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mise à jour du
27 mai 2004
Pharmacol Biochem Behav
1995; 50; 3; 339-343
Involvement of beta-adrenoceptors in regulation
of the yawning induced by neuropeptides,
oxytocin and a-Melanocyte-Stimulating Hormone in rats
M Fujikawa, K Yamada, M Nagashima, T Furukawa
Department of Pharmacology and Research Laboratory of Biodynamics, School of medicine, Fukuoka University, Japan
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren

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Although physiological significance is uncertain, yawning behavior has received a great deal of attention. From accumulated behavioral studies, including our previous experimental results, it has been shown that physostigmine, an anticholinesterase agent, and pilocarpine, a muscarinic receptor agonist, induce yawning behavior that is blocked by muscarinic receptor antagonists, but not by dopamine receptor antagonists. On the other hand, the yawning induced by dopamine D2 receptor agonists, such as bromocriptine and talipexole, is antagonized by both dopaminergic and muscarinic receptor antagonists.
 
On the basis of these findings, the yawning induced by cholinesterase inhibitors and muscarinic receptor agonists appears to involve cholinergic activation, and that in response to dopamine receptor agonists seems to require both dopaminergic and cholinergic activation. Thus, the cholinergic activation followed by unknown yawn-inducing neuronal mechanisms seems to be essential in eliciting yawning behavior.
 
In addition, yawning behavior seems to involve other neuronal mechanisms. Because the yawning responses to both dopaminergic and cholinergic receptor agonists arc increased by beta-adrenoceptor blockers and adrenaline synthesis inhibitors, the occurrence of yawning evoked by dopaminergic and cholinergic activation seems to be downregulated by the activity of central adrenergic neurons via stimulation of beta-adrenoceptors.
 
On the other hand, central administration of certain peptides, such as a-melanocyte-stimulating hormone a-MSH and adrenocorticotropic hormone (ACTH), is also capable of inducing a peculiar syndrome characterized by recurrent episodes of yawning, stretching, body shaking, and penile erection. Oxytocin has also been reported to elicit yawning behavior that is inhibited by muscarmic receptor antagonists but not by dopamine receptor antagonists.
 
The prescrit experiments were therefore performed to investigate whether beta-adrenoceptor activity is involved in regulation of the yawning induced by the neuropeptides oxytocin and a-MSH in rats.[...]
 
DISCUSSION
 
Previous studies have shown that a muscarinic receptor agonist, pilocarpine, induces yawning behavior, in rats. Muscarinic receptors have been designated as either 1 or M2 receptors, depending on whether they have high or low affinity for pirenzepine, although such classification is as yet tentative. In the present study, RS-86, a centrally acting potent muscarinic M1 receptor agonist, administered SC produced yawning in rats, as reported previously by Gower, suggesting that the muscarinic receptors participating in the induction of yawning may be M1 receptors.
 
From such dose-response studies on systemic administration of RS-86, 100 µg/rat was selected for ICV administration in the present study. On the other hand, central administration of nanogram amounts of oxytocin was reported to produce yawning in rats. For ICV administration of the peptides, oxytocin was given at doses of 50 and 100 ng/rat according to the previous reports by Argiolas et al., and a-MSH was administered at 20 µg/rat from the results of our previous experiments. In the present study, oxytocin and a-MSH injected ICV evoked yawning behavior, but the potency of oxytocin seemed to be less effective in causing yawning compared with the previous report by Argiolas et al. We have no adequate explanation for this difference in effect at prescrit, but it may be due, at least in part, to differences in species and/or strains used in both studies.
 
Previous experiments have shown that the yawning responses to dopaminergic agonists were increased by administration of beta-adrenoceptor antagonists such as pindolol and propranolol. The yawning responses to cholinergic agents such as physostigmine, pilocarpine, and tacrine were also increased by treatment with the a-adrenoceptor antagonist, pindolol Moreover, the potentiation was elicited by central beta-adrenoceptor blockers such as propranolol and others, which reach the brain through the blood-brain barrier, but not by peripheral a-adrenoceptor blockers (carteolol and atenolol), indicating that potentiation by beta-blockers occurs in the brain. The yawning induced by RS-86 administered SC and ICV was potentiated by treatment with the beta-adrenoceptor blocker pindolol in the present study. In addition, the occurrence of yawning behaviors produced by the neuropeptides oxytocin and a-MSH given ICV was markedly potentiated by treatment with pindolol.
 
It bas been reported that oxytocin-induced yawning is inhibited by [d(CH2)5Tyr(Me)2,Orn8]-vasotocin, an oxytocin receptor antagonist. In the present study, the yawning produced by oxytocin administered in combination with pindolol was also blocked by d(CH2)5Tyr(Me)2,Orn8] -vasotocin, whereas that by a-MSH or RS-86 plus pindolol was unaffected, suggesting that the yawning responses are elicited via different receptor mechanisms. The yawning evoked by ACTH, an a-MSH-related peptide, was also reported to be unaffected by oxytocin receptor antagonists.
 
The yawning induced by muscarinic receptor agonists was reported to be blocked by muscarinic receptor antagonists, but was unaffected by dopamine receptor antagonists. In the prescrit study, the yawning behavior elicited by RS-86, a muscarinic M1 receptor agonist, administered in combination with pindolol was inhibited by scopolamine, a muscarinic receptor antagonist, but not by spiperone, a dopamine D2 receptor antagonist.
 
The yawning produced by oxytocin after pindolol was also antagonized by scopolamine, without being affected by spiperone. These results seem to be in agreement with the previous proposal that the expression of yawning induced by dopaminergic agonists involves dopamine-oxytocin, but not oxytocin-dopamine, linkage. The yawning evoked by an a-MSH-related peptide, ACTH, which was unaffected by oxytocin receptor antagonists, was also reported to be prevented by cholinergic receptor antagonists.
 
Our previous results also indicated that none of the responses to a-MSH, yawning, stretching, and body shaking, are associated with changes in the activities of the nigrostriatal, mesolimbic, tuberoinfundibular, or tuberohypophyseal dopaminergic neurons, and that a-MSH-induced yawning is decreased by administration of cholinergic receptor antagonists. In the present study, the yawning evoked by a-MSH administered after pindolol was antagonized by scopolamine, but not by spiperone. From such findings, the oxytocin- and a-MSH-induced yawning responses appear to involve cholinergic, but not dopaminergic, activation, although further investigation is warranted to identify the neuronal circuit between the peptidergic-cholinergic-linked neuronal system involved in causing yawning behavior. It is also suggested that the activation of a muscarinic receptor constitutes the expression of yawning as a common mechanism. Moreover, the present results also indicate that beta-adrenoceptors seern to be involved in the yawn-inducing neuronal mechanism linked to cholinergic neurons and thereby play an inhibitory role in modulation of occurrence of the behavior.
 
Body shaking was reported previously after administration of various drugs such as a-MSH, thyrotropin-releasing hormone and 5-hydroxytryptophan, and after electrical stimulation of the hippocampus in rats. The present study also confirmed that ICV administration of a-MSH induced body shaking.
 
The present results suggest that the neuropeptides oxytocin and a-MSH and the muscarinic M1 receptor agonists produce yawning via activation of cholinergic mechanisms, and that beta-adrenoceptors are involved in regulation of the yawning induced by the neuropeptides.