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
Le bâillement, du réflexe à la pathologie
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
22 août 2011
Behav Pharmacol.
2010;21(3):171-181
Yawning and locomotor behavior induced by dopamine receptor agonists in mice and rats
Su-Min Li, Gregory T. Collins, Noel M. Paul, Peter Grundt, Amy H. Newman, Ming Xu, David K. Grandy, James H. Woods, Jonathan L. Katz
 
Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland USA.

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Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in Swiss&endash;Webster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 1000&endash;10 000-fold range of doses, with activity at control levels (U-91356A) or above control levels [(±)-7-hydroxy-2-dipropylaminotetralin HBr, quinpirole] at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors.
 
 
Introduction
 
The dopaminergic (DA) D3R is classified as a member of the D2-like family of dopamine receptors based on its close sequence homology to the DA D2R (Sokoloff et al., 1990). The relatively restricted localization of the DA D3R in mesolimbic brain areas has contributed to the interest in this receptor, and it has been suggested as a therapeutic target for various psychiatric disorders (see reviews by Joyce and Millan, 2005; Newman et al., 2005).
 
Despite a considerable amount of research on the DA D3R, an understanding of the receptor and the pharmacology of its ligands, particularly in vivo, remains incomplete (Levant, 1997; Xu et al, 1999). Moreover, the relative selectivity of various putative D3R ligands can vary substantially from one study to the next, and depend on features of the assays, including especially the radiolabel used (Levant, 1997).
 
In addition to the paucity of selective agonist and antagonist ligands, studies of the in-vivo pharmacology of putative DA D3R ligands have been hindered by a lack of functional assays that are uniquely and selectively responsive to actions at DA D3 receptors. Several in-vivo effects have been suggested as functional consequences of DA D3R activity. Reports of studies conducted, in rats show biphasic dose-effect curves with decreases in locomotor activity at low doses yielding to stimulation of activity at higher doses. Several investigators have suggested that the decreases obtained at low doses of DA agonists are because of actions at presynaptic DA receptors, whereas others have suggested that the decreases in activity were because of actions at the DA D3R (Daly and Waddington, 1993; Gilbert and Cooper, 1995; Pugsley et al., 1995; Bristow et al., 1996; Depoortere et al., 1996; Maj et al., 1999; Rogóz and Skuza, 2001). Most of the earlier reports on the effects of DA agonists on locomotor activity in mice indicate only dose-related decreases (Pugsley et al., 1995; Geter-Douglass et al., 1997; Tirelli et al., 1997; Xu et al., 1999; Boulay et al., 1999a, 1999b; Pritchard et al., 2003).
 
Yawning in rodents has long been associated with DA activity (e.g. Mogilnicka and Klimek, 1977; Holmgren and Urbá-Holmgren, 1980; Yamada and Furukawa, 1980). As noted by Collins et al. (2005), early hypotheses attributed yawning to various DA mechanisms, and more recently the biphasic dose-effect curve has been suggested to be because of a DA D3R mediated stimulation of yawning, accompanied by a DA D2R inhibition of the effect. Drugs with preferential activity at the DA D3R should produce a biphasic dose-effect curve (Kostrzewa and Brus, 1991; Levant, 1997). Indeed, studies of several DA agonists, including; PD 128907 ((S)-(+)-(4aR, 10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxa zin-9-ol HCl), quinelorane, and (±)-7-hydroxy-2-dipropy-laminotetralin HBr (7-OH-DPAT) produced significant, dose-dependent increases in yawning with maximum stimulation at an intermediate dose, and decreases from this maximum at the highest doses. Several antagonists with reported selectivity for the DA D3R, including U-99,194A, SB 277011A, PG01037, and less so nafadotride, shifted the ascending limb of the biphasic dose-effect curve rightward, without the effects on the descending limb. In contrast, the nonselective antagonists, haloperidol, and raclopride, shifted the entire biphasic dose-effect curve rightward, whereas the DA D2R preferring antagonist, L-741626, selectively shifted the descending limb of the biphasic dose-effect curve (Collins et al., 2005; Sevak et al., 2007).
 
These studies were initiated to further explore the respective roles of dopamine receptor subtypes in the yawning induced by DA D3R preferring agonists. It was hypothesized that the biphasic dose-effect curve for the agonists would be absent, or substantially modified, in mice with a genetic deletion (knockout) of the DA D2 receptor (DA D2R KO) compared with wild-type (DA D2R WT) mice. In the initial stages of the study it was determined that, in contrast to what was obtained in rats, yawning was not produced by DA D3R preferring agonists in mice, including 7-OH-DPAT, PD 128907, quinpirole, quinelorane, and the nonselective agonist, apomorphine. However, casual observations indicated that several of the DA D3R preferring agonists decreased locomotor activity which was then studied fully to ensure that the absence of yawning was not because of the lack of sufficient dosage. The decreases in activity became of interest because they were reversed at higher doses with several agonists, and because they occurred over a profound range of doses. The range of doses was much greater than that for the decreases in activity in rats, and indeed much greater than the range of doses over which most behaviorally active drugs have their effects. In this study, we focused on the decrease in activity using pharmacological tools and mutant mouse lines to characterize its mechanism.
 
Discussion
 
In this study the DA agonists, 7-OH-DPAT, and PD 128907, produced dose-related increases in yawning in rats at low to intermediate doses, and less of an increase at the highest doses, as in earlier studies (Collins et al, 2005, 2007). In addition, low doses of the drugs produced a decrease in locomotor activity that resolved at higher doses. In contrast, yawning was not produced in mice by any doses of several DA agonists, but was reliably produced by physostigmine. The effects of physostigmine indicate that the yawning response can be induced in mice, but does not appear to be activated by a variety of drugs that induce yawning in rats through DA D3R mechanisms.
 
Collins et al. (2005) suggested that the inhibition of yawning that appears at higher doses of DA agonists and contributes to the descending limb of the biphasic dose-effect curve appears to be mediated by DA D2R agonist actions. In their study, the DA D2R preferring antagonist L-741626, selectively antagonized the descending limb of the PD 128907 and quinelorane dose-effect curves. This effect was also obtained without appreciable change in the ascending limb of the dose-effect curve for a variety of other DA D3R-preferring agonists, consistent with these two dopamine receptors producing opposing effects on yawning (Collins et al, 2007).
 
Thus, the possibility exists that the absence of yawning in mice is because of prepotent DA D2R mediated inhibitory effects that preclude the expression of an otherwise DA D3R mediated stimulation of yawning.
 
We examined the hypothesis that prepotent DA D2R-mediated effects interfered with the expression of a DA D3R-mediated induction of yawning by examining mice with a genetic deletion of the DA D2R, and by administering the putative DA D2R selective antagonist, L-741626. According to the hypothesis, eliminating actions either by genetic deletion or by pharmacological blockade of the receptor would be expected to show a full expression of yawning behavior in the mouse.
 
However, neither DA D2R KO nor WT mice showed any yawning after administration of either 7-OH-DPAT or PD 128907. In addition, casual observations during studies of interactions of L-741626 and the agonists on locomotor activity did not show instances of yawning. Furthermore, the lack of difference between DA D2R WT and KO mice in the effects of physostigmine indicates the absence of a generalized DA D2R-mediated inhibitory effect on yawning.
 
Thus, the absence of yawning appears unrelated to the relative potencies of DA D2R-mediated and D3R-mediated actions in the mouse and suggests differences between rats and mice with regard to the pharmacological actions of DA D3R agonists.
 
 
Across the range of doses that were examined, several of the DA agonists produced a decrease in locomotor activity in mice and rats. In rats, the decreases in activity were obtained over a restricted range of doses. In particular with 7-OH-DPAT a significant effect at 0.03 mg/kg was not obtained at three-fold higher or three-fold lower doses. In contrast, the relation of this effect to dose in mice was remarkable in that decreases were obtained across a relatively wide range of doses, from 1000-fold to 10 000-fold with 7-OH-DPAT and quinpirole. There were substantial differences among the agonists with respect to effects at the higher doses in mice. For PD 128907, none of the higher doses returned activity to control levels, and with U-91356A, the highest dose studied only returned activity to control levels. The variability across drugs in the effects of the highest doses, and the remarkably wide range of doses over which the decreases in locomotor activity were obtained, prompted the present focus on the pharmacology of the decreases in activity. The observation that some, but not all DA agonists produced hyperactivity at the highest doses tested tempts an interpretation of differences among the drugs with respect to high-dose toxicity, however, that suggestion requires further investigation.
 
 
A low-dose inhibition of locomotor activity that is resolved at higher doses has been reported in the past (e.g. Daly and Waddington, 1993; Pugsley et al., 1995; Bristow et al, 1996; Maj et al, 1999), and has been variously attributed to presynaptic DA D2R activity (e.g. Millan et al, 2004) and actions mediated by the DA D3R (e.g. Gilbert and Cooper, 1995; Bristow et al, 1996; Shafer and Levant, 1998; Maj et al, 1999). These studies with DA D2R KO and WT mice suggest that the effect is mediated, at least in part, by the DA D2R, as it was obtained in the DA D2R WT but not KO mice. In addition, decreases in locomotor activity were obtained in both DA D3R WT and KO mice. The DA D2R actions mediated by both presynaptic or postsynaptic DA D2R requires additional studies.
 
None of the antagonists studied were effective in blocking the agonist-induced decreases in locomotor activity obtained at the low to intermediate doses. Indeed L-741626, rather than antagonizing, added to the locomotor decreasing effects of 7-OH-DPAT, quinpirole, and PD 128907. The lack of antagonism may not be surprising given the multitude of pharmacological agents that can decrease locomotor activity, and by implication the presumed mechanisms that may contribute to the effect on locomotor activity. Studies of antagonist effects in mutant mice may elucidate some of these mechanisms. Nonetheless, an antagonist with sufficient selectivity such as what has been reported at least among dopamine receptor subtypes (e.g. Grundt et al, 2007), should have blocked the effects of its respective agonist, if the agonist was sufficiently selective in producing its effects. Despite significant effects of genotype in the effects of L-741626 on DA D2R mutant mice, the differences in sensitivity to the effects of L-741626 itself were relatively small in the two lines of mice. That finding, along with the general lack of antagonism of the effects of the agonists underscores the extant need for more selective pharmacological tools, both agonists and antagonists, to study dopaminergically-mediated behavioral effects better.
 
These studies document significant differences in the pharmacology of DA agonists in mice and rats.
 
The most pronounced of these differences is the absence of yawning induced by the agonists in the mouse. Although yawning can be induced through other mechanisms in the mouse, it appears that yawning will not provide an in-vivo indication of DA D3R activation in the mouse. PD 128907 was different from the other DA agonists in that the decreases in locomotor activity were not resolved at high doses of the drug. Mechanisms contributing to the differences in the pattern of dose-effects on locomotor activity are not presently clear though it seems likely that these differences reflect differences in potencies for effects contributing to the decreases and the increases at higher doses.
 
 
In summary, the DA D3R preferring agonists, 7-OH-DPAT, and PD 128907, produced a biphasic stimulation of yawning in rats and a biphasic inhibition of locomotor activity. In contrast, these effects were different in mice; yawning was not produced by DA agonists, and the decreases in locomotor activity were characteristically obtained over a relatively broad range of doses. The decreases in locomotor activity appear to be because of the actions of the drugs at the DA D2R. These results are not inconsistent with earlier results indicating opposing modulation of yawning by the DA D3R and D2R in rats, though further studies on the role of the DA D3R in mice are clearly necessary.
 
 
-Collins C, Truccone A et al. Pro-erectile Effects of Dopamine D2-like Agonists are Mediated by the D3 Receptor in Rats and Mice. J J Pharmacol Exp Ther 2009;329(1):210-217
-Canales JJ, Iversen SD Psychomotor activating effects mediated by dopamine D2 and D3 receptors in the nucleus accumbens Pharmacol Biochem Behav 2000;67:161-168
-Canales JJ, Iversen SD Dynamic dopamine receptor interactions in the core and shell of nucleus accumbens differentially coordinate the expression of unconditioned motor behaviors Synapse 2000;36:297-306
-Collins GT, JM Witkin et al Dopamine agonist-induced yawning in rats: a dopamine d3 receptor mediated behavior. J Pharmacol Exp Ther 2005;314(1):310-319
-Collins GT, Newman AH,Woods JH et al.Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists. Psychopharmacology (Berl). 2007;193(2):159-170
-Collins GT. et al. Food restriction alters pramipexole-induced yawning, hypothermia, and locomotor activity in rats: Evidence for sensitization of dopamine D2 receptor-mediated effects. JEPT 2008;325:691-697
-Collins GT et al. Narrowing in on compulsions: dopamine receptor functions Exp Clin Psychopharmacol 2008,16(4):498,502
-Chen J, Gregory T. Collins, et al. Design, Synthesis, and Evaluation of Potent and Selective Ligands for the Dopamine 3 (D3) Receptor with a Novel in Vivo Behavioral Profile. J Med. Chem., 2008;51(19):5905&endash;5908
-Collins GT, Truong YN, et al. Behavioral sensitization to cocaine in rats: evidence for temporal differences in dopamine D(3) and D (2) receptor sensitivity. Psychopharmacology (Berl). 2011;215(4):609-20.
Li SM, Collins GT et al. Yawning and locomotor behavior induced by dopamine receptor agonists in mice and rat. Behav Pharmacol. 2010; 21(3):171&endash;181.