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mise à jour du
5 mai 2005
Naunyn-Schmiedeberg's Arch Pharmacol
1989; 340; 21-25
Occurrence of yawning and decrease of prolactin levels via stimulation of dopamine D2-receptors after administration of SND 919 in rats
Shin-ichiro Matsumoto, Katsushi Yamada, Mariko Nagashima, Mariko Domae, Koichi Shirakawa, Tatsuo Furukawa
Department of Pharmacology, Fukuoka University, Japan


Systemic administrations of low doses of dopamine receptor agonists such as apomorphine, bromocriptine and quinpirole have been reported to elicit yawning in rats. The yawning behavior induced by dopamine receptor agonists is blocked by both dopamine D2-receptor and muscarinic receptor antagonists. Previous investigations have also pointed out the involvement of the cholinergic system in yawning behavior. Physostigmine, an anticholinesterase agent, and pilocarpine, a muscarinic receptor agonist, induce a yawning behavior which is inhibited by muscarinic receptor antagonists. On the basis of such findings, it has been proposed that yawning seems to involve dopamine D2receptor stimulation and/or muscarinic receptor activation.
The secretion of prolactin in rats is regulated by neurotransmitters and hypothalamic hormones which have inhibitory or stimulatory effects. Especially, the tuberoinfundibular dopamine system is proposed to participate mainly in the regulation of prolactin secretion. Actually, serum prolactin levels are decreased by bromocriptine, a dopamine D2-receptor agonist, and increased by haloperidol, a dopamine receptor antagonist.
Recently, new types of dopamine receptor agonists have been introduced. 6-Allyl-2-amino-5,6,7,8-tetrahydro-4Hthiazolo [4,5-d] azepine (talipexole, B-HT 920) is characterized as an agonist for brain dopamine autoreceptors. This drug is found to induce yawning and to decrease basal prolactin levels in rats. (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (SND 919) is most recently synthesized and is expected to be a compound possessing talipexole-like dopamine receptor agonistic activities and fewer alpha-adrenoceptor stimulating effects.
Therefore, the aim of the present study was to investigate whether SND 919 induces yawning and decreases prolactin secretion via stimulation of dopamine D2-receptors.
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. The present study shows that SND 919 as well as talipexole possesses a selective dopamine D2-receptor agonistic property in the rat brain and the anterior pituitary gland. It has been proposed that talipexole does not exert any postsynaptic dopaminergic effects such as locomotor hyperactivity and stereotyped behavior 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 the dopamine D1-receptor agonist, SK&F 38393. This combined treatment with talipexole and SK&F 38393 induced a strong stereotyped behavior in either naive or reserpine plus alpha-MT-pretreated rats. This effect was analogous to the postsynaptic effect under high doses of apomorphine, a mixed dopamine D1/D2-receptor agonist. Thus, it has been proposed that talipexole is a selective dopamine D2-receptor agonist and that its own postsynaptic agonistic effects are masked in animals with normosensitive postsynaptic dopamine D2-receptors by its particularly potent action on the dopamine autoreceptors and consequent critical lack of synaptically available dopamine.
On the other hand, yawning is reported to be evoked, without eliciting stereotyped behavior, with low doses of dopamine receptor agonists such as apomorphine, piribedil, (+)-3-PPP, quinpirole or bromocriptine. The yawning induced by dopamine receptor agonists is also blocked by dopamine D2-receptor antagonists and muscarinic receptor antagonists. Actually, in the present experiment, low doses of SND 919, talipexole or (+)-3-PPP induced a marked yawning in naive rats without producing any stereotyped behaviors. Moreover, the administration of SND 919 in low doses (50, 100 .ig/kg, s. c.), which could induce yawning, failed to elicit stereotypy in the rats treated with SK&F 38393 (10 mg/kg, s. c.), but high doses (500, 1000 pg/kg, s.c.) of the drug did evoke stereotypy in the SK&F 38393-injected rats (unpublished data). Therefore, the stereotypy-producing dopamine D2receptors might not only cooperate with the dopamine D1receptors but they might also be less sensitive than the yawning-producing dopamine D2-receptors.
The yawning produced by SND 919 or talipexole was inhibited by the selective dopamine D2-receptor antagonists, spiperone at a dose of 0.5 mg/kg, YM-09151-2 at a dose of 0.1 mg/kg or the muscarinic receptor antagonist, scopolamine at a dose of 0.5 mg/kg. However, the yawning was unaffected by the selective dopamine D i-receptor antagonist, SCH 23390 at a dose of 0.5 mg/kg. The above mentioned receptor antagonist dosages were selected according to the other experiments. It is likely that these receptor antagonists at such doses produced inhibitory effects on the yawning behavior induced by SND 919 or talipexole in a pharmacologically relevant manner and did not exert their antagonistic actions through general motor debilitation. Taken together, it is assumed that the yawning observed following the administration of SND 919, talipexole or (+)-3-PPP is mediated by the stimulation of specific dopamine D2-receptors, which have a high affinity for dopamine receptor agonists similar to that of dopamine D2-autoreceptors and pituitary lactotroph dopamine D2-receptors.
It is well known that the tuberoinfundibular dopamine neurons, which originate in the arcuate and periventricular nuclei of the hypothalamus and terminate in the external layer of the median eminence, exert a inhibitory influence on the release of prolactin. Moreover, dopamine D1 and D2-receptors are documented for their important role in the regulation of prolactin secretion. In fact, prolactin release was inhibited by the dopamine D2-receptor agonist, bromocriptine, and was contrarily facilitated by the dopamine D1receptor agonist, SK&F 38393. It has been reported that (+)-3PPP acts as a preferential autoreceptor agonist at low doses, and stimulates postsynaptic dopamine receptors at high doses (Hjorth et al. 1981). Treatment with (+)-3-PPP decreased basal prolactin levels in naive rats and also decreased hyperprolactinemia induced by reserpine or alpha-MT). Talipexole has also been reported to decrease basal prolactin levels and reserpineevoked hyperprolactinemia. In the present experiments, basal prolactin levels were decreased as a result of treatment with SND 919, talipexole or (+)-3PPP. Increases in prolactin levels induced by alpha-MT were also antagonized by these compounds in doses which induced a yawning behavior. Moreover, SND 919 and talipexole inhibited prolactin release in vitro in slices of the rat anterior pituitary gland. Therefore, it seems reasonable to conclude that SND 919 can decrease prolactin secretion via stimulating dopamine D2-receptors in the anterior pituitary gland.
The present findings are in accord with previous reports which show that the yawning behavior elicited by dopamine receptor agonists seems to concomitantly involve dopamine D2-receptor stimulation and muscarinic receptor activation and that prolactin release is inhibited by dopamine D2-receptor agonists. Furthermore, the present results suggest that SND 919 as well as talipexole has a selective agonistic activity for specific dopamine D2-receptors, which are not related to the occurrence of stereotypy and have a high affinity for dopamine receptor agonists similar to that of dopamine D2-autoreceptors and pituitary lactotroph dopamine D2-receptors.