receptor agonist induced yawning.
Serotoninergic 5HT1c receptor agonist, mCPP
and TFMPP induced yawning in both the rat and
humans. These yawns are inhibited by NOS
inhibitor but not by oxytocin receptor
antagonist. As such, nitric oxide seems to be
implied in this induced yawning.
OPIOÏD PEPTID
Morphine, an opioid receptor agonist
inhibits dopamine receptor agonists
(bromocriptine), ACTH and cholinergic drugs
(physostigmine, pilocarpine) induced-yawning
in rats. Naloxone reverses this effect. The
paraventricular nucleus of the hypothalamus
contains endogenous opioid peptides and mu
subtype opoïd receptors. Moreover, a
decrease of nitric oxide was measured, during
in-vivo microdialyse, concomitant to the
inhibition of yawning behaviour. This
decrease could result from a decrease of the
calcium influx in the oxytocinergic cells
which in turn would induce a decrease in
nitric oxide synthetase. In humans, yawning
is a frequent withdrawal sign in heroin
addicts.
SEXUAL HORMONES
In rats, spontaneous yawning is more
frequent in males than in females. Dopamine
receptor agonists and oxytocin induced
yawning is abolished by castration. It can be
restored by substitution therapy with
estradiol alone or with estradiol and
testosterone. In intact male rats, estrogen
inhibits dopamine receptor agonist induced
yawning, and testosterone has no effect.
Sexual hormones modulate both spontaneous and
induced yawning behaviour. Luteinizing
hormone releasing hormone (LHRH) has been
reported to antagonize induced yawning.
However, in humans yawning frequency does not
differ between men and women.
Adrenalin and noradrenalin
Yawning induced by dopaminergic and
cholinergic agents, ACTH, MSH and oxytocin,
is facilitated by beta adrenoreceptor
blockade (propanolol, pindolol). However,
pindolol has also 5HT1a blocking properties
that might explain yawning facilitation. In
contrast, yawning is inhibited by alpha2
pre-synaptic receptor blockade, which
increases noradrenaline release. The central
adrenergic may thus take part in the
regulation of the yawning.
N.methyl-d-aspartic acid
(NMDA)
NMDA, an excitatory amino acid agonist of
NMDA receptor subtype, induces yawning NMDA
induces this behavioural response by
increasing intracellular calcium
concentration in the oxytocinergic neurons,
thus activating nitric oxide synthetase,
nitric oxide synthesis and hence
oxytocinergic transmission.
Gama amino butyric acid
(gaba)
GABA-B receptor agonists (baclofen
3mg/kg) inhibit the yawning response by
modulating acetylcholine transmission. GABA-A
receptor activation also inhibits yawning.
Neurotensin Neurotensine has been
reported to antagonize drugs that induce
yawning.
In conclusion the literature review
shows that the pharmacological mechanisms
underlying yawning are complex and that many
systems and neuro-mediators are involved.
Nonetheless, knowledge of the pharmacology of
yawning could be useful for the experimental
pharmacology of new drugs. First, it enables the
study of the actions of psychotropic drugs on
the different brain systems. For instance, a
drug that produces yawning but antagonizes
dopamine receptor agonist induced yawning may be
a dopamine receptor partial agonist. It is also
possible to functionally discriminate between
central and peripheral beta adrenoreceptor
antagonists. If apomorphine-induced yawning is
increased by a beta adrenoceptor antagonist, it
means that it has a central action. As clinical
evaluation of new psychoactive drugs is
difficult and animal screening is difficult to
transpose to humans, knowledge of their central
pharmacological action could be useful.
Moreover, hypotheses about the biological basis
of severe psychiatric illness have been
stimulated by knowledge of the mechanism of
action of psychotropic agents. Lastly, the
neuro-pharmacology of yawning provides
information about the physiology of yawning and
hence the physiopathology of diseases associated
with abnormal yawning behavior.
