Department of Pharmacology,
Research Laboratory of Biodynamics, Department
of Obstetrics and Gynecology, School of
Medicine, Fukuoka University, Japan
Summary. Subcutaneous injection of
B-HT 920, a dopamine D2-receptor agonist, in
doses ranging from 5 to 100µg/kg, induced
yawning behavior in rats. Yawning was also
elicited by low doses (25-500 µg/kg sc) of
SND 919, a newly synthesized dopamine receptor
agonist. The yawning evoked by B-HT 920 or SND
919 was increased by the beta adrenoceptor
antagonist pindolol (20 mg/kg ip) which alone
did not induce yawning. Stereotyped behavior did
not appear after B-HT 920 or SND 919 given alone
or in combination with pindolol. The results
suggest that SND 919 as well as B-HT 920 has
stimulatory activity at dopamine D2-receptors,
and that pindolol may exert its enhancement of
the yawning response to dopamine receptor
agonists via blockade of adrenoceptors.
Introduction
Systemic administration of low doses of
dopamine receptor agonists, such as apomorphine,
bromocriptine and quinpirole has been reported
to elicit yawning in rats. The yawning behavior
induced by dopamine receptor agonists is blocked
by dopamine D2-receptor antagonists and
muscarinic receptor antagonists. On the basis of
such findings, it has been proposed that the
yawning involves dopamine D2-receptor
stimulation and consequent cholinergic
activation (Yamada and Furukawa, 1980; Yamada et
al., 1986; Serra et al., 1986, 1987).
Recently, new types of dopamine receptor
agonists have been introduced. B-HT 920 is
characterized as an agonist at brain dopamine
autoreceptors (Andén et al., 1983;
Cichini et al., 1987; Pichler et al., 1987) and
is found to induce yawning in rats (Longoni et
al., 1987; Matsumoto et al., 1989). The recently
synthesized SND 919 is also expected to be a
compound possessing similar dopamine receptor
agonistic activities with fewer a-adrenoceptor
agonistic ones (Personal communication, M. H.
Jennewein, Boehringer Ingeiheim, Federal
Republic of Germany).
There is accumulated evidence showing that
adrenergic neurons containing high activity of
phenylethanolamine-N-methyl transferase, which
converts noradrenaline to adrenaline, exist in
the central nervous system (Hökfelt et al.,
1974). Systemic administration of propranolol
has been reported to decrease the accumulation
of dopa in the striatum via its direct
inhibitory effect on the activity of soluble
tyrosine hydroxylase (Tuross and Patrick, 1986).
Treatment with isoproterenol, in contrast,
enhances dopamine release in vitro in slices of
the rat striatum and hypothalamus and in vivo in
the cat caudate nucleus (Reisine et al., 1982;
Ueda et al., 1984). Thus, J3-adrenoceptors
localized in the dopaminergic nerve terminal
area have been proposed to play a role in the
regulation of release and synthesis of dopamine
(Reisine et al., 1982; Ueda et al., 1984; Tuross
and Patrick, 1986).
The present experiments were therefore
performed to investigate whether yawning is
induced by B-HT 920 or SND 919. In addition,
effects of the adrenoceptor antagonist pindolol
on the yawning were also investigated.
Discussion
The present study shows that low doses of
B-HT 920 or SND 919 induced marked yawning
without producing stereotyped behavior in naive
rats. The dose-response curves of yawning to the
drugs were basically bell-shaped, as previously
reported for conventional dopamine receptor
agonists such as apomorphine and piribedil
(Yamada et al., 1980, 1986). Although the real
reason for a bell-shaped dose-response curve is
obscure at present, it is a possibility that the
neuronal mechanisms participating in evoking
yawning are activated at low doses of B-HT 920
or SND 919 and that high doses produce changes
of the other neuronal activity which inhibit
occurrence of yawning.
Yawning is reported to be evoked in the
absence of stereotypd behavior by low doses of
conventional dopamine D,-receptor agonists, and
is blocked by dopamine D2-receptor antagonists
(Yamada and Furukawa, 1980; Yamada et al., 1986;
Serra et al., 1986; Longoni et al., 1987). B-HT
920 has been proposed to possess a particularly
strong dopamine autoreceptor agonistic activity
which produces a critical lack of
synaptically-available dopamine and consequently
an insufficient dopamine D1-receptor tone
(Andén et al., 1983; Hjorth and Carlsson,
1987; Pifi and Hornykiewicz, 1988; Meltzer et
al., 1988). Administration of B-HT 920
(5-1001g/kg Sc) or SND 919 (25-500 jig/kg sc) at
similar doses for inducing yawning also
decreased basal prolactin levels via their
action at pituitary dopamine D2-receptors
(unpublished data). High prolactin levels in
rats pretreated with reserpine were also
decreased at similar doses of B-HT 920 (Eriksson
et al., 1985). Accordingly, it appears that the
yawning observed after B-HT 920 or SND 919 is
mediated by the stimulation of a population of
dopamine D2-receptors having a high affinity for
dopamine receptor agonists similar to that of
dopamine D2-autoreceptors and pituitary
lactotroph dopamine D2-receptors.
B-HT 920 has been proposed not to exert
postsynaptic dopaminergic effects such as
locomotor hyperactivity and stereotyped behavior
in naive animals with normosensitive brain
dopamine receptors (Andén et al., 1983;
Hinzen et al., 1986). However, more recent
observations show that B-HT 920 can exhibit
postsynaptic dopamine receptor agonistic
properties after co-treatment with a dopamine
D1-receptor agonist, SK&F 38393 (Hjorth and
Carlsson, 1987; Pifi and Hornykiewicz, 1988;
Meltzer et al., 1988). This combined treatment
with B-HT 920 and SK&F 38393 induced
substantial stereotyped behavior in rats that
were untreated or that had received pretreatment
with reserpine plus alphamethyl-p-tyrosine
(Hjorth and Carlsson, 1987; Pill and
Hornykiewicz, 1988; Meltzer et al., 1988). This
is analogous to the postsynaptic effect of high
doses of apomorphine, a mixed dopamine
D1/D,-receptor agonist (Yamada and Furukawa,
1980). Accordingly, postsynaptic dopamine
D,-receptor agonistic effects of B-HT 920 and
SND 919 such as the occurrence of stereotypy
appear to be masked in the absence of
concomitant dopamine D1-receptor
stimulation.
In the present experiment, the yawning
elicited by B-HT 920 or SND 919 was enhanced by
pindolol. Recently, we also found that yawning
responses to dopamine agonists such as
apomorphine and piribedil were increased by
various 3-adrenoceptor antagonists such as
propranolol, pindolol, indenolol, aiprenolol and
bukumolol, and that this effect was blocked by
dopamine D2-receptor antagonists and muscarinic
receptor antagonists (Yamada et al., 1987,
1989). Pindolol is known to have serotonin
receptor blocking action in addition to
J3adrenoceptor antagonistic activity (Hjorth and
Carlsson, 1986; Maj et al., 1988). However,
serotonin receptor blocking action of the
antagonist may be not related to the effects
reported here since serotonin receptor
antagonists, ketanserin and metergoline, have
been found not to influence B-HT 920-induced
yawning (Longoni et al., 1987). Pindolol also
increased the yawning responses after
administration of an anticholinesterase agent,
physostigmine, or a muscarinic receptor agonist,
pilocarpine, and this effect was inhibited by
muscarinic receptor antagonists but not by
dopamine D,-receptor antagonists (Yamada et al.,
1987, 1989). Therefore, pindolol may exert its
enhancement of yawning via a blockade of
j3-adrenoceptors which facilitates the
cholinergic activation resulting from
stimulation of dopamine D,-receptors by B-HT 920
or SND 919.
Although further work is warranted to
clarify the role of central adrenergic neuron
activity in yawning behavior, yawning responses
could prove to be a useful model for the study
of the antagonistic activity at central
3-adrenoceptors and agonistic activity at
dopamine D,-receptors.
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