Department of pharmacology,
School of medecine, Fukuoka University,
Japan
Biochemical and pharmacological evidence
indicates the presence of at least two dopamine
receptor subtypes, dopamine D1 receptors linked
positively to adenylate cyclase and dopamine D2
receptors not linked or linked negatively to
adenylate cyclase
Previous observations show that apomorphine
and piribedil, mixed dopamine D1/D2 receptor
agonists, exert biphasic effects on behavior;
i.e., yawning and hypomotility in low
doses, and stereotypy and hypermotility in high
doses. The yawning behavior induced by dopamine
receptor agonists is blocked by dopamine D2
receptor antagonists and muscarinic receptor
antagonists, but not by dopamine D1 receptor
antagonists. On the basis of such findings, it
has been proposed that the yawning seems to
involve dopamine D2 receptor stimulation and
consequent cholinergic activation. On the
other hand, it has recently been reported that
concurrent stimulation of both dopamine D1 and
D2 receptors is required for the appearance of
stereotypy.
According to the dopamine receptor
classification, SK&F 38393
(1-phenyl-2,3,4,5-tetrahydro-(IH)-3-benzazepine-7,8-diol)
is a dopamine D1 receptor agonist and talipexole
(B-HT 920) is a dopamine D2 receptor agonist.
Talipexole is also characterized as a putative
dopamine autoreceptor agonist and does not evoke
stereotypy in naive animals with normosensitive
brain dopamine receptors. However, talipexole
was found to induce yawning in naive rats.
Recently, SND 919
(S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole)
has been reported to be a compound possessing
talipexole-like dopamine D2 receptor agonistic
activities.
The present experiments were therefore
undertaken to investigate difference in
characteristics of dopamine D2 receptors
participated in occurrence of yawning and
stereotypy after administration of dopamine D1
or D2 receptor agonists alone or in
combination.[...]
Discussion
Accumulated evidence shows that yawning is
evoked, without eliciting stereotypy, by low
doses of conventional dopamine receptor agonists
such as apomorphine, piribedil and
bromocriptine. The yawning induced by dopamine
receptor agonists is blocked by dopamine D2
receptor antagonists. Although some groups
reported that the yawning was also prevented by
the selective dopamine D1 receptor antagonist
SCH 23390, we did not confirm significant
inhibition by SCH 23390 of yawning. Our previous
experiments also showed that the yawning
produced by talipexole or SND 919 was inhibited
by the selective dopamine D2 receptor antagonist
spiperone, or the muscarinic receptor antagonist
scopolamine, but not by SCH 23390, suggesting
that the yawning observed after the
administration of dopamine receptor agonists is
mediated by the stimulation of dopamine D2
receptors and consequent cholinergic activation.
In other endocrinological experiments,
administration of talipexole or SND 919 in
respective yawning-inducing doses also caused a
reduction in both basal prolactin levels and the
hyperprolactinemia induced by reserpine or
a-methyl-p-tyrosine via acting on pituitary
dopamine D2 receptors. In the present
experiment, low doses of talipexole or SND 919
given alone induced marked yawning while
extremely high doses of both drugs elicited
virtually no yawning responses in naive rats.
These yawning responses were decreased by
treatment with SK&F 38393.
On the other hand, it has been proposed that
talipexole does not exert any postsynaptic
dopaminergic effects such as the induction of
stereotypy and locomotor hyperactivity in naive
animals with normosensitive brain dopamine
receptors. However, recent observations have
shown that talipexole also exhibits postsynaptic
dopamine receptor agonistic properties under
pretreatment with SK&F 38393. This combined
treatment with talipexole and SK&F 38393
induces strong stereotypy in both naive and
reserpine plusalpha-methyl-p-tyrosine-pretreated
rats. This effect is analogous to the
postsynaptic effect of high doses of the mixed
dopamine D1/D2 receptor agonist apomorphine. In
the present experiments, the administration of
very high doses of talipexole or SND 919 in
combination with SK&F 38393 evoked marked
stereotypy. Therefore, it is assumed that
postsynaptic agonistic effects of talipexole and
SND 919 are masked in animals with
normosensitive postsynaptic dopamine D2
receptors by its particularly strong dopamine
autoreceptor agonistic activity which produces a
critical lack of synaptically available dopamine
and consequently an insufficient dopamine D1
receptor tone.
Moreover, it has been reported that yawning
elicited by dopamine receptor agonists such as
apomorphine and talipexole markedly increased
after treatment with reserpine or
p-chlorophenylalanine without provoking
stereotypy such as licking and biting,
suggesting that the yawning induced by dopamine
receptor agonists in serotonin-depleted rats may
be associated with the dopaminergic neuron
systern which is not related to the occurrence
of stereotypy. In the present study, we also
confirmed that, in the presence of concurrent D1
receptor stimulation, the behaviors produced by
selective dopamine D2 receptor agonists were
markedly altered: yawning was inhibited and
stereotypy was potentiated. These effects are
compatible with the biphasic effects of
apomorphine which has agonistic activity for
both dopamine D1 and D2 receptors: yawning at
low doses with a bell shaped dose-response curve
and dosedependent stereotypy at high doses.
Moreover, the prescrit results are supported by
the recent finding showing that amphetamine
given alone induces strong stereotypy but the
combined treatment with amphetamine and SCH
23390 evokes yawning without inducing
stereotypy. Interestingly, the administration of
talipexole or SND 919, in low and effective
doses which could induce yawning, did not elicit
stereotypy in the rats treated with SK&F
38393, but extremely high doses of the drugs did
evoke stereotypy in the SK&F 38393-injected
rats. Taken together, it may be assumed thal
there are yawning-related high sensitive
dopamine D2 receptors and stereotypy-related low
sensitive dopamine D2 receptors. These
yawning-producing dopamine D2 receptors may be
not related to the occurrence of stereotypy and
may have a high sensitivity for dopamine
receptor agonists similar to that of dopamine D2
autoreceptors and pituitary lactotroph dopamine
D2 receptors.
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