mise à jour du
25 septembre 2003
Naunyn-Schmiedeberg's Arch Pharmacol
1981; 316; 155 -160  
The yawning elicited by alpha-melanocyte-stimulating hormone involves serotonergic-dopaminergic-cholinergic neuron link in rats
Katsushi Yamada and Tatsuo Furukawa
Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka, Japan


Introduction : Frequent yawning has been observed as a symptom in a patient with adrenoleucodystrophy accompanied by high blood adreno-corticotrophic hormone (ACTH) levels, and as a characteristic sign of morphine abstinence in man. Associated with these clinical observations have been the proposal that yawning can be elicited by administrations of certain agents to animals.
Intracerebral injection of ACTH, alpa-melanocytestimulating hormone (a-MSH) or beta-lipotrophic hormone produced a specific stretching-yawning syndrome, and cholinergic agonists also induced yawning in infant rats (Urba-Holmgren et al. 1977). We recently obtained the fact that intraperitoneal injection of apomorphine at low doses which inhibit dopamine release from presynaptic sites induced yawning in adult rats (Yamada and Furukawa 1980a). Although it is thus suggested that cholinergic and dopaminergic functions seem to participate in yawning behavior, neuronal mechanisms involved in yawning still remain to be elucidated.
In the present study, we found that a-MSH produced not only stretching-yawning syndrome but also 'Wet-Dog' body shaking, and investigated the neuronal mechanisms involved in the yawning as well as body shaking behavior.
Discussion : Piribedil, a direct dopamine receptor agonist, induced yawning without producing typical symptoms of behavioral excitation at low doses, but brought about stereotypy at higher doses. This yawning was blocked by a long-acting neuroleptic, fluphenazine, which blocks presynaptic receptors as well as postsynaptic dopamine receptors. These results are all consistent with our previous observation that apomorphine exerts biphasic effects on behavior, i. e., yawning and hypomotility at low doses, and stereotypy and hypermotility at higher doses.
Low doses of apomorphine preferentially activate presynaptic dopamine autoreceptors, which results in an inhibition of dopamine release and consequent decrease of its synthesis, while higher doses stimulate postsynaptic receptors. Accordingly, as our previous proposal with apomorphine, the yawning elicited by low doses of peribedil seems to be due to an activation of presynaptic dopamine autoreceptors, whereas stereotypy induced by higher doses may be attributed to a stimulation of postsynaptic dopamine receptors.
The septal-hippocampal cholinergic pathway has well been delined by histochemical, biochemical and electrophysiological techniques. Specific destruction of the doparninergic neurons projecting to the septum by injection of 6-hydroxydopamine into the all mesencephalic cell group and blockade of dopamine receptors by intraseptal haloperidol resulted in an increase in the turnover rate of acetylcholine in the hippocampus. On the contrary, systemic injection of apomorphine caused a dose-dependent decrease in the acetylcholine turnover rate in the hippocampus. Thus, the dopaminergic neurons seem to play an inhibitory role in the control of the septal-hippocampal cholinergie neurons. Recently, Wood et al. (1979) have proposed that the septal-hippocampal cholinergic neurons are necessary to elicit a specific stretching-yawning syndrome following a-MSH or ACTH since intraventrieular injection of a-MSH or ACTH increases the acetylcholine turnover rate in the hippocampus of rats.
In the present study, physostigmine, and anticholinesterase agent, and pilocarpine, a cholinergic agonist predominantly acting upon muscarinic receptors, similarly elicited yawning as previous observation.
Moreover, the piribedil-induced yawning was inhibited by scopolamine, which blocks muscarinic cholinergic receptors. On the basis of these experimental rindings, it is very likely that an activation of cholinergic neurons resulting from an inhibition of dopamine release from presynaptic sites in the dopaminergic-cholinergic neuron link is also involved.
In the present experiment, since high doses of apomorphine which stimulate postsynaptic dopamine receptors failed to inhibit the pilocarpine-induced yawning, postsynaptic sensitivity of cholinergic neurons to a direct acetylcholine agonist may be unaltered in the dopaminergic-cholinergic neuron system. However, the a-MSH- and physostigmine induced yawnings were blocked by high doses of apomorphine, suggesting that stimulation of postsynaptic dopamine receptors by dopamine agonist and consequent inhibition of cholinergic neurons seem to account for this blocking effect of apomorphine. On the other hand, high dose of piribedil conversely increased both physostigmine- and pilocarpine induced yawnings. There is no obvious explanation for this stimulation by piribedil, but this fact may favour the previous proposal that piribedil exerts different effects on dopaminergic neurons from those of apomorphine.
Methysergide, a selective antiserotonergic drug, suppressed both a-MSH and piribedil-induced yawnings though it did not affect both physostigmine- and pilocarpine-produced yawnings. There has been a proposal that serotonergic neurons play an inhibitory control of dopaminergic function in the extrapyramidal and mesolimbic dopamine system. It seems therefore that the inhibitory effects of methysergide on both a-MSH- and piribedil induced yawnings may be due to the disinhibition from the serotonergic inhibition and a consequent increase of dopamine release from dopaminergic terminals in the serotonergic-dopaminergic neuron link. However, the serotonergic activation produced by the combined administration of 5-HTP with Ro 4-4602 did not induce yawning though it markedly produced 'Wet-Dog' body shaking. Accordingly, although serotonergic activation may be a positive modulating factor in elicitation of yawning, serotonergic neurons appear to be less primary mechanisms than dopaminergic and cholinergic neurons. The present results thus point out the possibility that serotonergic activation, dopaminergic inhibition and cholinergic activation are concomitantly involved in the yawning.
However, as mentioned above, the inhibitory effect of methysergide on yawning was seen in both a-MSH- and piribedil-induced yawnings but was not observed in both physostigmine- and pilocarpine-induced yawnings. In addition, our previous work showed that blockade of dopamine receptors by systemic injection of fluphenazine increased the yawning elicited by physostigmine but did not affect that by pilocarpine. In this study, the a-MSH-induced yawning was inhibited by fluphenazine, as similar proposal that ACTH-induced stretching-yawning syndrome was suppressed by chlorpromazine. Therefore, these results might imply that situation in elicitation of yawning is more complicated than would appear, and that mode of action of alpha MSH and ACTH is dissimilar to those of physostigmine and pilocarpine.
It has been reported that "Wet-Dog" body shaking was interextingly observed , together with yawning, in morphine withdrawal rats. and after injection of thyrotrophin releasing hormone or 5-HTP. Intraventricular injection of alpha MSH also induced body shaking at early stage after injection, which was followed by stretching and yawning. This alpha MSH induced body shaking was blocked by methysergide, apomorphine or flphenazine, but was not blocked by scopolamine. the body shaking induced by 5-HTP was similarily inhibbited by methysergide, cryptheptadine, apomorphine or haloperidol but was not inhibited by scopolamine. Consequently, the body shaking elicited by alpha-MSH may involve in part an activation of serotoninergic neuron activity.
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