fig 6

figure 6


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mise à jour du
12 décembre 2002
Acta Neurobiol, Exp
Interaction of cholinergic and dopaminergic
inflences en yawning behavior
Holmgren B and Urba -Holmgren R
Departmento de neurofisiologia, La Habana, Cuba
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


Two different neurotransmitters, acéehylcholine (ACh) and dopamine (DA) have been recently postulated to neurohumoral mechanisms, underlying the act of yawning. One group of investigators working on physostigmine- and pilocarpine-induced yawning in infant rats, has stressed the role of central muscarinic cholinergic synapses, because the yawning effect induced by both cholinomimetic drugs is blocked by scopolamine. On the other hand, Mogilnicka and Klimek have described that low doses of systemically injected DA agonists in adult rats produce recurrent episodes of yawning, responses which are completely inhibited by the DA antagonist spiperone. Basically similar observations have been later reported by Di Chiara et al.

As physostigmine-induced. yawning, both in infant and in 45-dayold rats, is strongly potentiated by previous administration of Lu 10-171 (citalopram), a potent and selective serotonin uptake blocking drug, a suggestion has also been advanced that serotonin (5-HT) may exert a modulating effect on yawning behavior serotonergic-modulation.html.

Some questions immediately arise when these results are considered. Are the ontogenetic curves of yawning induced by cholinergic or dopaminergic drugs similar or different? May cholinergic and dopaminergic pathways somehow interact in the induction of yawning? Does serotonin also modulate dopaminergically-elicited yawning?

The experiments presented in this paper try to give an answer to these questions in the hope that a unified hypothesis regarding the neurohumoral basis of yawning may eventually emerge. This seems to be a relevant problem, since it has been shown that several other conditions or drugs are able to induce yawning: intraventricular infusions or intracerebral injections of adrenocorticotrophic hormone (ACTH) or fragments of ACTH, spreading depression of the neocortex and hippocampus, and administration of naloxone. [...]

Discussion : After Mogilnicka and Klimeik's demonstration that yawning may be elicited in adult rats by the administration of dopaminergie drugs, our previous suggestion that yawning might be a cholinergic response needed re-examination. Cowan had also, pointed out that other factors, aparat from cholinergic mechanisms, could induce yawning. He recalled that i.m. administration of dimethyltryptamine causes yawning in rhesus monkeys. DPI, (3,4 dihydroxyphenylamino)-2-imidazoline, which has been described to have specific and potent agonistic activity on DA inhibitory receptors, also elicits yawning in infant rats.

In the present experiments, using apornorphine in the same low dose range as Mogilnicka and Klimek, we have confirmed their and Di Chiara results, showing that this drug definitely elicits yawning in adult male albino rats. We have also traced the ontogenetic course of this effect. Apomorphine does not induce yawning in 7-day-old rats, does it only slightly before the eleventh day, but quite distinctly by the 15th day, when the effect praetically reaches the same level observable until the end of the first month. A 50% higher average effect is obtained in adult rats (3-month-old). Increase with age of oher behavioral effects of DA agonists has recently been reported. The ontogenetic evolution of apomorphine-elicited yawning thus follows an absolutely different curve than the one which illustrates the same behavior evoked by physostigmine or pilocarpine.

Cholinomimetically-induced yawning is highest during the first seven postnatal days, falling thereafter to a level which is not significantly different from spontaneous yawning on the 21st day. The different maturation course of cholinergic- and dopaminergic-induced yawning responses naturally suggest different underlying mechanisms. Nevertheless, the fact that both cholinomimetic- and apomorphineelicited yawning are blocked by low doses of scopolamine, points to the decisive importance of some muscarinic cholinergic synaptic links in the neuroanatomical circuits subserving yawning. How could one envisage the coupling of dopaminergic and cholinergic synapses in order that yawning might be elicitable both by dopamino- or cholinomimetic agents and subject to block by scopolamine whatever the eliciting drug? One possible explanation is offered by the tentative and simple model presented in Fig. 6, in which DA and ACh synapses appear organized "in series", the latter exerting an excitatory influence on the central pattern generator of yawning behavior, and thus being able to trigger the response. The early maturation of yawning, both spontaneous and cholinornimetically-induced justifies the suggestion that the central pattern generator "yawning center" and its cholinergic trigger may have a quite caudal location in the brainstem. This is in keeping with the observation of yawning in anencephalic humans, with the opinion of the early reviewers of yawning behavior and the most recent description of yawning in a completely tetraplegic patient suffering from a transecting glioma of the pons.

Figure 6 also suggests that the cholinergic yawn-triggering neurons are under the control of later maturing inhibitory dopaminergic neurons. In rats, their gradual restraining influence on yawning behavior may be illustrated by the declining tendency of cholinomimetic yawning from around the 7th postnatal day onwards, which corresponds roughly to the reciprocal evolution of apomorphine-elicited yawning. In agreement with previous authors we interpret apomorphine induced yawning as the result of activation of low threshold presynaptic inhibitory DA receptors, "autoreceptors" of Carlsson, by low doses of apomorphine, thus liberating the cholinergic neurons triggering yawning from a tonic dopaminergic restraining influence. Higher doses of apomorphine or other DA agonists, by directly stimulating high threshold postsynaptic DA inhibitory receptors on the cholinergic neurons, would exert an inhibitory effect on yawning. The dose-effect of apomorphine-induced yawning demonstrates the very narrow dose range of this effect, which begins to decline already with 0.20 mg/kg. This seems to be the reason why authors studying stereotyped activity with higher doses of apomorphine failed to observe its yawning-eliciting action. If this interpretation is correct it could be expected that if excessive apomorphine is injected (for an optimal yawn-eliciting effect), and the concentration of the drug falls, as a result of metabolic degradation, late yawning activity might appear. We have confirmed this expectation in a group of 5 young adult rats injected with apomorphine (1 mg/kg). In that case significant yawning appeared only in the second half of a 60 min observation period while in rats injected with 0.05 mg/kg yawning began already 5 min after injection and had practically disappeared after half an hour (unpublished observations).

The "crossed blocking" experiment, in which physostigmine induced yawning is increased after blocking DA receptors with spiroperidol, while the same behavior elicited by apomorphine is decreased, provides further evidence in support of the idea that an important dopaminergic tonic inhibitory influence on yawning is present around the 15th postnatal day in the rat. The potentiating effect of spiroperidol on physostigmine-induced yawning is not significant in rats 7 to 11 days old, in concordance with the relative immaturity of the dopaminergic influences on yawning, as illustrated by the ontogenetic course of apomorphine-elicited yawning.

An important serotonergic facilitatory effect on physostigmine-induced yawning has been previously described. If DA and ACh synapses influencing yawning were organized as suggested in Fig. 6, it would be reasonable to expect that serotonin uptake inhîbitors should have a similar effect on apomorphine-elicited yawning as they have on that behavior evoked by physostigmine. Our experiments testing the action of citalopram and fluoxetin on yawning induced by apomorphine failed to demonstrate such effect. This is contradictory to the demonstration that a significant depression of apomorphine-elicited yawning is obtainable with metergoline and, therefore, difficult to explain. Thus, the idea that serotonergic pathways may exert a general tonic facilitatory or modulatory influence on yawning, although appealing, should perhaps require further substantiation.

The exploration of the effect of drugs modifying dopaminergic and cholinergic synaptic transmission upon yawning induced by other methods may help in testing the more general validity of the tentative model of organization of the synaptic links regulating and triggering yawning behavior presented in this work (Fig. 6)