mise à jour du
20 novembre 2005
J Neural Transm (GenSect)
1990; 79; 19-24
B-HT 920 and SND 919 by pindolol in the rat
K. Yamada, S. Matsumoto, M. Nagashima K
Shirakawa, T. Furukawa
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.
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.
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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-Yamada K, S Matsumoto, M Nagashima, K Shirakawa, T Furukawa Potentiation of yawning responses to the dopamine receptor agonists B-HT 920 and SND 919 by pindolol in the rat J Neural Transm [GenSect] 1990; 79; 19-24