mystery of yawning
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La parakinésie brachiale oscitante
Yawning: its cycle, its role
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Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
 
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
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mise à jour du
30 avril 2012
Pharmacol Biochem Behav
2012;102(1):118-123.
Dopaminergic D2-like agonists produce yawning in the myelin mutant taiep and Sprague-Dawley rats
Eguibar JR, Cortes MD, Lara-Lozano M, Mendiola DM.
Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Apdo. Mexico
 
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren

Chat-logomini

Abstract
 
Systemic administration of D2-like dopaminergic-receptor agonists increases yawning behavior. However, only a few studies have been done in animals with pathological conditions. The taiep rat is a myelin mutant with an initial hypomyelination followed by progressive demyelination, being the brainstem one of the most affected areas. In our experiments, we analyzed the effects of systemic administration of the D2-family agonists and antagonists on yawning behavior, and correlated them with the lipid myelin content in the brainstem and other areas in the central nervous system (CNS) in 8month old male taiep and Sprague-Dawley rats. Subjects were maintained under standard conditions in Plexiglas cages with a 12:12 light-dark cycle, lights on at 0700 and free access to rodent pellets and tap water. Drugs were freshly prepared injected ip at 0800 and subjects were observed for 60min. When antagonists were used it was administered 15min before the agonist.
 
Sprague-Dawley and taiep rats significantly increased their yawning frequency after systemic injection of (-)-quinpirole hydrochloride, R(+)-7-Hydroxy-2-(dipropylamino)tetralin hydrobromide (7-OH-DPAT) or trans-(±)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol hydrochloride ((±)-PD 128,907). Among D2-like agonists used higher effects are obtained with (-)-quinpirole. The effects caused by (-)-quinpirole can be reduced by (-)-sulpiride; and yawning caused by 7-OH-DPAT was decreased by tiapride only in taiep rats. In Sprague-Dawley only (-)-sulpiride is able to decrease (-)-quinpirole-caused yawning.
 
In conclusion, dopaminergic D2-like agonists are still able to cause yawning despite the severe myelin loss in taiep rats. Similarly, patients with various CNS illnesses that affect myelin, such as stroke or multiple sclerosis, are able to yawn suggesting that trigger neurons are still able to command this innate behavior.
 
1. Introduction
 
At the Institute of Physiology of the Benemérita Autonomous University of Puebla, México during a strict inbreeding process to obtain a high-yawning (HY) subline from Sprague-Dawley rats, we obtained as a spontaneous mutation that affects myelin and it is called taiep. The name is the acronym of a neurological motor syndrome characterized by tremor, ataxia, immobility episodes, epilepsy and paralysis during the first year of life (Holmgren et al., 1989). The illness is transmitted as an autosomic recessive trait (Duncan et al., 1992; Holmgren et al., 1989). These mutants show an initial hypomyelination followed by a progressive demyelination in the central nervous system (CNS), but not in the peripheral one (Duncan et al., 1992; Lunn et al., 1997). At the ultrastructural level, the taiep rat shows an abnormal accumulation of microtubules in the cytoplasm and its processes in the oligodendrocytes (Couve et al., 1997; Duncan et al., 1992).
 
When the oligodendrocytes were cultured the polymerization of microtubules was greater than depolymerization, which produced an accumulation of these cytoskeleton proteins. This alteration was reversed by the use of nocodazole and colchicine that suppress the microtubule assembly and partially depolymerize the existing microtubules (Song et al., 2003). It has been proposed that the accumulation of microtubules disrupts the translocation of newly synthesized proteins from the endoplasmic reticulum to the cis-portion of the Golgi apparatus (Couve et al., 1997; O´Connor et al., 2000). The mutant shows a decrease of all major myelin proteins such as myelin basic protein (MBP), proteolipid protein (PLP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), and the myelin-associated glycoprotein (MAG) levels in different portions of the CNS (Möller et al., 1997). All the pathways that myelinate after birth, such as corticospinal,dorsal columns, and optic nerves are more affected than the pathways that were already myelinated at birth, such as ventral columns in the spinal cord, suggesting a nonhomogeneous alteration in the myelin pathways (Lunn et al., 1997). The frequency of yawning is strongly dependent on dopaminergic neurotransmission (Holmgren and Urbá-Holmgren, 1980; Holmgren et al., 1982; Mogilnicka and Klimek, 1977; Yamada and Furukawa, 1981). Because the D2-like dopamine receptors are more involved in the regulation of this behavior, the D2 and D3 agonists have stronger effects on yawning in different strains of rats (Argiolas and Melis, 1998; Collins et al., 2005; Holmgren and Urbá-Holmgren, 1980; Holmgren et al., 1982); but until now there were no studies reporting yawning studies in animals with brain alterations and the taiep rats allow us to do this.
 
Taiep rats came from subjects with a higher incidence of spontaneous yawning with more than 20 yawns per hour (Urbá-Holmgren et al., 1990). Importantly, our research group showed a strong correlation among spontaneous- and dopaminergiccaused yawns and penile erections (Eguibar et al., 2003; Holmgren et al., 1985). The taiep rats are directly derived from a high-yawning subline which have different sensitivity to the D2-like dopaminergic agonists producing yawning (Urbá-Holmgren et al., 1993; Eguibar et al., 2003).
 
Later studies demonstrated that D2 agonists produced an increase in yawning and penile erection frequency in an inverted U-shape with the ascending limb caused by a D3 effect and the descending limb of the curve caused by an activation of D2 receptors (Baladi et al., 2010; Collins et al., 2005; Collins et al., 2009). In our present experiments, we analyzed the participation of the dopaminergic D2-like agonists and antagonists on yawning after systemic intraperitoneal administration of specific agonists and antagonists in normal outbred Sprague-Dawley and myelin mutant taiep 8 months old. We also analyzed the total protein and lipid content in the brainstem and other structures in the CNS of both groups of rats.
 
4. Discussion
 
The 8 month old male taiep rats showed a severe demyelination with just 18% of lipids in the brainstem compared to the control group. Similar decreases were obtained in the spinal cord (21%), but the cortex and cerebellum were less affected with just a 50% decrease on the lipid content compared to the Sprague-Dawley animals at 8 months. Detailed microscopic studies showed a general decrease of the myelin thickness with age in taiep rats, particularly in all myelin tracts that mature after birth (Lunn et al., 1997).
 
Because lipids are the major solid component in the CNS, about 70%, measurements of the total myelin content has been believed to be an adequate way to evaluate the degree of demyelination in myelin mutants (Norton, 1981). Similar decreases in the lipid content were reported in several myelin-mutant mice, such as jimpy, shivering, and quaking (Ganser et al., 1988). Instead of a myelin decrease, the D2-like dopaminergic receptors are still functional to produce a significant increase of yawning frequency. In this study we showed that (-)-quinpirole increases yawning frequency in both strains of rats, being more potent than (±)-PD 128,907 and 7-(OH)-DPAT. Similar results were obtained by Collins and his group in outbred Sprague-Dawley rats (Collins et al., 2005, 2007, 2009), suggesting that myelin is not the fundamental component to obtain maximum effects caused by dopaminergicgenerated yawning with these higher doses.
 
Binding experiments clearly demonstrated that (±)-PD 128,907 has a similar affinity for D3 receptors as 7-(OH)-DPAT. These D3 receptors are more abundant in the islands of Calleja followed by the nucleus accumbens, nucleus of the horizontal limb of the diagonal band, and the ventral caudate-putamen (Bancroft et al., 1998). Taiep rats show higher levels of D1 receptors in the ventral subregions of the basal ganglia compared to normal Sprague-Dawley rats, with these differences greater in rats older than 9 months. However D2-like dopamine receptor levels are similar in both groups of rats (Flores et al., 2002). For yawning, it has been shown that dopaminergic pathways from mesocortical, mesostriatal, and local dopaminergic pathways in the paraventricular nucleus of the hypothalamus (PVN) are involved in the regulation of yawning (Argiolas and Melis, 1998; Collins and Eguibar, 2010; Dourish and Cooper, 1990). Dopaminergic drugs acting on the PVN and through magnocellular nucleus axons project to the brainstem in which the central ensemble of neurons that generated and coordinated the musculature in the pharynx, larynx, and facial musculature are involved in the yawn reflex pattern. The dopamine exerts a tonic inhibitory control over cholinergic neurons that produced yawning (Holmgren and Urbá-Holmgren, 1980; Holmgren et al., 1982; Yamada and Furukawa, 1981). It is clearly stablished that an inverted U-shape doseresponse curve was obtained with the ascending limb of the curve mediated by D3 receptors and the descending limb mediated by the D2 receptors (Collins et al.,2005, 2007; Baladi et al., 2010, 2011). Because of the higher doses used in this study, only the descending limb of the curve was explored because at these doses there was a significant increase in the gripping-produced tonic-immobility episodes, a cardinal sign of this myelin-mutant rat (Eguibar et al., 2010), suggesting that taiep rats are less sensitive to D3 and D2 effects on yawning. For the D2-family antagonist used, the lack of effect is probably caused by the low spontaneous yawning frequency. However, tiapride is able to antagonize the increase of yawning frequency produced by 7-OH-DPAT in taiep rats because the myelin mutants had different sensitivity in D3 receptors and so this dose in Sprague-Dawley rats is on the descending limb of the dose-response curve, as previously suggested (Baladi et al., 2010, 2011; Collins et al., 2007, 2009). Under free access to chow taiep and Sprague-Dawley rats showed different sensitivities to the action of the D2-like dopaminergic agonists, which could explain the differences obtained when antagonists were administered before the agonist, because at that dose the 7-OHDPAT falls on the ascending limb of the dose-effect curve on taiep rats, but it could be on the descending limb in the Sprague-Dawley rats. The agonist is acting at D3 receptors in the former and quite probably in the D2 receptors in the latter (see Table 1 and Figure 2). This differences in the response to dopaminergic drugs can be because of age, gender, genetics, and nutritional status, as previously suggested (Baladi et al., 2011). In our results it is quite clear that the differences in the response to tiapride and 7-OH-DPAT are caused by the genetic background of taiep rats and why yawning frequency differs in both groups of rats.
 
In stroke patients the voluntary contractions of paralyzed arms is impossible, however during yawning this paralyzed arm is stretched. In the case of taiep rats the progressive demyelination produced, at 8-9 months old, a large reduction in the myelin sheath reaching 100%, 70%, and 70% in the corticospinal tract, ventral column, and the optic nerve (Lunn et al., 1997), but they are still able to respond to the D2-like dopaminergic agonists as also for hemiplegic patients in which apomorphine in low doses increased yawning and concomitantly the stretching of the paralyzed arm (Blin et al., 1994). It is quite remarkable that in humans there are only a few clinical reports in which neurological stroke patients are able to move their paralyzed arm during yawning (Wimalaratna, 1988). This movement is strictly concomitant with the yawn and the arm persists in being inert once the yawn ends (Blin et al., 1994; Walusinski et al., 2005, 2010). For most of these patients the lesions, which are located on the internal capsule affecting cortical and subcortical areas, are with the loss of myelin one cardinal sign after a stroke (Walusinski et al., 2005, 2009).
 
It is quite probable that a set of motoneurons that produces yawning are located in the brainstem, near the nerve centers that control the respiratory, laryngeal, and pharyngeal musculature (Barbizet, 1958; Heusner, 1946). These sets of motoneurons respond reflexively to the changes of dopaminergic transmission, as demonstrated in hemiplegic patients and now in the myelin mutant taiep rats. The upper parts of the CNS are able to modulate the threshold of motoneurons that are responsible for the control of facial musculature involved in yawning and also the musculature that stretches the paralyzed arm in stroke patients, the so called Parakinesia brachialis oscitans (Walusinski et al., 2005). There is a strong correlation of yawning and stretching to increase awakening when light-dark changes happen (Provine et al., 1987), another circumstance in which both the motor acts are expressed together probably to increase the awakening state.
 
5.- Conclusion
 
In conclusion, it is possible to cause yawning in the myelin mutant taiep rat through systemic injection of the D2-like dopaminergic agonists. The taiep is a myelin mutant with a progressive demyelination, and this response correlates with clinical observations of the presence of yawning behavior in hemiplegic patients in which the myelin is altered, but this reflex response commanded by dopamine neurons happens suggesting that it is wired in a coordinated way to produce that motor sequence.