Yawning
produced by dopamine agonists in rhesus
monkeys
Robert A. Code and Andrew H. Tang
CNS Research, The Upiohn
Company, Kalamazoo, U.S.A
Introduction : Dopamine agonists,
such as apomorphine, produce yawning in rats and
humans. The pharmacology of this phenomenon in
rats has been extensively studied. The
dose-response relationship is biphasic, with the
optimal dose for yawning always below that to
elicit stereotypic behaviors and the order of
potency, among the agonists, correlates with
that of dopamine autoreceptor activation using
biochemical endpoints. There is, however, no
direct evidence relating the yawning response to
dopamine autoreceptor stimulation. The time
course of yawning after an injection of
apornorphine is also different from that of the
reduction of striatal extracellular dopamine
level as expected from dopamine autoreceptor
activation.
The role of the dopamine D1 receptor in the
yawning response to dopamine agonists in rats is
a matter of controversy. The D1-selective
partial agonist, SKF 38393, produces no yawning
when given alone. But, both antagonism and
potentiation by SKF 3839-3 on dopaminergic
yawning in rats have been reported. Likewise,
antagonism of dopamine rgic-induced yawning in
rats by SCH 23390, a selective D1 antagonist,
was found by some investigators, but not others
(Zarrindast. Mixed dopamine D1/D2 antagonists
(neuroleptics) are generally effective blockers
of dopaminergic-induced yawning in rats.
A limited study of dopaminergic- induced
yawning in human subjects indicates that it
occurs at sub-emetic doses. We are not aware of
any similar study in subhuman primates. This
study investigates doparninergic-induced yawning
in rhesus monkeys. [...]
Discussion : We have shown in this
study that rhesus monkeys responded to
dopamine agonists with increased yawning,
similar to that observed in rats and humans. In
contrast to rats, no yawning was observed in
monnkeys after physostigmine. The effective
doses for yawning were quite low when compared
to other behavioral esponses from dopaminergic
stimulation. For instance, we have studied the
discriminative stimulus effect of apomorphine in
monkets. In that study 0.01 and 0.03 mg/kg of
apornorphine or 1 mg/k-g of ( - )-3PPP produced
no effect on the rate of lever-press for food
pellets.
An absence of eyelid closure at the yawning
doses indicated no sign of drowsiness. We
previously used an identical procedure to
observe the sedative effect of benzodiazepines
by recording eyelid closure in monkeys. No
yawning was seen at doses of triazolani or
diazepam which produced prolonged eyelid
closure.
The dopaminergic-induced yawning in
monkeys, therefore, appears to be unrelated to
the sedative effects observed with these
compounds in humans.
( - )-3-PPP produced a significant increase
in instances of yawning in rhesus monkeys, but
not to the same frequency as apomorphine or
quinpirole. This compound has been reported to
produce a very low, statistically insignificant,
occurrence of yawning in rats. Since ( - )-3-PPP
produced yawning in human subjects at i.m. doses
of about 30 mg, the monkeys appear to be a
sensitive species, like humans, for this
response. The relatively low frequency of
response from ( - )-3-PPP, however, is
consistent with this compound being a dopamine
partial agonist.
It is surprising that in this study the
D2-selective antagonist, sulpiride, failed to
block the apomorphine induced yawning, since
studies in rats reported complete blockade. It
is possible that the 30-min pretreatment time
was too short for this compound to reach optimal
blood level. However, we did find in an earlier
study that the 10 mg/kg dose of sulpiride
blocked the discriminative cue effect of
apomorphine (0.1 mg/kg) with a similar
pretreatment protocol. It is possible that the
mechanism/site of the yawning response has a
greater D2 receptor reserve in monkeys than in
rats, which requires a greater antagonist
concentration for complete blockade. A higher
dose of sulpiride is expected to be effective,
although the poor solubility has kept us from
testing such doses in this study.
The effective antagonism of SCH 23390
confirms a permissive role of the D1 receptor in
the yawning response. This hypothesis is not
necessarily inconsistent with the fact that D1
agonist SKF 38393, had no effect when given
alone and had only a modest effect potentiating
quinrinole. If a certain threshold level of D1
activation is all that is needed, additional D1
stimulation may have no greater effect. Since
SKF 38393 is a partial agonist for D1 recpetor,
it may, in fact, behave as antagonist for that
receptor under certain circumstances. In
summary, the results in this study suggest that
dopaminergic induced yawning involves both D1
and D2 recpetors. The ralative importance of the
two receptors subtype depends on the species,
with the rhesus monkey perhaps being more
similar to humans than in rats.
Gessa GL
Stretchings and yawnings induced by
adrenocorticotrophic hormone
Nature 23/07/1966; n°5047;
p426-427
Gessa GL
Stretching and yawning movements after
intracerebral injection of ACTH
Revue Canadienne Bioliologie;
1967, 26, 3, 229-236
Kimura H,
Yamada K, Nagashima M, Matsumoto S, Ishii Y,
Yoshida S, Fujii K, Furukawa T Role of
adrenergic neuronal activity in the yawning
induced by tacrine and NIK-247 in rats.
Pharmacol Biochem Behav 1992
Dec;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 Apr; 53(4):1017-21
Laing J, Ogilvie R
EEG correlats of yawning during sleep onset
Sleep Research 1988; 17; p98
Molgilnicka
E REM sleep deprivation changes behavioral
response to catecholaminergic and serotoninergic
receptor activation in rats
Pharmacol Biochem Behav 1981;
15; 1; 149-151
Stahle
L Do autoreceptors mediate dopamine
agonist-induced yawning and suppression of
exploration ? a critical review.
Psychopharmacology 1992; 106;
1-13
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
Nov-Dec;308:32-8
Stahle
L Do autoreceptors mediate dopamine
agonist-induced yawning and suppression of
exploration ? a critical review.
Psychopharmacology 1992; 106;
1-13
Tufik
S Does REM sleep deprivation induce
subsensitivity of presynaptic dopamine or
postsynaptic acetylcholine receptors in the rat
brain? European Journal of
Pharrnacology 1987; 140; 215-219
Tufik S
Effects of stress on drug induced yawning
Physiology & behavior 1995;
vol 58; n 1; p 1881-18
