Involvement
of septal and striatal dopamine D2 receptors in
yawning behavior in rats
Katsushi Yamada, Tatsuo Furukawa
Department of pharmacology,
School of medecine, Fukuoka
University
Previous observations show that apomorphine
exerts biphasic effects on behavior, ie.,
yawning and hypomotility at low doses, and
stereotypy and hypermotility at higher doses.
Low doses of apomorphine preferentially activate
presynaptic dopamine autoreceptors, which
results in an inhibition of dopamine release and
decrease of its synthesis, while higher doses
stimulate postsynaptic receptors. Accordingly,
we have proposed that the yawning elicited by
low doses of dopamine receptor agonists is due
to an activation of presynaptic dopamine
autoreceptors, whereas stereotypy induced by
higher doses may be attributed to a stimulation
of postsynaptic dopamine receptors
In addition, previous investigations have
pointed out the involvement of the cholinergic
systein in yawning behavior. Physostigmine, an
anticholinesterase agent, and pilocarpine, a
muscarinic receptor agonist, induce yawning
behavior which is abolished by scopolamine, a
muscarinic receptor antagonist, but not by
mecamylamine, a nicotinic receptor antagonist.
Scopolamine also completely inhibited the
yawning induced by small doses of
apomorphine.
Assuming that small doses of apomorphine
produce an inhibition of dopamine release from
presynaptic sites which results in an activation
of cholinergic neurons, apomorphine-induced
yawning can result from secondary activation of
cholinergic neurons, and dopaminergic inhibition
and cholinergic activation are proposed to be
concomitantly involved in yawning behavior.
In vitro experiments indicate the presence
of at least two subtypes of dopamine receptors,
D-1 and D-2, according to the nomenclature
proposed by Kebabian and Calne (1979). The D-1
receptor is associated with adenylate cyclase
and can be labelled with the neuroleptic
thioxanthene ligands piflutixol or flupentixol,
whereas D-2 receptors are independent of
adenylate cyclase and can be labelled with the
butyrophenone ligands spiroperidol or
'haloperidol. Using this classification, it has
been shown that the standard dopamine agonist
apomorphine has effects on both types of
dopamine receptors in vitro, but the functional
consequences in vivo of this mixed effect are
unclear.
In the present study, we attempted to
evaluate the relative importance of D-1 and D-2
receptors in the effects of dopamine receptor
agonists including apomorphine in eliciting
yawning behavior. Furthermore, we investigate
whether or not intracerebral injections of
dopamine receptor agonists in the brain areas in
which a dopaminergiccholinergic neuron link has
been reported, could induce yawning.
[...]
Discussion The present study
confirmed our previous finding that both
apomorphine and piribedil induce yawning at very
low doses for which the dose-response curves
showed a bellshaped form and stereotypy at
higher doses
Recently, it was found that haloperidol
reduced the yawning induced by apomorphine at
doses much smaller than those needed for
inhibition of stercotypy or hyperactivity. These
support our previous proposal that the yawning
induced by dopamine receptor agonists may be
mediated by stimulation of presynaptic dopamine
receptors.
This conclusion is further supported by
prescrit results and the other observations
showing that the compounds 3-PPP and TL-99,
which have been reported to stimulate dopamine
autoreceptors induced yawning. Only the lower
dose range of 3-PPP was tested in the prescrit
study but our findings agree with those of
Hjorth et al. (1981), concerning the stimulating
properties of presynaptic dopamine receptors of
the drug. These agents at doses used did not
induce stereotypy or hyperactivity, in contrast
to apomorphine and piribedil, which indicates
that 3-PPP and TL-99 do not stimulate
postsynaptic dopamine receptors, responsible for
this behavior. Consequently, yawning may not be
mediated by the saine postsynaptic dopamine
receptors.
It has been reported that SK & F 38393
is a dopamine agonist with a novel profile of
action in that it does not affect dopamine
turnover in the brain or cause stereotypy or
emesis but does stimulate dopamine-sensitive
adenylate cyclase in vitro and causes
contralateral rotation in rats with unilateral
6-hydroxydopamine lesions of the nigrostriatal
pathway. In addition, SK & F 38393 does not
inhibit dopamine release in brain slices. Thus,
SK & F 38393 is apparently devoid of
autoreceptor stimulating actions and is a
putative dopamine D-1 receptor agonist
In the present study, SK & F 38393
failed to elicit yawning behavior, as shown by
Gower et al. (1984). On the other hand, a
distribution of dopamine D-2 receptors at both
presynaptic and post synaptic sites of dopamine
neurons in the striatum of rats has been
reported. Very recently, Plantje et al. (1985)
also reported that stimulation of dopamine D-2
receptors inhibited the electricallyevoked
release of [H]-dopamine in rat
neostriatum and entorhinal cortex.
Bromocriptine, which has been reported to
inhibit the prolactin secretion from the
anterior pituitary via a stimulation of dopamine
D-2 receptors, induced decrease of motor
activity and DOPAC levels and reversed the
-methyltyrosine-induced decline of dopamine in
mice, suggesting that bromocriptine can
stimulate presynaptic dopamine receptors.
In the present study, yawning was also
evoked by bromocriptine. Sulpiride, considered
to selectively block presynaptic dopamine D-2
receptors at low doses inhibited the yawning
responses induced by apomorphine, piribedil,
3-PPP or bromocriptine, giving evidence for the
involvement of dopamine D-2 receptors in yawning
behavior.
On the other hand, as mentioned above,
physostigmine and pilocarpine elicit yawning and
then the yawning induced by dopamine receptor
agonists is antagonized by scopolamine but not
by mecamylamine, suggesting that a
cholinergic-dopaminergie linked system is
involved in yawning induction
Various lines of evidence suggest that the
nigro-striatal dopaminergic neurons inhibit the
striatal cholinergic neurons, while a
dopaminergic-cholinergic link is lacking in the
mesolimbic area such as the nucleus accumbens
and olfactory tubercle. There is also
accumulated evidence that the mesoseptal
dopaminergic neurons seem to play an inhibitory
role in the control of the septal-hippocampal
cholinergic neurons
The septal-hippocampal cholinergic neurons
have been proposed to be necessary to elicit a
specific stretching-yawning syndrome following
a-MSH, since intraventricular injection of a-MSH
increased the acetylcholine turnover rate in the
hippocampus of rats and did not alter the
dopaminergic neuron activity in the
dopaminecontaining nerve terrninals such as
septum, striaturn and nucleus accumbens.
Therefore, in the present experiment,
dopamine receptor agonists such as apomorphine,
piribedil and 3-PPP were injected into the
striatum and septum, yawning responses being
markedly evoked after the intracerebral
injections. The local application of apomorphine
into the nucleus accumbens of rats has been
reported to inhibit the hyperactivity induced by
intra-accumbens amphetamine.
Injection of apomorphine or 3-PPP into the
nucleus accumbens also reduced spontaneous
locomotor activity, and the mechanisms of action
of dopamine receptor agonists appear to be a
selective activation of presynaptic dopamine
receptors. Therefore, the yawning elicited by
the striatal or septal application of
apomorphine, piribedil or 3-PPP may be mediated
via a stimulation of presynaptic dopamine
receptors which results in decrease of dopamine
release.
The results suggest that the yawning induced
by low doses of apomorphine, piribedil, 3-PPP,
TL-99 or bromocriptine is related to the
stimulation of dopamine D-2 receptors in the rat
striatum and septum.
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