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mise à jour du 9 janvier 2003
Cephalagia
1987;7(sup 6):131-137
lexique
Yawning:neurochemistry, physiology and pathology
Antonio Argiolas, M.Rosaria Melis, Gian Luigi Gessa
Department of Neurosciences, University of Cagliari, Italy
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren

Chat-logomini
The central administration of adrenocorticotropin (ACTH) and a-melanocyte stimulating hormone (alpha-MSH) induces in different animal species a complex behaviour characterized by recurrent episodes of yawning, stretching, penile erection and ejaculation.
This behaviour is considered a specific central effect of ACTH-MSH peptides, since it is not observed after their peripheral administration, nor is induced by any other known peptide tested (1-5). It was found that the total peptidic extract from few rat hypothalami produced penile erection. ejaculation, yawning and stretching when injected into the lateral ventricle of a recipient rabbit (3). This finding is surprising because the total hypothalamic content of the combination ACTH and a-MSH is about a thousand times lower than the minimum dose of these peptides necessary to induce the above mentioned effects (6,7). This raises the possibility that some other substance, able to induce these behaviours, might be present in the hypothalamus in addition to ACTH and a-MSH. In order to test this hypothesis, we fractioned a peptidic extract from rat hypothalamus by high pressure liquid chromatography (HPLC), and tested each fraction for its ability to induce yawning. stretching and penile erection. Here we report that another peptide is present in the hypothalamus which is capable of induping penile erection and yawning with a potency of at least 500 times that of ACTH and a-MSH. This peptide is oxytocin.

Among the 45 fractions tested, only that eluting at 15 min induced penile erection and yawning when injected into the recipient animals. The equivalent of 15 hypothalamic induced at least 4 penile erections and 20 yawns during the 60 min observation. Biological activity was destroyed by digestion with Pronase (Boehringer Kannheim) indicating that the active substance was a peptide(s). In order to identify the active peptide, the active fraction from 1000 hypothalami was combined after the first HPLC step, reinjected in the Bondapak C18 colomn, and eluted isocratically with 22% B. The activity eluted es a sharp peak at 13 min, either at 210 or 280 nm. Amino acid and sequence analysis, performed as previously described (10), revealed that the peptide was identical to oxytocin.We calculated from amino acid anilysis that 6 nmol of oxytocin were isolated from 1000 hypothalami. Indeed synthetic oxytocin coeluted with the hypothalamic peptide.

The ability of oxytocin to induce penile erection and yawning was unexpected since in previous studies oxytocin was found completely inactive(3). These contrasting observations led us to further characterize oxytocin effect on penile erection and yawning. A significant increase in the number of penile erections and yawns occurred when a dose as low as 5 ng of oxytocin was injected into a lateral ventricle. Yawning episodes, alone or together with stretching, usually started 8-10 min after i.c.v. injection, and the highest number of yawns was seen with the dose of 20 and 60 ng of the peptide. These doses also induced the highest number of penile erections and intense genital grooming. The symptomatology lasted for 1 to 2h. However, in contrast to low doses, the injection of oxytocin in doses of 120 and 1200 ng produced neither yawning nor penile erection.

Unlike oxytocin, the i.c.v.injection of equimolar doses of arg-vasopressin, which differs from oxytocin only in 2 amino acids, Phe3 and Arg8 instead of ile3 and Leu8 failed to induce sexual stimulation and yawning. In agreement with previous studies (11), doses of arg-vasopresssin higher than 5 ng caused severe motor disturbances and barrel rotation, a symptonatology that lasted for 15-20 min after treatment. After recovery the animals showed an apparently normal behaviour but failed to show yawning or penile erection for up to 1 hr. Equimolar amounts of i.c.v. ACTH 1-24. a-MSH, corticotropin releasing factor (CRF), delta sleep inducing peptide, neurotensin and substance P produced no-overt behavioural changes. ACTH 1-24 and a-MSH induced stretching, yawning and penile erection at doses of 2 nmol (results not shouwn), in agreement with previous studies (1-3).

In order to clarify the mechanism of oxytocin-induced penile erection and yawning, we studied the influence of different drugs on this behaviour. Pretreatment with antimuscarinic atropine (10 mg/kg i.p.) or morphine (5 mg/kg i.p.) completely abolished penile erection and yawning induced by the peptide. On the contrary, methylatropine (10 mg/kg i.p.), that does not cross the blood brain barrier, and the opiate antagonist naloxone (l mg/kg i.p.) were ineffective. Haloperidol (l mg/kg i.p.), a dopamine receptor antagonist, prevented sexual behaviour, but not yawning.

The present results show that the intraventricular injection of very low doses of oxytocin induces penile erection and yawning in male rats. No explanation is available at present for the ineffectiveness of relatively high doses of the peptide to induce such behaviours, although this is in agreement with previous studies showing an inverted U-shaped dose-response curve for other effects of oxytocin (12,13).

The ability by different drugs to interfere with oxytocin-induced penile erection and yawning, gives an indication of the complex central mechanisms underlying such behaviours. Atropine prevention of oxytocin effects indicates that the central cholinergic system plays a role in the expression of penile erection and yawning in agreement with previous studies (14). Similarly, prevention by morphine of penile erection and yawning suggests that central opioid systems are implicated in the expression of such behaviours induced by oxytocin. However it is unlikely that opioids exert a tonic inhibitory control. on such behaviours since opioid receptor blockade by naloxone was ineffective in modifying oxytocin effect. On the other hand, central dopaminergic systems seen to be implicated mainly in the expression of the sexual response to oxytocin since the latter effect but not yawning was antagonized by dopamine receptor blockade suggesting that the two behaviours might be mediated by different mechanisms, in spite of the fact that they often appear concomitantly. Accordingly, castration has been shown to eliminate the sexual response, but leaving the yawning response to ACTH-MSH peptides unmodified (2,3).

So far only two means were known to be able to induce both penile erection and yawning in experimental animals: one is the systemic injection of apomorphine and other dopaminomimetic agents (15-17), the second is the injection of ACTH-MSH peptides into the cerebrospinal fluid or specific brain areas (2,3). We have shown that oxytocin also induces these behaviours. Whether or not penile erection and yawning induced by oxytocin, ACTH-MSH peptides and dopaminomimetic drugs, are mediated by the same mechanisms (i.e. endogenous oxytocin is implicated in the expression of such behavicurs in:juced by ACTH-MSH peptides and dopaminergic drugs or vice-versa), is unknown at present.

 
Indeed oxytocin effects are antagonized by atropine and morphine, but not by naloxone, similarly to ACTH-MSH- and dopaminomimetic-induced yawning and sexual behaviour (1,2,14). However, two important features distinguish oxytocin effect from that of ACTH-MSH peptides: 1) the doses of oxytocin that induce penile erection and yawning (5.-60 pmol) are much lower than those of ACTH-MSH peptides (1-2 pmol) (2,3); and 2) oxytocin-induced penile erection and yawning be&in 8-10 min afte.-.i.c.v. injection of the peptide, while a lag of 25-30 min is always observed after i.c.v. injection of ACTH-MSH peptides (2,3). The reason for the long latency in the effect of ACTH-MSH peptides has never been clarified. It is tempting to speculate that ACTH-MSH peptides induce yawning, stretching and sexual behaviour by releasing oxytocin in some brain area. The latency in ACTH-MSH response might be due to the time necessary for ACTH-MSH peptides to release enough oxytocin to elicit the symptomatology.
 
Similarly dopaminomimetic drugs might induce yawning and penile erection by enhancing oxytocin release in some brain area. According to this hypothesis, experimental evidence indicates that oxytocin may act as a neuropeptide. Indeed oxytocin is synthetized in neurons originating in the hypothalamus that send their projections not only to the neurohypophysis but elso to other brain areas, such as amygdala, frontal cortex, septum, hippocampus, pons and medulla (18-20), with an innervation independent from that of the other neurohypophyseal peptide vasopressin (21-23), and an oxytocinergic receptor has been characterized in rat brain (24). Furthermore oxytocin has been implicated in the modulation of memory processes (11,25-27), in the induction of maternal behaviour (28), in the development of narcotic tolerance and physical dependence (13), and may be the precursor of patent biologically active neuropeptides (29).

In conclusion, oxytocin is the most patent agent discovered sa far that produces penile erection and yawning. Although the mechanism and the site(s) of action of the peptide responsible for the induction of such behaviours are unknown, the present results suggest a physiological role of oxytocin in the expression of Bexual behaviour and yawning, and provide further evidence that oxytocin, in addition ta its hormonal rolc in parturition and lactation, acts as a neuropeptide in the central nervous system.

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