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6 mars 2003
Behavioral Neural Biology
Androgenic influences on apomorphine-induced yawning in rats
Hemmie H G Berendsen and Victor J Nickolson
Department of CNS Pharmacology, Organon Scientific Development Group, Oss, The Netherlands


It is well established that receptors for steroid sex hormones exist in various brain regions of vertebrates (McEwen, Gerlach, Luine, & Lieberburg, 1977) and that sex steroid hormones influence catecholaminergic processes in the brain (Heritage, Stumpf, Sar, & Grant, 1980). The precise nature of this influence is not clear. It has been reported that the sensitivity of catecholaminergic systems to exogenously applied dopamine agonists like apomorphine (APO) is increased after chronic estrogen treatment of male rats (Hruska & Silbergeld, 1980). Other authors, however, reported that the sensitivity to APO is decreased after chronic estrogen treatment (Euvrard, Oberlander, & Boissier, 1980). Thus far, interactions of androgens with catecholaminergic systems have received little attention. During studies on the low-APO-induced yawning syndrome in rats (Nickolson & Berendsen, 1980) it was noticed that male rats reacted more strongly to low APO compared to females. The present experiments were carried out to study the possible involvement of sex hormones in this phenomenon.

Randomly bred adult rats were used. Male rats weighed 280-400 g, females weighed 200-340 g. They were housed in black PVC cages (48 x 24 X 21 cm) under a controlled light-dark cycle (lights on at 6:00 Am, lights off at 6:00 Pm). They had access to standard pelleted food and tap water ad lib. Experiments were done between 8:30 Am and 12:30 Pm.

Castration and ovariectomy were performed under pentobarbital sodium anesthesia (40 mg/kg ip). After surgery rats were allowed to recover for at least 6 weeks. Female rats were checked for complete ovariectomy by examination of vaginal smears.

Unless stated otherwise, yawning was induced by 0.08 mg/kg sc APO, freshly dissoived in 0.9% NaCl in water containing 0.5 mg ascorbic acid per milligram of APO. Ascorbic acid protects APO from oxidation but does not affect the yawning response (unpublished). Immediately after APO injection rats were placed in perspex observation cages (7.5 x 18 X 30 cm) and the number of yawns was recorded for 20 min. Experiments were carried out in blocks of five animals. Resuits were analyzed statistically with the use of the randomization test.

Intact or castrated male rats were treated sc with either arachis oil (0.2 ml per rat per day) or testosterone propionate (TEP) in arachis oil (50 or 100 µg per rat per day) or dihydrotestosterone (DHT, Stanolone) in arachis oil (50 or 100 µg per rat per day) during the 3 days preceding the yawning experiment. After the experiment the castrated rats were sacrificed and the weights of seminal vesicles and ventral prostate glands were determined. Intact and ovariectomized female rats were treated with either arachis oil (0.2 ml per rat per day) or DHT in arachis oil (50 or 100 µg per rat per day) during the 3 days preceding the yawning experiment.

Preliminary studies had shown that 0.08 mg/kg APO induced yawning less effectively in female rats than in male. To see whether this difference was due to a difference in sensitivity to APO or to a difference in responsiveness, a dose-response study was carried out. The dose-response curves for female and for male rats, shown in Figs, lb and la, respectively, indicate that the main sex difference lies in the maximal magnitude of the yawning response and not in the sensitivity to APO. This renders it unlikely that the sex difference in APO-induced yawning is due to a difference in the metabolism of APO.

To see whether female sex hormones might be responsible for the lower response to APO, the effect of ovariectomy was studied. As can be seen from Table 1, ovariectomy did not result in an increase of APOinduced yawning. This observation strongly suggests that female sex hormones do not suppress APO-induced yawning, although there is no absolute proof since extra ovarian stores for female sex hormone like the adrenals are not eliminated by ovariectomy. On the other hand, removal of sex organs had a profound effect on APO-induced yawning of male rats. Castration resulted in a considerable decrease of yawning when 0.08 mg/kg of APO was used. Higher doses of APO failed to increase the yawning response (not shown) which suggests an effect of castration on responsiveness and not on the sensitivity to APO.

Treatment of both intact and castrated male rats with TEP resulted in an increase of APO-induced yawning. To exclude the possibility that the effect of TEP is caused by estradiol formed from TEP the effects of DHT, which cannot be metabolized to estradiol and is therefore a more "pure" androgen, were studied. Table 1 shows also that DHT treatment of castrated male rats resulted in an increase of APO-induced yawning, In intact male rats no significant increase could be observed. Upon examination of ventral prostate and seminal vesicle weights of castrated rats a discrepancy between the effects on APO-induced yawning and on peripheral androgenic effects of TEP and DHT became apparent. TEP, 50 and 100 µg, resulted in 196 and 265% increases of ventral prostate weight and 157 and 205% increases in seminal vesicle weight, respectively, whereas only 100 µg of TEP was effective in increasing yawning. On the other hand, DHT, 50 and 100 µg, resulted in only 38 and 62% increases of ventral prostate weight and 30 and 57% increases in seminal vesicle weight, respectively, whereas both doses of DHT were effective in increasing APO-induced yawning in castrated rats. The present results thus confirm previous findings that DHT is less potent than TEP with regard to androgenic properties as measured on ventral prostate and seminal vesicle weight. With respect to yawning, however, both steroids seem to be equally effective.

Further studies employing pharmacokinetically similar steroids (e.g., testosterone vs dihydrotestosterone or testosterone propionate vs dihydrotestosterone propionate) are needed to establish whether real differences exist between the responsiveness to androgens of peripheral sex organs and cerebral tissue.

Finally, the effect of DHT in intact and ovariectomized female rats was studied. As in castrated male rats, DHT in doses of 50 or 100 µg per rat per day increased APO-induced yawning in both intact and ovariectomized females, although the effect seemed to be somewhat greater in ovariectomized rats (Table 1). To see whether the effects of DHT in low-APO-induced yawning might be related to its general anabolic rather than to its androgenic character, a preliminary experiment was performed with the anabolic steroid nandrolone decanoate. Three-day treatment of female rats with this steroid failed to increase low-APO-induced yawning.

Taken together, the present results indicate that low-APO-induced yawning is under the influence of androgenic steroids. In contrast to, e.g., the sensitization toward APO brought about by des-tyrosine-gamma-endorphin the nature of this influence seems to be permissive rather than sensitizing. This suggests that androgens do not directly affect the receptor system which is challenged by low doses of APO but facilitate the expression of the yawning syndrome. In this respect it is interesting to note that testosterone also potentiates the effectiveness of intraventricularly administered ACTH, in inducing a syndrome which is characterized by stretching and yawning.

Effects of testosterone in intact rats may be explained by assuming that after subchronic treatment with testosterone a stable, high level of circulating testosterone is established, in contrast to the level of circulating testosterone in normal intact rats which shows a diurnal variation which has its own characteristics for each individual rat. This may mean that in testosterone-treated intact rats testosterone-dependent biological phenomena show less variation and occur with an average intensity higher than that in placebo-treated intact rats.

In contrast to high-APO-induced behavioral syndromes, estrogens seem to play only a minor role in low-APOinduced yawning. In a preliminary experiment TEP treatment had no effect on high-APO-induced stereotyped gnawing in intact female rats. Further studies are needed to establish whether androgens also influence other behavioral effects of low APO like depression of open field activity and affect high-APO-induced stereotypies.


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« It is ironic that testosterone "the male sex hormone," is more closely associated with the yawning rate than with the mounting or intromitting rates » Charles Phoenix
Sexual steroids exert several effects on both central dopaminergic and oxytocinergic systems by acting either at the genomic or membrane level  
credit photo : "Asif A. Ghazanfar and Aristides Arrenberg"
Max Planck Institute for Biological Cybernetics
Tuebingen; Germany.

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