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Yawning.

The ubiquitousness of normal yawning and the existence of abnormal yawning warrant an understanding of this reflex. Its mechanisms and functional role are not entirely known. A review of the literature reveals that yawning is a brain stem arousal reflex with both peripheral and central loops subserving reversal of brain hypoxia or hypoxemia. Behaviorally, yawning is a semi-involuntary act that occurs also because of loss of interest in the surroundings and it is not necessarily associated with fatigue. Socio-environmental factors can influence the emergence of yawning. Dopaminergic, acetylcholinergic, ACTHergic and oxytocinergic systems are involved in the generation and modulation of yawning in animal experimentation.

Animals↗

Yawning and stretching induced by transcranial application of AC pulsed electromagnetic fields in Parkinson's disease.

Yawning is considered a brainstem regulated behavior which is associated with changes in arousal and activity levels. Yawning and stretching are dopamine (DA) mediated behaviors and pharmacological studies indicate that these behaviors are associated with increased DA release coupled with stimulation of postsynaptic DA-D2 receptors. Despite their relation to the dopaminergic system, yawning and stretching are poorly documented in untreated or treated patients with Parkinson's disease (PD). A 49 year old fully medicated female patient with juvenile onset PD is presented in whom recurrent episodes of yawning and stretching developed during transcranial administration of AC pulsed electromagnetic fields (EM Fs) of picotesla flux density. These episodes have not been observed previously in this or other patients during treatment with levodopa or DA receptor agonists or in unmedicated PD patients during treatment with AC pulsed EMFs. It is suggested that yawning and stretching behavior resulted in this patient from a synergistic interaction between EMFs and DA derived from levodopa supplementation with EMFs possibly facilitating the release of DA and simultaneously activating postsynaptic DA-D2 receptors in the nigrostriatal dopaminergic pathways. In addition, it is postulated that the release of ACTH/MSH peptides from peptidergic neurons in the brain upon stimulation of the DA-D2 receptors reinforced the yawning and stretching behavior.

Antiparkinson Agents↗

[Yawning. Physiopathology and neuropharmacology].

Yawning is a common physiological phenomenon, induced by hunger, sleepiness or impersonation. Its behavioral aim seems to be an effort to vigilance. There are numerous pathological reasons explaining yawning, as for example global (infectious, metabolic and toxical) or focal neurological diseases. The modification of yawning in pathology where a dopaminergic dysfunction is to be found, as well as some data of animal experimentation, support when it takes place the dopaminergic system's implication. The pre-synaptical receptor's role had been suggested for a long time but actually yawning seems to be linked with a D1-D2 cooperation. The cholinergic system probably control a final effective pathway. We also imply the peptidergic, serotoninergic, androgine and opiace systems. If the localization of a putative center of yawning is impossible, the nigrostriatal dopaminergic pathway, the paraventricular nucleus of hypothalamus and the pituitary gland play a major role. Yawning can be used as a functioning index of the dopaminergic system in vivo in the human being.

Animals↗

Yawning elicited by systemic and intrastriatal injection of piribedil and apomorphine in the rat.

The behavioural effects of systemic and intrastriatal injections of the dopamine agonists piribedil and apomorphine in male rats were examined. Bilateral application of piribedil (50 and 100 micrograms) or apomorphine (5, 10 and 20 micrograms) to the striatum produced yawning and chewing mouth movements accompanied by intermittent stretching and sexual arousal. Low doses of piribedil (1.25 and 2.5 mg/kg) and apomorphine (0.1 and 0.2 mg/kg) injected SC produced an identical yawning syndrome. Previous work has suggested that yawning elicited by systemic dopamine agonist treatment is a consequence of dopamine autoreceptor stimulation. Similarly, the most likely explanation of the present data is that yawning elicited by systemic and central dopamine agonist treatment was due to activation of dopamine autoreceptors. Systemic injection of haloperidol and scopolamine abolished yawning induced by intrastriatal piribedil and these data provide tentative support for the proposal that a dopamine-acetylcholine link may be involved in the expression of yawning.

Animals↗

Dopamine receptors mediating yawning: are they autoreceptors?

Yawning was induced in rats by the (+) enantiomer of 3PPP, while (-)-3PPP was inactive. Yawning was present 24, but not 1, 6 and 12 h after reserpine treatment. The (+)-3PPP-induced yawning was antagonized by haloperidol and sulpiride but not by domperidone. Reserpine-induced yawning was antagonized by sulpiride and by alpha-methyltyrosine suggesting that this behavior may be induced by endogenously released dopamine. Reserpine-pretreatment potentiated (+)-3PPP-induced yawning. The results argue against the view that yawning is the behavioural correlate of autoreceptor-mediated inhibition of DA transmission, and suggest that this behaviour is due to the stimulation of a special population of central postsynaptic DA receptors.

Animals↗

Effects of apomorphine, TL-99 and 3-PPP on yawning in rats.

Dopaminergic agonists, apomorphine (APO) (0.025-0.25 mg/kg, s.c.), TL-99 (0.5-3 mg/kg, s.c.) and 3-PPP (0.15-10 mg/kg, s.c.) elicited yawning in rats and the dose-response curves of all 3 compounds showed a bell-shaped form. Haloperidol (0.02 mg/kg, s.c.) reduced the yawning induced by DA-agonists to about 50%. The potencies of the DA-agonists in inducing yawning were APO greater than TL-99 greater than 3-PPP (comparable to potencies obtained in other in vivo tests, determining DA-ergic activity). The findings support the validity of the yawning phenomenon as a screening test for DA-agonists. Additionally, it was found that apomorphine induced yawning was significantly and dose-dependently enhanced by the beta-agonist, formoterol. This effect was counteracted by scopolamine, not changed by metergoline and further increased by l-propranolol. These data support the hypothesis of cholinergic involvement in yawning and indicate a role, though unclear at present, of beta-receptors in this behaviour.

Adrenergic beta-Agonists↗

Post-lesion yawning and thalamotomy site.

Yawning during hyperventilation occurred in certain patients post-thalamotomy. It was found that all of the lesions which elicited yawning (during the routine recording of electroencephalograms) were localized to the medial portion of the center-median nucleus. Yawning was noted to persist up to 3(1/2) years post surgery. Another group of patients who yawned when hyperventilated were patients with a history of a recent head injury who showed post-traumatic behavioral changes. Patients in both groups were young. There was no direct relationship between yawning and EEG abnormality. It was suggested that yawning during hyperventilation may serve as a sign of brain damage, especially at the brain stem level, in young patients.

Adolescent↗

Opiate-androgen interactions in drug-induced yawning and penile erections in the rat.

The effects of pretreatment with drugs on drug-induced yawning and penile erection in intact and chronically castrated rats were investigated. Naloxone partially blocked yawning in intact rats and in castrated rats pretreated with dihydro-testosterone propionate (DHTP) but not in control castrates. In contrast, naloxone potentiated apomorphine-induced penile erections in intact rats. Morphine, haloperidol and atropine blocked yawning and penile erections. Methyl naloxone, methyl atropine and domperidone at doses which are selectively peripheral-acting had no effect on drug-induced yawning or penile erection indicating that both effects are mediated centrally. Pretreatment with morphine did not change the naloxone effects in intact rats. The results indicate a naloxone-androgen interaction in drug-induced yawning but the results with morphine are not consistent with a role of opiates in this interaction. The penile erection data support a direct opiate-dopamine receptor interaction in this response. The haloperidol and atropine effects support a cholinergic-dopaminergic interaction in both yawning and penile erections.

Animals↗

Apomorphine-induced yawning in rats is abolished by bilateral 6-hydroxydopamine lesions of the substantia nigra.

Apomorphine-induced yawning was studied in male rats with bilateral 6-hydroxydopamine lesions of the substantia nigra. Apomorphine 10, 20 and 50 micrograms/kg SC induced dose-dependent yawning in unoperated controls and animals with sham lesions. In the lesioned animals (in which the mean striatal dopamine depletion was 67%), the maximum yawning response rate was greatly attenuated with no evidence that the dose response curve was shifted in either direction. Furthermore, blockade of yawning in the lesioned animals was not simply due to suppression by other stereotyped behaviours, since there was no evidence of increased sniffing or chewing in these animals. These data provide further support for the hypothesis that apomorphine-induced yawning is mediated by dopamine autoreceptors and requires intact nigrostriatal projections.

Animals↗

Potentiation of yawning responses to the dopamine receptor agonists B-HT 920 and SND 919 by pindolol in the rat.

Subcutaneous injection of B-HT 920, a dopamine D2-receptor agonist, in doses ranging from 5 to 100 micrograms/kg, induced yawning behavior in rats. Yawning was also elicited by low doses (25-500 micrograms/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 beta-adrenoceptors.

Adrenergic beta-Antagonists↗

Effects of acetylcholine agonists and antagonists on yawning and analgesia in the rat.

The ability of acetylcholine muscarinic agonists, injected subcutaneously (s.c.) to elicit yawning and analgesia (tail-flick response) in rats was examined. Yawning was elicited by physostigmine, RS86 and pilocarpine with an inverted 'U'-shaped dose-response relationship; maximal effects occurred at 0.1, 0.5 and 2.0 mg/kg respectively. Neostigmine (0.05-0.2 mg/kg); arecoline (0.5-2.0 mg/kg); bethanecol (0.1-10 mg/kg) and McN-A-343 (5-20 mg/kg) had marginal or no activity. In contrast, dose-related analgesia was obtained following oxotremorine (0.01-0.3 mg/kg) and arecoline (0.5-4.0 mg/kg) and physostigmine (0.1-0.4 mg/kg), RS86 (0.25-2.5 mg/kg) and pilocarpine (0.5-8.0 mg/kg). The effects of acetylcholine antagonists on physostigmine-induced yawning and physostigmine-induced analgesia were also investigated. Following their s.c. injection, trihexyphenidyl, atropine, dicyclomine, secoverine and methylatropine but not pirenzepine, inhibited both yawning and analgesia; there were clear differences in their potencies on the two responses. Pirenzepine, intracerebroventricularly (i.c.v.), inhibited yawning (ED50 value 5.7 micrograms/rat) but not analgesia (3-100 micrograms/rat). The results are discussed in terms of a possible functional differentiation of central muscarinic receptors.

Acetylcholine↗

Effect of excitatory amino acid receptor antagonists on apomorphine-, oxytocin- and ACTH-induced penile erection and yawning in male rats.

The effect of excitatory amino acid receptor antagonists, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5, 10-imine hydrogen maleate ((+)-MK-801), (+/-)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and (+/-)-2-amino-4-phosphonobutanoic acid (AP-4), on penile erection and yawning induced by subcutaneous apomorphine (80 micrograms/kg), intracerebroventricular (i.c.v.) oxytocin (30 ng) and adrenocorticotropin (ACTH)-(1-24) (10 micrograms) was studied in male rats. Intraperitoneal (0.1-0.4 mg/kg) and i.c.v. (10-50 micrograms) (+)-MK-801 prevented dose dependently the penile erection and yawning induced by the three drugs. The (+)-MK-801 effect coincided with the appearance of head weaving, body rolling, hyperlocomotion and ataxia. Haloperidol (0.5 mg/kg i.p.) antagonized the prevention by (+)-MK-801 of oxytocin responses. Penile erection but not yawning was also prevented by high, but not low doses of CPP and CNQX, which impaired motor performance, AP-4 was ineffective at all doses tested. The above compounds were ineffective when injected into the paraventricular nucleus of the hypothalamus, the brain area where apomorphine and oxytocin act to induce penile erection and yawning. The results suggest that excitatory amino acid transmission is not involved in the expression of penile erection and yawning induced by the above compounds.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

Effects of adenosine receptor agonists and antagonists on physostigmine-induced yawning.

The effect of adenosine receptor agonists and antagonists on physostigmine-induced yawning was investigated in intact or cannulated rats. Intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of physostigmine to rats induced yawning dose dependently. I.p. or i.c.v. treatment of the animals with atropine, theophylline, 5-N-ethylcarboxamidoadenosine (NECA) or N6-cyclohexyladenosine reduced the yawning induced by i.p. injection of physostigmine. I.p. administration of theophylline decreased the yawning induced by i.c.v. injection of physostigmine. The inhibitory action of N6-cyclohexyladenosine (i.p.) also was decreased by 8-phenyltheophylline (i.p.) pretreatment. It is concluded that yawning induced by a central cholinergic mechanism and a central adenosine mechanism interacts with the cholinergic-induced behaviour.

Adenosine↗

Penile erection and yawning induced by 5-HT1C receptor agonists in male rats: relationship with dopaminergic and oxytocinergic transmission.

1-(3-Chlorophenyl)piperazine (m-CPP) (0.1-4 mg/kg s.c.) and N-(3-trifluoromethylphenyl)-piperazine (TFMPP) (0.5-4 mg/kg s.c.), 5-HT1C receptor agonists, but not 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT) (0.1 and 0.2 mg/kg s.c.), a 5-HT1A receptor agonist, induced penile erection and yawning with a U-inverted dose-response curve in male rats. The maximal effect was found with 0.5 mg/kg s.c. of m-CPP and with 1 mg/kg s.c. of TFMPP. The m-CPP (0.5 mg/kg s.c.) and TFMPP (1 mg/kg s.c.) responses were prevented by mianserin (0.2 mg/kg s.c.) and by ritanserin (1 mg/kg s.c.) given 15 min before m-CPP and TFMPP. In contrast, m-CPP- or TFMPP-induced penile erection and yawning were not antagonized by haloperidol (0.1 mg/kg s.c.) or by [d(CH2)5Tyr(Me)2,Orn8]vasotocin (5 micrograms i.c.v.). Apomorphine- and oxytocin-induced penile erection, but not yawning, was also antagonized by mianserin and less effectively by ritanserin. The results suggest that 5-HT1C receptor agonist-induced penile erection and yawning are not mediated by increased dopaminergic and/or oxytocinergic transmission, and raise the possibility that a neuronal dopamine-oxytocin-5-HT link is involved in the control of penile erection and not necessarily of yawning in male rats.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Nitric oxide donors induce penile erection and yawning when injected in the central nervous system of male rats.

In order to provide further support for a role of central nitric oxide as a mediator of penile erection and yawning, the nitric oxide donors sodium nitroprusside, hydroxylamine, isoamyl nitrite and S-nitroso-N-acetyl-penicillamine were injected into the lateral ventricles (i.c.v.) or into the paraventricular nucleus of the hypothalamus of male rats. Of the above compounds injected i.c.v., only isoamyl nitrite (10-100 micrograms) induced penile erection and yawning, while the others induced dramatic behavioral changes, such as motor hyperactivity and convulsions, that masked the above responses. Nevertheless, nitric oxide donors in doses ranging from 10 to 50 micrograms, for except S-nitroso-N-acetyl-penicillamine that was injected only at the dose of 10 micrograms and isoamyl nitrite that was not injected at all because of poor solubility, induced penile erection and yawning when injected in the paraventricular nucleus. Nitric oxide donor-induced responses were prevented by methylene blue and LY 83583, inhibitors of guanylate cyclase, the best known target of nitric oxide, given i.c.v. but not in the paraventricular nucleus. However, 8-bromo-guanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a stable cGMP analog, and hemoglobin, a nitric oxide scavenger, were ineffective in inducing and preventing, respectively, penile erection and yawning when injected either i.c.v. or in the paraventricular nucleus. Nitric oxide donor-induced responses were also prevented by the nonapeptide oxytocin receptor antagonist d(CH2)5-Tyr(Me)-Orn8-vasotocin given i.c.v. but not in the paraventricular nucleus. The present results suggest that nitric oxide donors induce penile erection and yawning by activating central oxytocinergic transmission in the paraventricular nucleus of the hypothalamus via a cGMP-independent mechanism.

Animals↗

Blockade of apomorphine-induced yawning in rats by the dopamine autoreceptor antagonist (+)-AJ 76.

The effects of the putative, selective dopamine autoreceptor antagonist (+)-AJ 76 on yawning, penile grooming and mouth movements induced by small doses of apomorphine in male rats were examined. Yawning induced by 0.05mg/kg apomorphine was dose dependently blocked by (+)-AJ-76, significant decreases being observed at 0.86 and 3.5mg/kg of the drug. A dose of 0.86mg/kg (+)-AJ 76 caused a two fold shift to the right of the apomorphine dose response curve for yawning. In contrast, (+)-AJ 76 had no effect on penile grooming and vacuous mouth movements induced by small doses of apomorphine. This pattern of results is similar to that observed after bilateral 6-hydroxydopamine-induced lesions of the substantia nigra which also blocked apomorphine-induced yawning but spared penile grooming and mouth movements. Previous studies have suggested that (+)-AJ 76 is a selective dopamine autoreceptor antagonist that has little or no effect on behaviour mediated by post-synaptic dopamine receptors. Therefore, these data provide further support for the hypothesis that apomorphine-induced yawning is mediated by dopamine autoreceptors.

Animals↗

Field observations of yawning and activity in humans.

Rates of wrist activity and yawning were recorded continuously for 7-15 days in adult human male and female subjects. In the 15 min following 747 yawns wrist motion increased reliably in all subject records. The data were consistent with an hypothesis that yawning is predictive of an increase in activity level. In a second study, data from daily logs kept by 45 subjects confirmed previous findings that yawning frequency is unrelated to prior amount of sleep, or to times of awaking or retiring. More yawning occurred during the week than during weekends.

Adolescent↗

Penile erection and yawning induced by paraventricular NMDA injection in male rats are mediated by oxytocin.

The effect of N-methyl-D-aspartic acid (NMDA), (+-)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA), or (+-)-trans-1-amino-1,3-cyclo-pentanedicarboxylic acid (ACPD) (5-60 ng in 0.3 microliter of saline) microinjected in the paraventricular nucleus of the hypothalamus on penile erection and yawning was studied in male rats. NMDA induced both penile erection and yawning in a dose-dependent manner. AMPA and ACPD also induced penile erection but less potently than NMDA, but were ineffective in causing yawning. NMDA effect on penile erection and yawning was prevented by (+)-MK-801 (0.05-0.1 mg/kg IP, 10 min before NMDA), by the oxytocin antagonist d(CH2)5Tyr(Me)-Orn8- vasotocin (50-100 ng ICV 10 min before NMDA), but not by haloperidol (0.1-0.5 mg/kg IP 10 min before NMDA). The results suggest that NMDA induces penile erection and yawning by increasing oxytocinergic transmission by acting in the paraventricular nucleus of the hypothalamus.

Animals↗