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20 janvier 2008
Europ J Pharmacol
Estrogens antagonize apomorphine-induced
yawning in rats
Serra G, Collu M, Serra A, Gessa GL
Institute pharmacology, University Cagliari, Italy
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


Several recent reports indicate that estrogens are capable of modulating dopamine (DA) receptor sensitivity in experimental animals.
The data concerning the capacity of estrogens to influence postsynaptic DA receptors are controversial. Supersensitivity of DA receptors induced by various estrogen treatments is suggested by the fact that these treatments enhance apomorphine- and amphetamine-induced stereotypy, increase circling behavior in 6-OH-DA-lesioned animals and increase [3 Hspiroperidol binding sites in the striatum (Hruska and Silbergeld, 1980). Other authors have however, reported that estrogens reduced apomorphine-induced stereotypy, the circling behavior elicited by apomorphine in rats with a unilateral lesion of the entopeduncular nucleus and the increase in striatal acetylcholine levels observed after dopamine agonists. These discrepancies may be partially explained by the different schedules used, such as different estrogen dosage, length of hormone treatment, intervals between treatment and challenge with DA agonists and dosage of agonists.
Contrary to what was observed for postsynaptic DA receptors, all reports concerning the influence of estrogens on DA autoreceptor sensitivity suggest that these receptors become subsensitive after estrogen treatment. Indeed, Chiodo and Caggiula (1980) reported that estrogens significantly decreased apomorphine inhibition of the firing of DA neurons in the rat substantia nigra. Piccardi et al. (1983) reported that estrogens antagonized both the hypomotility and the decrease in stnatal DA turnover induced by low doses of apomorphine and other DA agonists in rats. Moreover, these authors found that apomorphine was less effective in decreasing motility and striatal DA turnover in female than in male rats (Piccardi et al., 1983), suggesting that endogenous estrogens reduce DA autoreceptor sensitivity.
Small doses of apomorphine also elicited repeated episodes of yawning in rats (Molginicka and Klimek, 1977; Serra et al., 1983), suggesting that the DA receptors mediating yawning may have pharmacological properties similar to those of DA autoreceptors. Thus, in order to clarify whether estrogens modify the sensitivity of the DA receptors mediating yawning, we studied the estrogen effect on apomorphine-induced yawning in rats.
The results indicate tha short-term treatment with the 17B-estradiol benzoate antogonized apomorphine induced yawning in male rats. Morover, apomorphine appeared to be less effective in inducing yawning in female than in male rats.
The present results indicate that exogenously administrered estrogens antagonize apomorphine-induced yawning in male rats. Moreover, in agreement with a previous report (Berendsen and Olson, 1981), they show that apomorphine is less effective in inducing yawning in female than male rats.
Although estrogens are known to alter the metabolism of various drugs, it can be excluded that the effect of these hormones on the response to apomorphine depends on alterations in the metabolism of the drug, since the half-life of 3H apomorphine in the plasma of rats treated with estrogens is not significantly changed (Gordon et al., 1980).
Since apomorphine-induced yawning is considered to be due to stimulation of DA receptors in CNS (Mogilnicka and Klimek, 1977; Serra et al 1983), subsensitivity of these receptors may explain the reduction of this behavioral response served in males following estrogen treatment or in normal female animals.
Until now, these receptors have been identified with DA autoreceptors (Mogiinicka and Klimek, 1977; Serra et al., 1983), which mediate apomorphine-induced hypomotility, decrease DA synthesis and release and inhibition of dopaminergic firing. This hypothesis is essentially supported by the observation that the doses of apomorphine needed to produce yawning are in same range as those needed to stimulate DA autoreceptors. Therefore, according to this hypothesis, yawning may be a behavioral correlate of the inhibition of DA transmission in the CNS.
However, our recent results suggest that dopaominomimetic drugs induce yawning by stimulating postsynaptic DA receptors in the CNS. Indeed, the selective stimulant of DA autoreceptors, (- )- 3PPP (Hjorth et al., 1983), fails to induce yawning in rats while (+)-3PPP, which stimulates DA autoreceptors as well as postsynaptic DA receptors (Hjorth et al., 1983), induces repeated episodes of yawning (Serra et al., 1984). Thus, it may be suggested that stimulation of apomporphineinduce yawning by stimulating a special kind of postsynaptic DA receptor with an affinity for DA agonists similar to that of DA autoreceptors. According to this hypothesis, yawning could be considered the step in the arousal responses induced by the stimulation of DA transmission in the CNS, which culminate in the appearance stereotypy when higher doses of dopaminomimetic drugs are administered.
Irrespective of the nature and anatomical location of DA receptors mediating yawning, the finding that they become subsensitive in male animals treated with estrogens and that they appear to be subsensitive in female rats may contribute to explain the physiological significance of yawning. Some observations have suggested that yawning is a behavior more typical of the male animal. Indeed, yawning is usually related to the display of social dominance by male monkeys and is often associated with mounting behavior when male monkeys are paired with female partners (Goy and Resko, 1971). Moreover, in his description of the behavior of monkeys towards mirror images, Hall (1962) observed that among the arousal responses in the adult male animal yawning was very frequent and at times accompanied by penile erection, while the adult female "...rarely, if ever, yawned."