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mise à jour du
11 novembre 2002
Pharmacol Biochem Behav
1992; 43; 483-486
Age-dependent changes in serotoninergic modulation of yawning in the rat
Urba-Holmgren R, Holmgren B, Leon B, Ugarte A
Departemento de ciencas fisiologicas, Universidad Autonoma de Puebla, Mexico
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


In a previous article, it was reported that physostigmine (PHY)-induced yawning in infant (6-7 days old) and young (45 days old) rats was significantly increased when animals were pretreated with citalopram, a selective serotonin (5-HT) uptake inhibitor. Because this effect was counteracted by metergoline, which blocks 5-HT receptors, and this drug per se did not show any action on yawning, it was suggested that 5-HT may exert a positive modulatory effect on this behavior. Similar results were obtained when infant rats were tested with fluoxetine and pirandamine, two other 5-HT uptake inhibitors.

A few years later, Okuyama et al reported that both apomorphine (APO)- and PHY-induced yawning in adult rats were reduced by administration of the 5-HT precursor 5hydroxytryptophan. Moreover, they found that APO- but not PHY-induced yawning was enhanced by pretreatment with p-chlorophenylalanine, a 5-HT synthesis inhibitor, or by the serotonin neurotoxin 5-7 dihydroxytryptamine. Because these drugs do not elicit yawning when given alone, their results led them to suggest that 5-HT exerts a negative modulatory influence on yawning.

Although different serotonergic drugs were used in the above-mentioned studies, perhaps the main difference between them was the age of rats, a methodological fact that might have led to the opposite findings. Therefore, it was decided to repeat the experiments with citalopram, exploring its effects on rats 15 days to 5 months old from a SpragueDawley inbred subline of rats characterized by its low incidence of spontaneous yawning (LY subline). From this last point of view, these animals may be comparable to the Wistar rats used in the former experiments.

The discovery of several subtypes of central 5-HT receptors and the subsequent development of selective serotonergic agonists and antagonists allows a new approach for research on the role of this neurotransmitter in yawning behavior. To extend previous findings, two of these compounds were used - methiothepine (5-HT, /5-HT2 antagonist) and ritanserin (5-HT1c/5-HT2 antagonist)-to counteract citalopram effects. [...]

Discussion : The age-related effects of citalopram on PHY-induced yawning here described agree with previous reports on the pharmacological manipulation of serotonergic systems modulating yawning. Former results with infant and young rats were confirmed: These animals show a significant increase in PHY-induced yawning when preinjected with citalopram. On the other hand, and confirming Okuyama et al.'s results, an increase in serotonergic tone in adult rats reduces yawning. Hence, it seems necessary to consider these results in the context of what is now known about the development of 5-HT neurones in the rat brain after birth.

It is well known that rats are born neurologically and behaviorally immature and that neuronal and glial growth in the CNS are mainly postnatal events. Loizou, studying the postnatal ontogeny of monoamine-containing neurones in the CNS of the rat with histochemical and biochemical techniques, found that at the end of the first postnatal week 5-HT terminals in the lower brain stem and the spinal cord have almost the same densities as in the adult. Mesencephalic, diencephalic, and telencephalic 5-HT terminal proliferation occurred later, between the second and third weeks. Loizou also reported that adult 5-HT concentration is reached at the end of the fourth week in all brain areas with the exception of the telencephalon, in which at this period it bas only reached a level of 68%. The main features of these results have been confirmed by other authors. These data raise the possibility that serotonergic pharmacological manipulation might have different electrophysiological and behavioral consequences depending upon the age of animals, as Frambes et al. demonstrated studying feeding behavior in infant rats, and could be related to differential development of various 5-HT receptor subtypes. To explain the apparent discrepancies between Okuyama et al.'s and Urba-Holmgren et al.'s results, it is suggested that a gradual decline in serotonergic facilitatory effects on yawning takes place due to a particular 5-HT receptor subtype disappearing with age or being gradually replaced or counteracted by another 5-HT receptor subtype population with opposite effects. The second alternative seems more attractive and is supported by histochemical, biochemical, and electrophysiological evidence. Nevertheless, Borton and Docherty recently reported that 5-HTIB-mediated responses in rat vas deferens are lost with maturation and aging. Therefore, the first alternative canne be excluded without further research.

5-HT receptors have recently been classified into three major groups: 5-HT1, 5-HT2, and 5-HT3. The 5-HT, receptor subgroup is further subdivided into 5-HT1a, 5-HT,1b, 5-HT1c, and 5-HT1d, subtypes. This classification has led to the development of new and relatively more selective 5-HT agonists and antagonists, such as methiothepine, which antagonizes both 5-HT2 and all 5-HT, receptor subtypes, and ritanserin (5-HT1c/5-HT2 antagonist). Because methiothepine, but not ritanserin, counteracts citalopram positive modulatory effects on PHY-induced yawning, when infant rats are used as experimental subjects it might be suggested that this action is due to 5-HT1a or 5-HT1b receptor activation rather than through 5-HT1c or 5-HT2 receptor subtypes.

In regard to yawning in adult animals, because both above-mentioned antagonists are ineffective the suggestion might be that the inhibitory effect of citalopram could be due to 5-HT3 receptors and that 5-HT1 and 5-HT2 may be ruled out. Definitive and less speculative conclusions must await the development of (and experimental trials with) more specific antagonists of each of the different serotonergic receptor subtypes than methiothepine and ritanserin.

Interactions between serotonergic and cholinergic systems in the control of different functions and behaviors have been reported, some of them possibly exerted directly through presynaptic receptors localized on cholinergic terminals in the CNS. Serotonergic facilitatory or inhibitory effects on yawning behavior might be exerted directly through different types of serotonergic receptors localized on central cholinergic neurones, which play an important role in yawning behavior. But, the possibility should be explored that these serotonergic influences could be exerted indirectly by modulating, or interacting with, the activities of other monoaminergic neurotransmitters (dopamine or norepinephrine) or neuropeptides (corticotropin, oxytocin, prolactin), the effects of which on yawning behavior are also well known and have been reviewed recently . A deeper discussion of these possibilities is clearly beyond the purposes of this experimental report.