Interactions
of drugs acting on central dopamine receptors
and cholinoceptors on yawning responses in the
rat induced by apomorphine, bromocriptine or
physostigmine
Zarrindast MR, Poursoltan M
Department of pharmacology,
Medical faculty, Teheran, Iran
Introduction : Biochemical and
pharmacological evidence indicate that two
différent dopamine receptors, termed D1
and D2 mediate the dopamine functions in brain.
These two categories of dopamine receptors are
distinct molecular entities with
différent distributions. Both D1 and D2
dopamine receptors, which exist in striatum, can
stimulate and inhibit the striatal cyclic AMP
formation respectively.
Striatum contains the highest concentration
of acetylcholine in the brain . Available
evidence suggests that dopamine receptors have a
regulatory role on striatal acetylcholine. The
opposing effects of D1 and D2 receptors on
striatal cholinergic neurones have also been
shown.
Yawning can be induced in experimental
animals by the dopamine receptor agonists
apomorphine, norpropylnorapomorphine and
lisuride. It bas been proposed that stimulation
of dopamine autoreceptors, and therefore
inhibition of dopaminergic transmission in, the
brain, causes yawning. This behaviour appears to
be centrally mediated and due to septal and
striatal D2 receptor activation, although
results obtained by some workers (Morelli
et al., 1986) contradict the hypothesis that
apomorphine produces yawning by acting on
dopamine autoreceptors.
Some investigators have suggested that
central cholinergic mechanisms arc involved in
yawning behaviour. Drugs acting on both
cholinoceptors and dopamine receptors have been
used to investigate the influence of D1 and D2
receptors on yawning
behaviour.[...]
Discussion :
Apomorphine with D1 and D2 agonist
properties in small doses (0.1-0.6mgkg) induced
yawning in rats. This syndrome was decreased by
increasing the dose of the drug. Pretreatment of
animals with sulpiride a D2 dopamine receptor
antagonist reduced the ability of apomorphine to
induce yawning. Our present results are in
agreement with previous observations of others
that apomorphine influences yawning biphasically
in rats.
Such a biphasic effect bas been attributed
to the successive involvement of D1 and D2
dopamine receptors; the lower doses of
apomorphine stimulate D2 receptors which
decrease tonic dopaminergic transmission with a
consequent . induction of yawning, while the
higher doses activate D1 receptors and cause the
abolition of yawning .
Pretreatment of animals with low doses of
the specific D1 receptor antagonist SCH 23390
increased the ability of apomorphine to induce
yawning. When dopamine activation of D1 sites is
impaired by SCH 23390, apomorphine activates
only D2 sites and therefore more frequent
yawning can be observed. Administration of SCH
23390 alone also induced a low degree of yawning
in rats, which may indicate inhibition of D1 and
unmasking of D2 agonist properties of endogenous
brain dopamine.
These effects of SCH 23390 confirm the
hypothesis that D1 receptor stimulation can
decrease the yawning episodes and contradict the
suggestion of some investigators that
autoreceptors are not involved, e.g. Morelli et
al. (1986), who found SCH 23390 was able to
antagonize yawning induced by apomorphine. For
further evaluation of the opposite influences of
D1 and D2 dopamine receptor activation on
yawning, some studies were carried out with D1
and D2 agonists. Bromocriptine, a D2-agonist bas
been reported to induce yawning through the
stimulation of dopamine D2-receptors in the rat
striatum and septum. In the present study,
bromocriptine caused yawning dosedependently.
The effect was decreased in animals pretreated
with sulpiride. SCH 23390 did not alter the
frequency of yawns induced by bromocriptine.
These findings support the view that D2-receptor
stimulation may cause yawning.
SKF 38393 which does not induce yawning is a
D1 receptor agonist devoid of D2 receptor
stimulation properties . This drug decreased
yawning induced by both apomorphine and
bromocriptine. These data may suggest that D1
receptor stimulation exerts opposite influence
on yawning. On the other band, the ability of
SKF 38393 to stimulate dopamine-sensitive
adenylate cyclase has been shown. It has been
suggested that activation of D1 receptors is
associated with stimulation of adenylate cyclase
while D2 receptor activation may cause
inhibition of cyclic AMP formation in striatum.
Theophylline which increases cycflc AMP levels,
inhibits yawning induced by apomorphine,
bromocriptine or physostigmine. Whether the
opposite effects of D1 and D2 receptors on
yawning behaviour are due to an increase or
decrease of cyclic AMP levels is not clear and
remains to be elucidated.
Previous investigations have pointed out the
involvement of the cholinergic system in the
induction of yawning syndrome. The present data
show that neostigmine, which is not able to
enter the CNS, does not induce yawning behaviour
and that atropine can antagonize episodes of
yawning in rats treated with apomorphine,
bromocriptine or physostiginine. This points to
a possible central muscarinic component in the
yawning induced by these drugs. These results
are supported by the suggestion of Yamada &
Furukawa (1980) who showed that apomorphine
induced yawning through indirect activation of
cholinergic neurones. Our results show that
bromocriptine potentiates and SK&F 38393
decreases the frequency of yawns induced by
physostigmine. li is therefore postulated that
yawning may be induced through a cholinergic
activation mechanism, while D1 and D2 receptor
stimulation may have opposite effects on this
behaviour.
-Zarrindast
MR, Poursoltan M Interactions of drugs
acting on central dopamine receptors and
cholinoceptors on yawning responses in the rat
induced by apomorphine, bromocriptine or
physostigmine Br J Pharmacol 1989; 96; 4;
843-848
-Zarrindast,
MR, Jamshidzadeh A Inhibitory effect of
morphine on yawning induced by cholinoceptor and
dopamine D2 receptor activation in rats Br J
Pharmacol 1992; 105; 3; 675-8
-Zarrindast
MR, Toloui V, Hashemi B Effects of GABAergic
drugs on physostigmine-induced yawning in rats;
Psychopharmacology (Berl) 1995; 122; ;
:297-300
