Department of Neuroscience,
University of Cagliari, Cagliari,
Italy
Small doses of apomorphine and other
dopamine (DA) receptor agonists produce repeated
episodes of yawning in rats and in humans. This
behavioural response seems to be due to the
stimulation of DA receptors in the central
netvous system (CNS) being prevented by
centrally acting neurolepticsbut not by
domperidone, a DA receptor blocker which does
not cross the bloodbrain barrier.
It has been suggested that DA receptors
mediating yawning have to be identified with DA
autoreceptors. DA autoreceptors are a special
kind of DA receptors located on the dopaminergic
neuron itself, the stimulation of which results
in inhibition of dopaminergic firing and of DA
synthesis and release.
This hypothesis is mainly based on the
observation that the minute doses of DA receptor
agonists needed to produce yawning are within
the same range as those needed to stimulate DA
autoreceptors, while the higher doses, which
stimulate postsynaptic DA receptors as well,
produce locomotor hyperactivity and stereotypy
and suppress yawning. The presynaptic origin of
the yawning response to DA agonists is further
suggested by the fact that it is abolished by
bilateral 6-OH-dopamine (6-OH-DA)-induced
denervation of the striatum and olfactory
tubercles and by the fact that yawning is
elicited by DA agonists such as
3-(3-hydroxyphenyl)-N-n-propylpiperdine (3PPP)
and TL-99, which are considered to
preferentially, or selectively stimulate DA
autoreceptors.
On the basis of these observations it has
been proposed by various authors, including
ourselves that yawning is a behavioural
consequence of DA autoreceptor mediated
inhibition of DA-transmission. In addition,
since anticholinergic drugs antagonize
apomorphine-induced yawning, Yamada
and Furukawa (1980) have suggested that this
behaviour is mediated by cholinergic activation
secondary to the inhibition of DA
transmission.
However some data argue against this
hypothesis. For example, inhibition of DA
transmission obtained by other means e.g.
neuroleptic administration or-degeneration of DA
neurons is not associated with yawning.
Moreover, the selectivity of 3PPP and TL-99 for
DA autoreceptors has been questioned and their
stimulating property for postsynaptic DA
receptors has been demonstrated. In particular,
one of the two enantiomers of 3PPP, (+)-3PPP was
found to elicit yawning while the other,
(-)-3PPP, was found to be either inactive or
less active than the (+)-enantiomer. The two
enantiomeric forms differ in their action on
auto- and postsynaptic DA receptors. (-)-3PPP
activates DA autoreceptors but is an antagonist
at postsynaptic DA receptors, whereas ( +)-3PPP
is a DA agonist at both autoreceptors and at
postsynaptic DA receptors as weil. If yawning
reflected the inhibition of DA transmission,
(-)-3PPP, because of its pre- and postsynaptic
action, should have been more effective than the
( + ) enantiomer.
All these considerations prompted us to
reinvestigate the nature and the location of DA
receptors mediating yawning. The results suggest
that yawning is mediated by the stimulation of a
population of DA receptors having a high
affinity for DA agonists similar to that of DA
autoreceptors but located postsynaptically.
[...]
Discussion : We have confirmed that
(+)-3PPP induces yawning while its (-)enantiomer
is inactive.
Both enantiomers of 3PPP are considered to
act onagonists at DA autoreceptors but to have
diifferential effects postsynaptically. Namely
at high doses (-)-3PPP is an antagonist, while
(+)-3PPP is an agonist of postsynaptic DA
receptors.
If yawning reflected the inhibition of DA
transmission, (-)-3PPP, because of its pre- and
post synaptic action, it should have produced
the response more effectively than the ( + )
enantiomer. On the contrary only the (+)
enantiomer, acts as an agonist for postsynaptic
DA receptors was capable of inducing yawning.
Further support for the hypothesis that yawning
reflects activation of postsynaptic DA receptors
rather than inhibition of DA transmission is,
paradoxically offered by the results with
reserpine, a drug that inhibits DA transmission.
In fact, reserpine elicited yawning 24 h after
treatment but not at 6 and 12h when DA depletion
and impairment of DA transmission are known to
be maximal. Moreover, reserpine-induced yawning
was antagonized both by the centrally actingDA
receptor antagonist, (-)sulpiride, and by
the
inhibitor of tyrosine hydroxylase, a-MT,
suggestting that DA synthesis and release are
needed for the yawning response. An important
aspect of these results is that they are the
first evidence that yawning may be induced by
endogenously released DA.
It is likely that the newly synthetized DA,
released in the synaptic cleft, becomes
sufficient to induce yawning at 24 h after
treatment, partly because super-sensitivity has
developed at postsynaptic DAreceptors. This
possibility is supported by the finding that the
administration of a dose of ( + ) -3PPP
ineffective in control rats, was effective in
further increasing th number of yawns in
reserpine-treated animals. This finding is in
agreement with that of Yamaka Furukawa (1980),
showing that reserpine potentionates
apomorphine-induced yawning, and with that of
Arnt et al. (1983b) indicating that 3PPP shows
ahigh efficacy in stimulating supersensitive
post-synaptic DA-receptors.
In agreement with previous reports we found
that (+)-3ppP-induced yawning was antagonised by
haloperidol, a blocker of D1 and D2 receptors
and by (-)sulpiride, a selective D2 antagonist,
butnot by domperidone, a peripheral DA receptor
blocker. Moreover, as mentioned above, we found
that (-)sulpiride also blocked reserpine-induced
yawning.
Finally, unpublished results from our
Institute have shown that SCH 23390, a rather
selectiveD1 receptor blocker fails to prevent
apomorphine-induced yawning. These findings
suggest that, irrespective of their location, DA
receptors mediating yawning may be classified as
D2 receptors, according to the classification of
Kebabian and Calne (1979). However, with their
higher sensitivity to agonists, these receptors
differ markedly from D2 receptors subserving
motor stimulation and stereotypies.
As to the physiological meaning of yawning,
it should be recalled that this bebaviour, often
associated with stretching, is displayed when
sleep is pressing because of fatigue or boredom,
but sleep has to be postponed because it might
be dangerous or, as in civilised society,
impolite (socially dangerous). Probably
yawning and stretching are an elotutionary
vestige of a behaviour subserving arousal when
attention is decreasing in front of a
danger. This interpretation might explain why
this behaviour has peculiar traits in common
with behaviour (typically, in a cat, wide
opening the mouth, showing of teeth and claws,
back and tail and stretching of the legs).
Yawning might be considered to indicate a
low of degree arousal, mediated by the
activation of t he most sensitive population of
DA receptors. Further activation of DA
transmission might progress to full arousal,
exploratory behaviour, steretyped sniffing,
licking and gnawing. This hypothesis offers a
logical explanation for the fact that yawning
and stereotypy are mutually exclusive, namely
when the latter is elicited the former is
suppressed.
Accordingly, it is likely that DA agonists
fail to induce yawning in 6-OH-DA lesioned
animals, a condition in which presynaptic
terminals bearing DA autoreceptors are lost,
simply because they produce a higher degree of
arousal, due to the supersensitivity of
postsynaptic DA receptors. Whether the different
behaviours elicited by DA agonists reflect
different populations of receptors or the
recruitment of a larger number of the same kind
of receptors is not known.
Finally in addition to DA agonists, ACTH and
MSH-related peptides also elicit yawning and are
released in response to stress and subserve
camouflage purposes, respectively. Another
intriguing problem is whether DA receptors are
also involved in the yawning response to ACTH
and MSH peptides or, vice versa, whether the
release of such peptides mediates the yawning
induced by DA agonists.
-Lynch
MR Dissociation of autoreceptor activation
and behavioral consequences of low doses
apomorphine treatment Prog Neuro-Psychopharmacol
& Biol Psychiat 1991; 15; 689-698
-Morelli
M et al Antagonism of apomorphine-induced
yawning by SCH 23390: Evidence against the
autoreceptor hypothesis Psychopharmacology 1986;
89; 259-260
-Stahle
L Do autoreceptors mediate dopamine
agonist-induced yawning and suppression of
exploration ? a critical review.
Psychopharmacology 1992; 106; 1-13
-Stahle
L, Ungerstedt U Yawning and suppresssion of
exploration induced by dopamine agonists: no
relation to extracellular strital levels of
dopamine Pharmacol Biochem Behav1990; 35;
201-209
-Stahle
L, Ungerstedt U Assessment of dopamine
autoreceptor agonist properties of apomorphine,
(+)3ppp and (-)3ppp by recording of yawning
behaviour in rats Europ J Pharmacol 1984; 98;
307-310
