Muodification
of apomorphine, physiostigmine and pilocarpine
indiced yawning after long-term treatment with
neuroleptic or cholinergic
agents
I Ushijima, K Yamada, T Inoue, T Tokunaga, T
Furukawa
Department of
neuropsychiatry, School of Medicine, Yamaguchi
University, Japan
Abstract : Chronic treatment with
haloperidol, physostigmine and scopolamine
exerted different effects on the frequency of
yawning induced by apomorphine (0.25 mg/kg,
i.p.), physostigmine (0.2 mg/kg, i.p.) and
pilocarpine (4 mg/kg, i.p.) as compared with
chronic treatment with saline. Haloperidol
decreased the apomorphine- and
physostigmine-induced yawning but not the
pilocarpine-induced yawning. Physostigmine
reduced only the pilocarpine-induced yawning
without affecting the apomorphine- and
physostigmine-induced yawning. However,
physostigmine showed the most rapid onset- and
peaktime of yawning induced by a high dose of
physostigmine (0.75 mg/kg, i.p.) as well as that
of pilocarpine (8 mg/kg, i.p.), and potentiated
apomorphine (1 mg/kg, i.p.)-induced stereotypy,
as compared with that observed in the saline
group. Scopolamine potentiated the
physostigmine- and pilocarpine-induced yawning
but not the apomorphine-induced yawning. A
single pretreatment with scopolamine (0.5 mg/kg,
i.p.), however, depressed these yawning
responses. The results suggest that yawning
induced by physostigmine, but not by
pilocarpine, may be modified by long-term
treatment with haloperidol. The stereotypy
mediated by the postsynaptic dopaminergic
system, but not the yawning mediated by the
presynaptic system, may be altered by chronic
treatment with physostigmine, while long-term
treatment with scopolamine seems to produce a
supersensitivity to cholinergic receptors.
Introduction
Physostigmine, an anticholinesterase agent,
and pilocarpine, a cholinergic agonist
predominantly acting upon muscarinic receptors,
have been reported to elicit yawning in infant
rats (Urbá-Holmgren et al., 1977) and in
adult rats (Yamada and Furukawa, 1980a). This
behavior is inhibited by scopolamine, but not by
methyiscopolamine, suggesting that yawning is
mediated by stimulation of the central
'muscarinic' receptor (Urbá-Holmgren et
al., 1977; Yamada and Furukawa, 1980a, 1981).
Moreover, a low dose of apomorphine which
produces an inhibition of dopamine release from
presynaptic sites, and consequently, results in
an activation of cholinergic neurons (Carlsson,
1975; Di Chiara et al., 1976), also elicits
yawning in adult rats. Accordingly, a
dopaminergic inhibition and a cholinergic
activation are concomitantly involved in this
yawning behavior (Yamada and Furukawa, 1980a).
Physostigmine-induced yawning is potentiated by
fluphenazine, a long-acting neuroleptic, but
decreased with a high dose of apomorphine.
Pilocarpine induced yawning is not affected by
either of these drugs (Yamada and Furukawa,
1980b, 1981). A dopaminergic-cholinergic link
may be involved in physostigmine-induced yawning
but not in pilocarpine-induced yawning.
There is evidence supporting a
dopaminergic-cholinergic interaction in that the
catalepsy elicited by neuroleptic agents 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).
With regard to alteration of receptor
sensitivity by long-term administration of
drugs, it has been reported that chronic
treatment with atropine or scopolamine produced
a supersensitivity to cholinergic agents
(Takeyasu et al., 1979; Gianutsos, 1979).
Repeated injections of haloperidol (Dunstan and
Jackson, 1977) or treatment with
6-hydroxydopamine (Kato et a!., 1978), elicited
a cholinergic hyposensitivity as a consequence
of the hyperactivity of cholinergic neurons
which are regulated by dopaminergic neurons. In
addition, the observation that chronic treatment
with cholinergic stimulants attenuates the
catalepsy induced by neuroleptics or
cholinomimetic drugs (Gianutsos, 1979) suggests
that the sensitivity of postsynaptic dopamine
receptors may be potentiated and/or that of
acetylcholine receptors attenuated.
The present experiments were performed to
clarify the possible role of the dopaminergic
and cholinergic systems in mediating the effects
of chronic treatment with haloperidol,
physostigmine and scopolamine on yawning induced
by apomorphine, physostigmine or
pilocarpine.
Results
Yawning induced by apomorphine,
physiostigmine or pilocarpine
In animals chronically treated with saline,
floowed by low dose of apomorphine (0.25 mg/kg),
yawning began within 5 min (mean, 4.3 mm),
reached a maximum after 10-20 min (mean, 15 mm)
and usually ceased within 60 min. Stereotypy did
not appear. After a high dose of 1 mg/kg,
stereotypy began within 10 min (mean, 8.5 mm),
reached a peak after 20 min (mean, 19.5 mm), and
usually disappeared within 60 min. There was no
occurrence of yawning in this condition. After a
low dose of physostigmine (0.2 mg/kg) and
pilocarpine (4 mg/kg), yawning began at about 10
min (mean, 7.8 mm), reached a peak after 20-30
min (mean, 24.4 mm), and terminated within 60
min. There was no occurrence of chattering. At
higher doses of physostigmine (0.75 mg/kg) and
pilocarpine (8 mg/kg), chattering appeared
immediately after the drug administration,
reached a maximum 5 min later and, lasted for 10
mm; while yawining occurred at about 20 min
(mean, 19.1 mm), reached a maximum 40-60 min
(mean, 53 mm) later, and ceased within 90 min
after the drug administration.
Effects of chronic treatment with
haloperidol, physostigmine and scopolamine on
yawning induced by apomorphine, physostigmine or
pilocarpine
Following chronic haloperidol treatment, the
frequency of pilocarpine (4 mg/kg)-induced
yawning was unaffected, while apomorphine (0.25
mg/kg)and physostigmine (0.2 mg/kg)-induced
yawning was decreased.
Following chronic physostigmine treatment,
the frequency of pilocarpineinduced yawning was
reduced, while that of apomorphine and
physostigmine was unaffected.
Following chronic scopolamine
administration, the frequency of physostigmine-
and pilocarpine-induced yawning was markedly
increased while apomorphine-induced yawning was
not affected, when compared with the respective
saline groups. However, a single pretreatment
with scopolamine (0.5 mg/kg) completely
inhibited these yawning responses. These results
are summarized in Table I.
Effects of chronic treatment with
physostigmine on the sensitivity of cholinergic
receptors
Following chronic treatment with
physostigmine, the frequency of yawning induced
by 0.2 and 0.75 mg/kg of physostigmine was not
modified, as compared to chronic treatment with
saline. At 0.75 mg/kg of the agent, the onset
(11 mm)- and peak (23.5 mm)time of the yawns
were significantly more rapid rather than those
of the saline group. In contrast, with 4 mg/kg
and 8 mg/kg of pilocarpine, the frequency of the
yawns was inhibited, but the onset and duration
of the yawns were similar to those induced by
physostigmine (0.2 and 0.75 mg/kg). The chatters
induced by high doses of physostigmine (0.75
mg/kg) and pilocarpine (8 mg/kg) were attenuated
by repeated treatment with physostigmine (data
not shown). The frequency, onset-, and peak-time
of the yawns induced by a low dose of
apomorphine (0.25 mg/kg) was not affected by
repeated treatment with physostigmine (data not
shown).
Effects of acute and chronic treatment
with haloperidol, physostigmine or scopolamine
on the sensitivity of dopaminergic
receptors
The stereotypy induced by apomorphine (1
mg/kg, i.p.) was inhibited by a single
administration of haloperidol (0.2 mg/kg, i.p.)
or physostigmine (0.25 mg/kg, i.p.) and was
increased by repeated treatments with these
drugs. Acute treatment with scopolamine also
increased the apomorphine-induced stereotypy
whereas repeated treatment with the drug tended
to decrease this behavior, but not
significantly.
Discussion
Apomorphine, physostigmine and pilocarpine
have been reported to elicit yawning behavior in
rats. The doses which produced the highest
frequency of yawning were 0.25 mg/kg, 0.2 mg/kg
and 4 mg/kg, respectively (UrbáHormgren
et al., 1977; Yamada and Furukawa, 1980a). Rats
given chronic treatment with haloperidol,
physostigmine and scopolamine exhibited
different yawning behavior induced by
apomorphine, physostigmine and pilocarpine.
Following haloperidol treatment,
pilocarpine-induced yawning was unaffected,
while apomorphine and physostigmine-induced
yawning were reduced.
The stereotypy induced by high doses of
apomorphine was potentiated. The inhibitory
effect on apomorphine- and physostigmine-induced
yawning may be accounted for by the
supersensitivity of postsynaptic dopamine
receptors induced by the chronic treatment with
the dopamine antagonist and a consequent
inhibition of cholinergic neurons. It appears
that the effects of physostigmine seem to depend
upon the status of cholinergic neurons and
modification of the cholinergic system by
dopaminergic agents can alter the effects of
physostigmine (Dunstan and Jakson, 1977; Guyenet
et al., 1975; Yamada and Furukawa, 1980a, 1981).
Repeated injections of haloperidol may produce a
cholinergic subsensitivity as a consequence of
the hyperactivity of cholinergic neurons which
are regulated by dopaminergic neurons. However,
since the chronic treatment with haloperidol
failed to inhibit pilocarpine induced yawning,
the postsynaptic sensitivity of cholinergic
neurons to a direct acetylcholine agonist
pilocarpine may be unaltered by chronic
haloperidol in the dopaminergic cholinergic
neuron system.
As a result of physostigmine treatment,
apomorphine- and physostigmine induced yawning
were unaffected, while pilocarpine-induced
yawning was decreased. After a single injection
of a high dose of physostigmine (0.75 mg/kg) or
pilocarpine (8 mg/kg), chattering appeared
first, while yawning occurred only after the
chattering behavior had almost ceased. The
onset- and peak-time of yawning induced by the
high dose of physostigmine (0.75 mg/kg) was
delayed, as compared with 0.2 mg/kg of the agent
in a previous study (Ushijima et al., 1984). It
is probable that yawning is produced by a weaker
stimulation of central cholinergic neurons
whereas chattering is due to stronger
stimulation of these neurons. However, following
chronic treatment with physostigmine, the onset
and the peak-time of yawning induced by a high
dose of physostigmine (0.75 mg/kg) was faster
than that seen in the saline group. In addition,
chattering behavior was decreased, suggesting
that the sensitivity of cholinergic receptors is
probably attenuated. The effect of physostigmine
on the onset and the peak-time of
pilocarpine-induced yawning was also similar to
the physostigmine-induced yawning. The yawning
induced by a low dose of apomorphine, which
preferentially stimulates presynaptic dopamine
autoreceptors, was not affected by
physostigmine. However, the stereotypy induced
by a high dose of apomorphine which stimulates
postsynaptic dopamine receptors (Kelly et al.,
1975), was potentiated. From these results, it
is suggested that chronic treatment with
physostigmine may produce subsensitivity of
cholinergic receptors and supersensitivity of
postsynaptic dopamine receptors while not
affecting the sensitivity of presynaptic
dopamine autoreceptors.
Following scopolamine treatment,
physostigmine- and pilocarpine-induced yawning
was potentiated. It is suggested that
scopolamine may induce cholinergic receptor
supersensitivity which would be manifested by an
increase in the response to physostigmine or
pilocarpine. Although a single administration of
scopolamine completely depressed yawning
behavior, as has been previously reported
(Urbi-Holmgren et al., 1977; Yamada and
Furukawa, 1980a), and potentiated the stereotypy
induced by a high dose of apomorphine, repeated
treatment with the drug failed to modify both
the yawning and stereotypy as compared with the
saline group. This finding suggested that
repeated treatment with scopolamine may alter
the sensitivity of postsynaptic dopamine
receptors as well as that of cholinergic
receptors. Since apomorphine-induced yawning is
mediated via an enhanced acetylcholine release,
and consequently, via an increased stimulation
of the acetylcholine receptor, it would be
expected that chronic scopolamine would also
affect apomorphine-induced yawning. Accordingly,
it was found that chronic treatment with
scopolamine also changes the sensitivity of the
dopaminergic system. The results suggest that
the sensitivity of postsynaptic dopamine
receptors, but not that of presynaptic
aûtoreceptors, may be modified by chronic
treatment with physostigmine. In addition,
chronic treatment with haloperidol may modify
the sensitivity of cholinergic receptors
affected by physostigmine, but not that affected
by a direct acetylcholine receptor agonist,
pilocarpine.
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