The neuropharmacology of yawning
Argiolas A, Melis MR
Dopamine agonist-induced yawning in rats: a dopamine D3 receptor mediated behavior
Collins G et al
 Influence of different adrenoceptor agonists and antagonists on physostigmine-induced yawning in rats
Zarrindast MR
 Treatment with dexamethasone alters yawning behavior induced by cholinergic but not dopaminergic agonist
Hipolide DC
Yawning: an evolutionary perspective
Smith EO
EEG correlats of yawning during sleep onset
JV Laing & RD Ogilvie
Role of adrenergic neuronal activity in the yawning induced by tacrine in rats
Kimura H et all
Yawning behavior for preclinical drug evaluation
Furukawa T
Direct evidence for involvement of dopaminergic inhibition and cholinergic activation in yawning Yamada K  
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20 octobre 2002
 Sleep Medicine Reviews
Hypocrétine et vigilance
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Neuropharmacolgy of yawning
G Daquin, J Micallef, O Blin
Schematic model of neurotransmitter circuits that are involved in the three states of vigilance
The neuropharmacology of yawning Argiolas A, Melis MR
On yawning and its functions R Baenninger
Yawning: an evolutionary perspective Smith EO
The neurobiology of sleep: genetics, cellular physiology and subcortical networks Pace-Schott, Hobson
Yawning J Barbizet 1959
Neural basis of drug induced yawning
Cooper SJ, Dourish CT in Neurobiology of Stereotyped Behaviour
Yawning is under the control of several neurotransmitters and neuropeptides. While its neuropharmacology is complex and not yet fully understood, it could have useful applications.
In rats, dopamine receptor agonists--such as apomorphine and bromocriptine--are able to induce yawning, often together with penile erection in rats. This response is induced by selective D2 receptor agonists but not by type D1. Extremely low doses of a dopamine receptor agonist (quinpirole), that has 100 fold greater affinity for D3 than D2 receptors, induced yawning behaviour in absence of other effects. Therefore the authors have suggested that yawning may be a D3 mediated process. Logically, dopamine receptor antagonists like classical neuroleptics block these responses. The implication of dopamine presynaptic autoreceptor agonists has been amply discussed. For instance, Morelli demonstrated that a dopamine receptor agonist with high D1 receptor affinity was able to significantly reduce yawning evoked by apomorphine. Since dopamine autoreceptors are type D2, a D1 receptor antagonist is not expected to interact with them. Furthermore, Stalhe et al. demonstrated that apomorphine can induce hypomotility and yawning even when amphetamine elevated the extracellular level of dopamine.They showed, moreover, that apomorphine-induced yawning does not follow autoreceptor-induced reductions in neurotransmitter metabolism in the striatum . Lynch et al. obtained the same result in the mesolimbic region . These results suggest that D2 post synaptic receptors are involved in induced yawning, but that presynaptic autoreceptors, or D1 receptors are not. Proof of a possible involvement of D3 receptors must await further investigation. The site of action of dopamine receptor agonists is the paraventricular nucleus of the hypothalamus. This hypothalamus nucleus contains dopaminergic nerve endings; immunocytochemical studies have showed that dopaminergic synapses impinge on the cell bodies of oxytocinergic neurones in this nucleus. Moreover, oxytocin receptor antagonists prevent apomorphine induced yawning. These results suggest that dopamine receptor agonists induce yawning by activating oxytocinergic neurones. In healthy humans, we demonstrated that low doses of apomorphine also induce yawning, and various pathologies mainly related to dopaminergic system dysfunction show variations of spontaneous yawning frequency. Typical neuroleptics that have a dopamine receptor antagonist action, such as haloperidol, prevent apomorphine induced yawning. Concerning atypical neuroleptics, while certain authors have concluded that they do not prevent apomorphine-induced yawning, others have ascertained the contrary. In a double-blind placebo controlled study conducted in 1995, we investigated the effect of a pretreatment with amisulpiride (a D2-D3 blocker) on apomorphine induced yawning in healthy volunteers. Amisulpiride (300mg), which has been shown to improve negative symptoms in schizophrenic patients with predominant negative signs, and was therefore suggested to block dopamine presynaptic D2 receptors did not block apomorphine induced yawning. Several explanations might be proposed, among them are the following : yawning is not related to either D2 presynaptic receptor stimulation, or D3 receptor stimulation.
Oxytocin, a neuropeptid of the neurohypophysis, is mainly implicated in parturition and lactation. In fact, it is also present in the hypothalamus and is able to induce penile induction and yawning when injected in the central nervous system and especially in the paraventricular nucleus of the hypothalamus, in rats. This oxytocin-induced yawning is abolished by both atropine and scopolamine, which are antimuscarinic drugs, but not by dopamine D2 receptor antagonists such as neuroleptics. We can thus speculate that dopamine receptor agonists induce yawning by releasing oxytocin, which subsequently activates cholinergic transmission in another brain area. Experimental studies suggest that, in the paraventricular nucleus of the hypothalamus, oxytocin induces yawning by activating its own transmission. One of the oxytocinergic pathways, activated by oxytocin itself, which projects to extrahypothalamic areas and whose activation induces yawning, might be a hypothalamo-hippocampus pathway. However, oxytocin also projects endings to the pons and to the medulla oblongata.
Nitric Oxide (NO) is produced from arginine by Nitric Oxide Synthetase (NOS), a calciumÐcalmodulin dependent enzyme. Many compounds that induce yawning such as dopamine receptor agonist, NMDA, oxytocin increase NOS activity and thus NO production. Yawning induced by dopamine receptor agonists, NMDA, oxytocin is prevented by calcium channel blockade (w-conotoxin), a NOS inhibitor and oxytocin receptor antagonist. A NO-releasing compound injected in the medial part of the paraventricular nucleus of the hypothalamus (PVN) induces the stereotypical yawning response. The paraventricular nucleus of the hypothalamus is one of the brain areas richest in NOS activity. In the PVN, parvocellular and magnocellular neurons contain NOS. Parvocellular cells in the PVN send descending axons to the lower brainstem . These results suggest that dopamine D2 receptor agonists, NMDA, Oxytocin induce yawning by increasing intracellular calcium, which in turn activates NO synthesis, in the parvocellular cells of the paraventricular nucleus of the hypothalamus. These parvocellular neurons would project to respiratory, cardiovascular, motor and arousal systems in the lower brain stem.
Cholinergic drugs (physostigmine, pilocarpine …) induce yawning and muscarinic receptor antagonists prevent
yawning induced by dopamine receptor agonist, ACTH, MSH, oxytocin. These results suggest that yawning induced by these four drugs is mediated by cholinergic activation. In fact, M1 type muscarinic receptors are involved in this reaction. Cholinergic transmission has therefore been suggested being the final step of the neuronal pathway involved in yawning. The site of the brain where acetylcholine receptor agonists induce yawning may well be the hippocampus; indeed mesoseptal dopaminergic neurons play a role in the control of the hippocampal cholinergic neurons. Moreover MSH, when inducing yawning, increases acethylcholin turnover rate in the hippocampus of the rat. However, in humans, Skorzewska did not find a significant correlation between yawning and a muscarinic receptor antagonist injection.
The central administration of adrenocorticotropin hormone (ACTH) or melanocyte stimulating hormone
(MSH) induced recurrent episodes of yawning and stretching in different animal species. Beta adrenoceptor agonist (salbutamol) and muscarinic M1 receptor antagonist inhibit yawning produced by these wo neuropeptides, but not by dopaminergic activation or inhibition. Hence, ACTH and MSH produce yawning via activation of a cholinergic mechanism. Recent studies have led to the cloning of the ACTH- MSH receptor genes. They are present in several brain areas including the hypothalamus, the midbrain and the brainstem. One of these sites is probably involved in the yawning-stretching syndrome. ACTH and ?MSH induced yawning and stretching (when injected into the hypothalamus periventricular region of the third ventricule) is prevented by a selective melanocortine 4 (MC4) receptor antagonist. A MC1 receptor selective agonist was able to induce yawning and stretching. ACTH-MSH induced yawning is prevented by calcium channel blockade and by nitric oxide synthetase inhibitor, suggesting that these neuropeptids probably exert their effect via nitric oxide activation. In humans, Melaton II, a non selective melanocortin receptor agonist, induces erections, increase of sexual desire, nausea and stretching-yawning behaviour.
Post-synaptic serotoninergic 5HT1a receptor agonists have an inhibitory effect on yawning induced by dopamine receptor agonists. Inhibitory serotoninergic receptors seem to be located on the terminal dopaminergic neuron on the striatum. Depletion of serotonin potentiates dopamine receptor agonist induced yawning. Serotoninergic 5HT1c receptor agonist, mCPP and TFMPP induced yawning in both the rat and humans. These yawns are inhibited by NOS inhibitor but not by oxytocin receptor antagonist. As such, nitric oxide seems to be implied in this induced yawning.
Morphine, an opioid receptor agonist inhibits dopamine receptor agonists (bromocriptine), ACTH and cholinergic drugs (physostigmine, pilocarpine) induced-yawning in rats. Naloxone reverses this effect. The paraventricular nucleus of the hypothalamus contains endogenous opioid peptides and mu subtype opoïd receptors. Moreover, a decrease of nitric oxide was measured, during in-vivo microdialyse, concomitant to the inhibition of yawning behaviour. This decrease could result from a decrease of the calcium influx in the oxytocinergic cells which in turn would induce a decrease in nitric oxide synthetase. In humans, yawning is a frequent withdrawal sign in heroin addicts.
In rats, spontaneous yawning is more frequent in males than in females. Dopamine receptor agonists and oxytocin induced yawning is abolished by castration. It can be restored by substitution therapy with estradiol alone or with estradiol and testosterone. In intact male rats, estrogen inhibits dopamine receptor agonist induced yawning, and testosterone has no effect. Sexual hormones modulate both spontaneous and induced yawning behaviour. Luteinizing hormone releasing hormone (LHRH) has been reported to antagonize induced yawning. However, in humans yawning frequency does not differ between men and women.
Adrenalin and noradrenalin
Yawning induced by dopaminergic and cholinergic agents, ACTH, MSH and oxytocin, is facilitated by beta adrenoreceptor blockade (propanolol, pindolol). However, pindolol has also 5HT1a blocking properties that might explain yawning facilitation. In contrast, yawning is inhibited by alpha2 pre-synaptic receptor blockade, which increases noradrenaline release. The central adrenergic may thus take part in the regulation of the yawning.
N.methyl-d-aspartic acid (NMDA)
NMDA, an excitatory amino acid agonist of NMDA receptor subtype, induces yawning NMDA induces this behavioural response by increasing intracellular calcium concentration in the oxytocinergic neurons, thus activating nitric oxide synthetase, nitric oxide synthesis and hence oxytocinergic transmission.
Gama amino butyric acid (gaba)
GABA-B receptor agonists (baclofen 3mg/kg) inhibit the yawning response by modulating acetylcholine transmission. GABA-A receptor activation also inhibits yawning. Neurotensin Neurotensine has been reported to antagonize drugs that induce yawning.
In conclusion the literature review shows that the pharmacological mechanisms underlying yawning are complex and that many systems and neuro-mediators are involved. Nonetheless, knowledge of the pharmacology of yawning could be useful for the experimental pharmacology of new drugs. First, it enables the study of the actions of psychotropic drugs on the different brain systems. For instance, a drug that produces yawning but antagonizes dopamine receptor agonist induced yawning may be a dopamine receptor partial agonist. It is also possible to functionally discriminate between central and peripheral beta adrenoreceptor antagonists. If apomorphine-induced yawning is increased by a beta adrenoceptor antagonist, it means that it has a central action. As clinical evaluation of new psychoactive drugs is difficult and animal screening is difficult to transpose to humans, knowledge of their central pharmacological action could be useful. Moreover, hypotheses about the biological basis of severe psychiatric illness have been stimulated by knowledge of the mechanism of action of psychotropic agents. Lastly, the neuro-pharmacology of yawning provides information about the physiology of yawning and hence the physiopathology of diseases associated with abnormal yawning behavior.
New Scientist: The Big Yawn 19 Dec 98 (pdf)