The
yawning elicited by alpha-melanocyte-stimulating
hormone involves
serotonergic-dopaminergic-cholinergic neuron
link in rats
Katsushi Yamada and Tatsuo Furukawa
Department of Pharmacology,
School of Medicine, Fukuoka University, Fukuoka,
Japan
Introduction : Frequent yawning has
been observed as a symptom in a patient with
adrenoleucodystrophy accompanied by high blood
adreno-corticotrophic hormone (ACTH) levels, and
as a characteristic sign of morphine abstinence
in man. Associated with these clinical
observations have been the proposal that yawning
can be elicited by administrations of certain
agents to animals.
Intracerebral injection of ACTH,
alpa-melanocytestimulating hormone (a-MSH) or
beta-lipotrophic hormone produced a specific
stretching-yawning syndrome, and cholinergic
agonists also induced yawning in infant rats
(Urba-Holmgren
et al. 1977). We recently obtained the fact
that intraperitoneal injection of apomorphine at
low doses which inhibit dopamine release from
presynaptic sites induced yawning in adult rats
(Yamada and
Furukawa 1980a). Although it is thus
suggested that cholinergic and dopaminergic
functions seem to participate in yawning
behavior, neuronal mechanisms involved in
yawning still remain to be elucidated.
In the present study, we found that a-MSH
produced not only stretching-yawning syndrome
but also 'Wet-Dog' body shaking, and
investigated the neuronal mechanisms involved in
the yawning as well as body shaking
behavior.
Discussion : Piribedil, a direct
dopamine receptor agonist, induced yawning
without producing typical symptoms of behavioral
excitation at low doses, but brought about
stereotypy at higher doses. This yawning was
blocked by a long-acting neuroleptic,
fluphenazine, which blocks presynaptic receptors
as well as postsynaptic dopamine receptors.
These results are all consistent with our
previous observation that apomorphine exerts
biphasic effects on behavior, i. e., 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 consequent decrease of its
synthesis, while higher doses stimulate
postsynaptic receptors. Accordingly, as our
previous proposal with apomorphine, the yawning
elicited by low doses of peribedil seems to be
due to an activation of presynaptic dopamine
autoreceptors, whereas stereotypy induced by
higher doses may be attributed to a stimulation
of postsynaptic dopamine receptors.
The septal-hippocampal cholinergic pathway
has well been delined by histochemical,
biochemical and electrophysiological techniques.
Specific destruction of the doparninergic
neurons projecting to the septum by injection of
6-hydroxydopamine into the all mesencephalic
cell group and blockade of dopamine receptors by
intraseptal haloperidol resulted in an increase
in the turnover rate of acetylcholine in the
hippocampus. On the contrary, systemic injection
of apomorphine caused a dose-dependent decrease
in the acetylcholine turnover rate in the
hippocampus. Thus, the dopaminergic neurons seem
to play an inhibitory role in the control of the
septal-hippocampal cholinergie neurons.
Recently, Wood et al. (1979) have proposed that
the septal-hippocampal cholinergic neurons are
necessary to elicit a specific
stretching-yawning syndrome following a-MSH or
ACTH since intraventrieular injection of a-MSH
or ACTH increases the acetylcholine turnover
rate in the hippocampus of rats.
In the present study, physostigmine, and
anticholinesterase agent, and pilocarpine, a
cholinergic agonist predominantly acting upon
muscarinic receptors, similarly elicited yawning
as previous observation.
Moreover, the piribedil-induced yawning was
inhibited by scopolamine, which blocks
muscarinic cholinergic receptors. On the basis
of these experimental rindings, it is very
likely that an activation of cholinergic neurons
resulting from an inhibition of dopamine release
from presynaptic sites in the
dopaminergic-cholinergic neuron link is also
involved.
In the present experiment, since high doses
of apomorphine which stimulate postsynaptic
dopamine receptors failed to inhibit the
pilocarpine-induced yawning, postsynaptic
sensitivity of cholinergic neurons to a direct
acetylcholine agonist may be unaltered in the
dopaminergic-cholinergic neuron system. However,
the a-MSH- and physostigmine induced yawnings
were blocked by high doses of apomorphine,
suggesting that stimulation of postsynaptic
dopamine receptors by dopamine agonist and
consequent inhibition of cholinergic neurons
seem to account for this blocking effect of
apomorphine. On the other hand, high dose of
piribedil conversely increased both
physostigmine- and pilocarpine induced yawnings.
There is no obvious explanation for this
stimulation by piribedil, but this fact may
favour the previous proposal that piribedil
exerts different effects on dopaminergic neurons
from those of apomorphine.
Methysergide, a selective antiserotonergic
drug, suppressed both a-MSH and
piribedil-induced yawnings though it did not
affect both physostigmine- and
pilocarpine-produced yawnings. There has been a
proposal that serotonergic neurons play an
inhibitory control of dopaminergic function in
the extrapyramidal and mesolimbic dopamine
system. It seems therefore that the inhibitory
effects of methysergide on both a-MSH- and
piribedil induced yawnings may be due to the
disinhibition from the serotonergic inhibition
and a consequent increase of dopamine release
from dopaminergic terminals in the
serotonergic-dopaminergic neuron link. However,
the serotonergic activation produced by the
combined administration of 5-HTP with Ro 4-4602
did not induce yawning though it markedly
produced 'Wet-Dog' body shaking. Accordingly,
although serotonergic activation may be a
positive modulating factor in elicitation of
yawning, serotonergic neurons appear to be less
primary mechanisms than dopaminergic and
cholinergic neurons. The present results thus
point out the possibility that serotonergic
activation, dopaminergic inhibition and
cholinergic activation are concomitantly
involved in the yawning.
However, as mentioned above, the inhibitory
effect of methysergide on yawning was seen in
both a-MSH- and piribedil-induced yawnings but
was not observed in both physostigmine- and
pilocarpine-induced yawnings. In addition, our
previous work showed that blockade of dopamine
receptors by systemic injection of fluphenazine
increased the yawning elicited by physostigmine
but did not affect that by pilocarpine. In this
study, the a-MSH-induced yawning was inhibited
by fluphenazine, as similar proposal that
ACTH-induced stretching-yawning syndrome was
suppressed by chlorpromazine. Therefore, these
results might imply that situation in
elicitation of yawning is more complicated than
would appear, and that mode of action of alpha
MSH and ACTH is dissimilar to those of
physostigmine and pilocarpine.
It has been reported that "Wet-Dog" body
shaking was interextingly observed , together
with yawning, in morphine withdrawal rats. and
after injection of thyrotrophin releasing
hormone or 5-HTP. Intraventricular injection of
alpha MSH also induced body shaking at early
stage after injection, which was followed by
stretching and yawning. This alpha MSH induced
body shaking was blocked by methysergide,
apomorphine or flphenazine, but was not blocked
by scopolamine. the body shaking induced by
5-HTP was similarily inhibbited by methysergide,
cryptheptadine, apomorphine or haloperidol but
was not inhibited by scopolamine. Consequently,
the body shaking elicited by alpha-MSH may
involve in part an activation of serotoninergic
neuron activity.
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