- It has been reported that the characteristic
yawning behavior appears after intracerebral
injection of adreno-corticotrophic hormone
(ACTH), melanocytestimulating hormone (MSH) or
beta-lipotrophic hormone (beta-LPH) in many
animals, such as monkeys, dogs, cats, rabbits,
rats and mice (Gessa
et al., 1966, Baldwin et al., 1974; Gispen
et al., 1975; Rees et al., 1976). In infant
rats, cholinergic agonists also elicited yawning
(Urba
Holmgren et al., 1977), suggesting that
yawning is due to cholinergic stimulation.
However, few studies have been made on the
neurological mechanisms involved in yawning
which still remain to be elucidated.
There is evidence that catalepsy elicited by
neuroleptic agents, which are dopamine
antagonists, is blocked by anticholinergic
agents (Costail and Olley, 1971 ; Maj et al.,
1976), and that the nigro-striatal dopaminergic
neurons inhibit the striatal cholinergic neurons
(Trabucchi et al., 1975; Agid et al., 1975; Roth
and Bunney, 1976). Apomorphine may be a
directacting dopamine receptor agonist
(Andén et al., 1967; Carlsson, 1975),
and, at a low dose, produces an inhibition of
dopamine release from presynaptic sites that
results in activation of cholinergic neurons
(Carlsson, 1975; Chiara et al., 1976).
Consequently apomorphine, at a low dose, ought
to elicit yawning.
In the present investigation, we found that
apomorphine did elicit yawning in adult rats and
we attempted further to understand the
neurological mechanism involved.
[...]
-
- Discussion : Low doses of apomorphine
induced yawning without producing typical
symptoms of behavioral excitation, such as
stereotypy and hypermotility. Yawning was
accompanied by penile erections which were
similar to those seen in the sexual arousal
elicited by ACTH, MSH or beta-LPH in rats
(Colbern et al., 1977) and rabbits (Bertolini et
al., 1969; Baldwin et al., 1974). Higher doses
of apomorphine produced stereotypy. It bas been
proposed that apomorphine exerts biphasic
effects on behavior, i.e., decrease of motor
activity at low doses, and stereotypy and
hypermotility at higher doses (Carlsson, 1975;
Strômbom, 1976, Chiara et al., 1976).
-
- It has also been reported that low doses of
apomorphine preferentially activate presynaptic
dopamine autoreceptors, which results in an
inhibition of dopamine release and consequent
decrease in its synthesis, whereas higher doses
stimulate postsynaptic receptors (Roberts et
al., 1975, Groves et al., 1975, Walters and
Roth, 1976). Accordingly, yawning elicited by
low doses of apomorphine seems to be due to an
activation of presynaptic dopamine
autoreceptors, while stereotypy induced by
higher doses may be attributed to a stimulation
of postsynaptic dopamine receptors as previously
proposed (Kelly et al., 1975).
-
- Apomorphine-induced yawning was not
inhibited by the predominantly peripherally
acting methylscopolamine but was blocked by
scopolamine, an anticholinergic agent.
Physostigmine, an anticholinesterase agent, and
pilocarpine, a direct acetylcholine agonist,
also elicited yawning in adult rats, as observed
previously in infant rats with cholinergic
agents (Urba-Holmgren et al., 1977). This was
abolished by scopolamine but not by
methylscopolamine, suggesting that yawning is
mediated by activation of cholinergic neurons in
the brain. Recently bilateral intranigral
injection of picrotoxin combined with SC
injection of apomorphine, 0.2 mg/kg, was found
to induce simultaneous catalepsy and yawning in
rats (Olianas et al., 1978), suggesting that the
nigro-striatal dopaminergic neurons are
involved. There is also accumulated evidence
that the nigro-striatal doparninergic neurons
inhibit the striatal cholinergic neurons
(Trabucchi et al., 1975, Roth and Bunney, 1976,
Choi and Roth, 1978), while a
dopaminergic-cholinergic link is lacking in the
mesolimbic area such as the nucleus accumbens
septi and tuberculum olfactorium (Consolo et
al., 1977, 1978). Therefore, in
apomorphine-induced yawning, in addition to an
inhibition of dopamine release resulting from
activation of presynaptic dopamine
autoreceptors, a consequent activation of
cholinergic neurons seems to be concomitantly
involved.
Further studies on inhibitory and stimulative
effects of certain drugs corroborate the
prescrit proposal that yawning may be induced
through activation of cholinergic neurons
which are regulated by dopaminergic neurons.
Reserpine, an amine depletor (Furukawa et al.,
1976, 1979; Yamada and Furukawa, 1979), markedly
increased not only the apomorphine-induced
yawning, with little increase in stereotypy, but
also the physostigmine- and pilocarpine-elicited
yawnings. This increase in yawning thus seems to
be due to an inhibition of dopamine release
resulting from a presynaptic depletion of
dopamine produced by reserpine.
On the other hand, fluphenazine, a
long-acting neuroleptic, blocks both pre- and
postsynaptic dopamine receptors (Nowycky and
Roth, 1977; Choi and Roth, 1978; Yamada et al.,
1979). In the present study, fluphenazine
decreased the apomorphine-induced yawning,
markedly increased the physostigmineinduced
yawning, but failed to affect the
pilocarpineinduced yawning. This inhibitory
effect of the dopamine antagonist on the
apomorphine-induced yawning can be explained by
the blockade of presynaptic dopamine
autoreceptors. While the effects of
physostigmine, an indirect cholinergic agonist,
seein to depend on the status of cholinergic
neurons. Modification of the cholinergic system
by dopaminergic agents can alter the effects of
physostigmine (Guyenet et al., 1975; Dunstan and
Jackson, 1977). Accordingly, blockade of
postsynaptic dopamine receptors by the dopamine
antagonist and a consequent activation of
cholinergic neurons may account for the
stimulatory effect on the physostigmine-induced
yawning. With regard to alteration of receptor
sensitivity by long-term administration of a
drug, it bas been reported that chronic
treatment with atropine for 21 days produced a
supersensitivity to direct cholinergic agents
(Takeyasu et al., 1979), whereas repeated
injections of haloperidol (Dunstan and Jackson,
1977) or treatment with 6hydroxydopamine (Kato
et al., 1978), elicited a cholinergic
hyposensitivity as a eonsequence of
hyperactivity of cholinergic neurons which are
regulated by dopaminergic neurons. However,
since fluphenazine failed to potentiate the
pilocarpine-induced yawning in this study, it
seems not to induce an alteration in
postsynaptic sensitivity to direct acetylcholine
agonists after 24 h.
From these results, it is suggested that the
sites of action of neuroleptics on pre- or
postsynaptic dopamine receptors can be
determined by observing their inhibitory or
stimulatory effects on yawning induced by
aportiorphine or physostigmine.
The yawning elicited by intracranial
injection of peptides, such as ACTH, MSH and
f~-LPH, appeared with a time lag of about 40 -
60 min and then lasted for 1 - 2 h (Ferrari,
1958; Ferrari et al., 1963; Gessa et al., 1967;
Izumi et al., 1973; Baldwin et al., 1974). ACTH
and MSH were also considered to activate
cholinergic neurons in the brain (Torda and
Wolff, 1952, Marx, 1975). In fact, the
ACTH-induced yawning was suppressed by
chlorpromazine or atropine (Ferrari et al.,
1963) suggesting a possible involvement of
dopaminergic and cholinergic neurons. It is
therefore probable that the effect of the
peptides may involve other neurological
mechanisms, presumably dopaminergic and/or
cholinergic neurons, when they ceicit yawning
beliavior.
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