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mise à jour du
29 janvier 2004
1990; 100; 141-144
Possible involvement of differing classes of
dopamine d2 receptors
in yawning and stereotypy in rats 
Katsushi Yamada, Tatsuo Furukawa
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.[...]
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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