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
23 mai 2011
Pharmacol Biochem Behav
2011;98:169-172
5-HT6 pharmacology inconsistencies
 
Franco Borsini , Fabio Bordi, Teresa Riccioni

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1. Introduction
 
Despite considerable research as summarized in several thorough reviews on serotonin type-6 (5-HT6) receptor physiopharmacology within the past decade the functional role of 5-HT5 receptors remains ambiguous. For example, it is not yet understood why putative 5-HT5 receptor agonists and antagonists may share some odd similarities in their pharmacological properties, as in the case of their potential antidepressant Underlying some of these behavioral discrepancies are, we believe, ambiguous results on some basic aspects of 5-HT5 receptor pharmacology. The discrepancies in the literature began even before the identification of selective 5-HT5 receptor ligands, in work with antisense oligonucleotides to critical portions of the 5-HT6 receptor.
 
 
2. A 5-HT6 behavioral syndrome (yawning, stretching and chewing)?
 
A particular behavior syndrome resulting from blockade of 5-HT5 receptors was characterized by Bourson et al. (1995). Lacking selective 5-HT6 receptor antagonists, Bourson et al. (1995) utilized 5-HT antisense oligonucleotides (AO) complementary to bases into 18 of the rat 5-HT6 cDNA. After intracerebroventricular oligonucleotide administration twice a day at 6 or 12 pg/rat for four days, AO-treated animals displayed a dose-dependent specific behavioral syndrome consisting of yawning, stretching and chewing 16 h after the final treatment, which continued for the following 7-8 days. This syndrome was dose-dependently attenuated by the antimuscarinic compound atropine, but unaffected by the dopamine antagonist haloperidol. Food-intake, body temperature, body weight, and heat sensitivity were unchanged by AO administration. The regimen of AU treatment was found to reduce the number of 5-HT5 receptors by 30% in the frontal cortex, without modifying 5-HT1A and 5-HT2A receptor binding sites. AU administration also did not affect striatal dopamine and DOPAC levels.
 
However, subsequently the same group reported that intracerebreventricular AU for 5-HT6 receptors reduced body weight and food intake, in apparent contrast to their prior publication. Moreover, Yoshioka et al. (1998) administered intracerebroventricularly 14 pg/rat/day AU with an osmotic pump for 7 days and also found a reduction in 5-HT6 receptors by 30% in membranes coming from whole brain, with no specific behavioral signs observed after AO administration. Similarly, Hamon et al. (1999) and Utano et al. (1999) with AU administration regimens lasting 4-7 days also did not observe the specific behavioral syndrome first reported by Bourson et al. (1995). Several years later, Wolley et al. (2001) again found no evidence of the specific behavioral syndrome after AO twice daily for 6 days, and again in contrast to the initial Bourson et al. (1995) results, they reported an effect on food intake and body weight reduction after AU administration.
 
Using the selective 5-HT5 antagonist Ro04-6790, stretching and chewing were observed but not yawning. Similar observations were made by other researchers at Hoffman-LaRoche, by using a different 5-HT5 receptor antagonist (Bos et al., 2001). Lindner et al. (2003) found that, in contrast to cholinesterase inhibitor physostigmine, Ro04-6790 and the other 5-HT6 receptor antagonist SB-271046 induced stretching, whereas chewing was increased by Ro04-6790 and physostigmine but not by SB-271046; neither Ro04-6790 nor SB-271046 nor physostigmine modified yawning. Marcos et al. (2008) found that oral SB-271046 induced yawning, a behavior that was also maintained after 7 days of repeated administrations. However, no behavioral syndrome was observed by Reavill and Rogers (2001) with SB-271046, as well as by Stean et al. (2002) after oral SB-357134 (at doses ranging between 0.1 and 30 mg/kg, either after single or 7-day administration). Compound 4, a claimed 5-HT5 receptor antagonist, also failed to induce yawning, stretching and chewing (Russell and Diaz, 2002).
 
Although the majority of results with AU showed that rats did not display the behavioral syndrome, some of the studies with 5-HT6 receptor antagonists indicate the induction of at least some elements of the behavioral syndrome with the drugs tested. However, in general, the overall behavioral syndrome (stretching, yawning and chewing) is not a consistent phenomenon observed with either AO or 5-HT6 receptor antagonists in rats. This points out how the interpretation of the interaction between ligands and 5-HT5 receptors may possibly defect of better understanding of 5-HT6 receptor ligands, both in their pharmacodynamic and pharmacokinetics/metabolic properties.
 
6. Conclusions
 
Although experimental inconsistencies also exist for other 5-HT receptors, i.e. 5-HT1A and 5-HT2, the marked paucity of information on 5-HT6 receptors, due to the insufficient data on 5-HT5 receptor ligands, particularly hampers our understanding of 5-HT5 receptor pharmacology.
 
However, the picture of 5-HT5 receptors is more complex than expected, as their interaction with 5-HT6 ligands might also depend on neuroanatomical region. In fact, there is even a report that shows that the up-regulation in activity-regulated cytoskeleton-associated protein (Arc) mRNA expression caused by subcutaneous administration of the purported agonist LY586713 is blocked by the subcutaneous administration of the antagonist/inverse agonist SB-27 1046 in hippocampus and parietal cortex but not in cingulate and orbital cortex. Moreover, in the latter brain regions, the antagonist SB-27 1046 increased Arc mRNA expression similarly to the agonist LY-586713. Thus, regional brain differences also may then account for some of the inconsistencies. Such regional difference may well account for the discrepancies in microdialysis studies as well. Additionally, it remains to document whether the G proteins linked to 5-HT6 receptors are differently expressed in the different brain regions.
 
In the field of 5-HT6 receptors there are several inconsistent findings in need of further study. We think that experimental and procedural flaws might be, at least in part, at the source of these inconsistencies and such inconsistencies could be avoided if some precautions were taken. These include: 1) the use of different radioligands which can provide quite different results in affinity characterization studies; 2) the use of different tissues receptor density and biochemical readouts as these may affect the definition of a compound as silent antagonist, agonist or inverse agonist: 3) more information on possible active metabolites and/or pharmacokinetic differences across compounds that may produce vastly different in vivo neurochemical and behavioral profiles; and 4) more information on receptor selectivity.
 
Additionally, only very few studies use a 5-HT6 receptor antagonist to block the effect of an 5-HT6 receptor agonist. The reverse (5-HT6 receptor agonist against an effect mediated by 5-HT6 receptor antagonist) has never been assessed. If the 5-HT6 ligands competitively bind to the same site, the effect of an agonist should be counteracted by an antagonist, and vice versa.