Cooper SJ, Dourish CT in Neurobiology of
Stereotyped Behaviour
Studies on yawning and associated phenomena
date back on the observation of Ferrari (1958)
that intracisternal administration of the
peptide hormones adrenocorticotrophic ormone
(ACTH) and melanocyte stimulating hormone a-MSH
produce a stretching-yawning crisis in dogs,
cats, rabbits, and rats. Recent pharmacological
research has focussed on a syndrome elicited by
various compounds in rats which consists of
yawning, often accompanied by stretching and
sexuaI arousal.
We are interested in the proposal that
dopamine neurones are involved in the mediation
of' yawning and associated responses. Thus, low
doses of the dopamine agonists piribedil,
apomorphine, nomifensine, lisuride,
bromocriptine, lergotrile, and L-dopa,
administered systemically, produce yawning,
stretching, and penile grooming in rats. At
higher doses of the dopamine agonists the
yawning disappears and recurrent sniffing is
observed. This biphasic effect of dopamine
agonists on yawning can be differentially
modified by neuroleptic pretreatment. Low doses
of neuroleptics antagonise yawning produced by
0.1 mg/kg apomorphine, whereas increasing doses
of haloperidol, chlorpromazine, mezilamine,
metocloprarnide, and thioridazine make yawning
reappear in rats injected with 0.6 mg/kg
apomorphine.
There appears to be a relationship between
dopamine agonist-induced and peptide-induced
yawning. Thus, inhibition of protein synthesis
by administration of cycloheximide prevents
apomorphine-induced yawning and penile grooming.
Similarly, the lack of pituitary peptides caused
by hypophysectomy abolishes yawning and penile
erection induced by apomorphine.
Additional evidence suggests that cholinergic
mechanisms may be involved in the expression of
yawning. UrbaHolmgren
et al. (1977) have reported that systemic
injection of the muscarinic agonists pilocarpine
and physostigmine elicits yawning and stretching
in infant and adult rats. The elicited responses
can be inhibited by pretreatment with the
muscarinic antagonist scopolamine. It has been
proposed that dopaminergic and cholinergic
influences may interact to produce yawning
behaviour (Holmgren
and Urba-Holmgren 1980). Thus, in
cross-blocking studies. it has been demonstrated
that scopolamine abolishes apomorphine-induced
yawning whereas the neuroleptics spiroperidol
and fluphenazine potentiate physostigmineinduced
yawning.
There has been no attempt made, to date, to
investigate the neural substrates of yawning and
associated responses by intracranial application
of drugs. The aims of the present study were
threefold: first, to describe the effects of
microinjection of dopamine agonists into a
dopamine-rich terminal region of the forebrain
on yawning and associated phenomena and on
locomotor activity; second, to compare these
effects with those elicited by systemic dopamine
agonist administration; and third, to attempt to
reverse the elicited behavioural effects by
systemic injection of haloperidol and
scopolamine. [...]
Discussion
Local bilateral application of piribedil and
apomorphine to the striatum of male rats
produced yawning which was both preceded and
succeeded by chewing mouth movements. On some
occasions, yawning was accompanied by sexual
arousal (penile grooming, erection and
ejaculation) and forelimb stretching. Both
piribedil and apomorphine are direct dopamine
receptor agonists, and it therefore seems likely
that yawning was produced by dopamine receptor
stimulation.
The yawning syndrome produced by central
application of piribedil and apomorphine was
compared with that elicited by systemic
administration of small doses of the same drugs.
Both routes of injection produced doserelated
yawning and chewing with intermittent penile
grooming and stretching. These results confirm
that yawnmg is produced by systemic
administration of low doses of dopamine agonists
(Mogilnicka and
Klimek 1977; Protais
et al. 1983). In the present study, peak
effects on yawning were produced by SC doses of
0.1 mg/kg apomorphine and 2.5 mg/kg piribedil,
which is consistent with previous studies on the
dose-response effects of dopamine agonists on
yawning. In addition, our results indicate that
the response involves brain dopamine receptors
since yawning is produced by intracerebral
application of piribedil and apomorphine.
Generally, the syndrome induced by intrastriatal
piribedil had a shorter latency to onset and a
longer duration than that produced by systemic
injection of the drug, which suggests that the
response is centrally mediated. Indeed, it seems
implausible that the response could be due to
stimulation of peripheral dopamine receptors,
since it has recently been reported that the
peripheral dopamine antagonist domperidone does
not inhibit yawning induced by systemic
apomorphine. In contrast, central dopamine
receptor blockade by haloperidol abolishes
yawning induced by systemic or intracerebral
dopamine agonists.
Interestingly, only one previous study has
noted that yawning elicited by SC piribedil is
associated with increased chewing mouth
movements. The present data convincingly
demonstrate that there is a sigificant
correlation between yawning and chewmg produced
by both systemic and intracranial administration
of dopamine agonists. Therefore, we believe that
chewing is an integral part of the yawning
response in rats. Furthermore, haloperidol
pretreatment or bilateral 6-hydroxydopamine
(6-OHDA) lesions of the striatum abolish yawning
and chewing induced by dopamine agonists.
Yawning induced by systemic dopamine agonist
injection is thought to be the consequence of an
inhibition of dopaminergic transmission mediated
by the stimulation of dopamine autoreceptors in
the brain. Thus, doses of dopamine agonists
which induce yawning after systemic injection
are within the range thought to activate
autoreceptors, but lower than doses required to
produce signs of postsynaptic dopamine receptor
stimulation such as hyperactivity and
stereotypy. Furthermore, two recently
synthesized drugs, TL-99 and (+) 3-PPP which
have been claimed to have a selective agonistic
action at dopamine autoreceptors induce yawning
in rats. In addition, 6-OHDA lesions of the
striatum abolish yawning induced by systemic
apomorphine injection, indicating that the
dopamine receptors involved in the production of
the response are probably located
pre-synaptically.
Considerable interest is now developing in
dopamine agonist-induced yawning and the
suggestion has been made that it can be used as
a behavioural index of central dopamine
autoreceptor stimulation. This
suggestion is fully consistent with the
evidence available from systemic drug
administration studies and it is difficult to
conceive of an alternative explanation of these
data. The present data show that an identical
yawning syndrome can be elicited by direct
injection of dopamine agonists into the
striatum. The most parsimonious explanation of
these data is that yawning induced by central
dopamine agonist injection is also autoreceptor
mediated, particularly in view of the
observation that a very low dose of haloperidol
abolished yawning elicited by intrastriatal
piribedil. However, this interpretation is
speculative and the possibility of postsynaptic
dopamine receptor mediation of the syndrome
elicited by intracerebral application of
piribedil and apomorphine cannot be ruled out
because of the relatively large drug doses which
were applied to the striatum to produce yawning.
Further studies, incorporating central
application of the putative autoreceptor
agonists 3-PPP and TU 99 and the putative
autoreceptor antagonist sulpiride are necessary
to directly test the dopamine autoreceptor
hypothesis. In addition, in vivo studies of
striatal dopamine metabolism after dopamine
agonist treatment using brain dialysis may prove
extremely valuable in the investigation of
dopaminergic involvement in yawning.
The muscarinic antagonist scopolamine
inhibited yawning elicited by intrastriatal
piribedil and therefore it appears that there is
some cholinergic involvement in yawning. It has
been claimed that yawning may be a consequence
of the release of cholinergic neurones from
inhibition by dopaminergic neurones. The present
data are compatible with such a proposal.
However, this hypothesis was not tested directly
and further studies of the effects of central
application of cholinergic agonists and
antagonists (e.g., carbachol, scopolamine)
should provide important information on the
neural substrates of yawning.
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Witkin et al Dopamine agonist-induced
yawning in rats: a dopamine d3 receptor mediated
behavior J Pharmacol Exp Ther 2005
