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8 décembre 2005
Physiol Behav.
1995; 57; 6; 1139-1143
Paradoxical sleep deprivation in female rats
alters drug-induced behaviors
Hipolide DC, Tufik S
Department of Psychobiology, Escola Paulista de Medicina, Sao Paulo, Brazil


Paradoxical sleep deprivation (PSD) induces changes in behaviors induced by dopaminergic and cholinergic agonists, including increased aggressive behavior and stereotypy, decreased number of yawns, and shedding of bloody tears in male rats. In female rats, however, very little is known about the relationship between PSD and the effect of these drugs. The present study sought to examine this issue. As in males, PSD in females resulted in increased apomorphine-induced stereotypy, decreased pilocarpine-induced chromodacryorrhea, and hyperthermia. Unlike males, however, no apomorphine-induced aggressiveness or apomorphine- and pilocarpine-induced yawning were observed in PSD females. These findings suggest that female sexual hormones may affect the expression of some behaviors and not the neurotransmission as a whole, because drug-induced behaviors in PSD females were partly similar to those observed in PSD males.
The introduction of methods for selective deprivation of paradoxical sleep in both humans and experimental animals provided us with a new approach to in vivo investigation of its functions. It is well established that paradoxical sleep deprivation (PSD) in experimental animals results in behavioral changes, such as increase in aggressive behavior induced by dopaminergic agonists, in stereotypy , in locomotion, and in colonic temperature, and decrease in number of dopaminergic and cholinergic agonist-induced yawning.
The behavioral changes in response to dopaminergic drugs following PSD can be explained by either a supersensitivity of dopaminergic postsynaptic or a subsensitivity of dopaminergic presynaptic receptors. Some reports, however, state that PSD induces specific changes in the dopaminergic system, such as increased density of D1 type receptors in the mesolimbic pathway, which is not observed in the corpus striatum in rats, and decreased function of postsynaptic receptors in the mesolimbic pathway, but not in the nigrostriatal pathway in mice.
Catecholaminergic systems and sexual steroids have central effects that are of significance for the regulation of physiological processes, including ovulation and copulatory behavior. The expression of behaviors mediated by both mesolimbic and nigrostriatal dopaminergic pathways seems to be related directly to the effects of ovarian hormones on the central nervous system. For example, ovariectomized female rats exhibit a decrease in rotational behavior induced by both electric stimulation and amphetamine. Administration of physiological doses of es-
trogen in ovanectomized female rats potentiates the release of dopamine and amphetamine-induced rotational behavior. Moreover, chronic administration of estradiol increases the density of D2 type receptors in corpus striatum.
Because female sexual steroids regulate behaviors that are mediated by the dopaminergic system, we investigated whether or not PSD induces behavioral changes in non-ovariectomized female rats. Behavioral (aggressiveness, stereotypy, and yawning) as well as physiological (colonie temperature) measurements were taken for this purpose.
The results of the present study showed that administration of a dopaminergic agonist (i.e., apomorphine), did not induce aggressive behavior in either control or PSD females. These findings differ from those reported for males. Administration of high doses of dopaminergic agonists to controls or low doses to PSD animals result in increased aggressiveness. Studies involving removal and/or administration of testicular hormones reveal the importance of androgens on the expression of aggressiveness. Female rats, on the other hand, are generally less aggressive than males. Under specific circumstances, how ever, females show increased aggressiveness, specially during pregnancy, lactation, cohabitation with a sterile male, competitive experiences, or repeated exposure to unusual situations.
Several studies show a differential effect of apomorphine in males and females. Thus, contrary to males, very high doses of the dopaminergic agonist do not induce aggressive behavior in females. In additon, apomorphine does not alter verticalization of stereotyped behavior and colonic temperature. These gender differences in the expression of aggressiveness may suggest an important modulatory effect of sexual hormones on the neural systems involved with this class of behavior.
Our results on stereotyped behavior were similar to those found for males. PSD animals presented higher scores of stereotypy than controls. Contrary to the males, however, I mg! kg of apomorphine did not intensify stereotypy in PSD females.
It is important to note that in intact females apomorphine induced stereotypy does not seem to correlate with any hormonal change during the estrous cycle. Data (unpublished) from our lab and others show that PSD interferes with regularity of the estrous cycle. However, each of our females had its estrous cycle registered before behavioral testing. There was no correlation between phase of the cycle and behavioral manifestation. In ovariectomized rats treated with estrogen and progesterone, however, apomorphine-induced stereotypy is diminished compared to that of untreated ovariectomized females, suggesting a possible action of these hormones upon dopaminergic transmission.
It is believed that stereotypy is a consequence of dopaminergic stimulation of the caudate nucleus. The lack of gender differences on this kind of behavior (our findings compared to those in males) suggests that sexual steroids modulate this dopaminergic pathway in a similar way. These findings confirm the results of Jackson et al. and Kelly et al. who reported that the expression of aggressiveness and stereotypy may involve different dopaminergic pathways.
Gender differences in apomorphine-induced yawning was reported by Nickolson and Berendsen. This study showed that males present a more robust response to low doses of apomorphine than females. Thus, the authors suggest that apomorphine induced yawning is under the influence of androgens and that estrogens play a minor role on the mediation of this behavior. In the present study, both control and PSD females presented a very low number of apomorphine,? and pilocarpine-induced yawning. This is in discrepancy with the data for males, indicating a reduction of yawning in 96-h PSD compared to control animals (36). These results in females may be due to the very low frequency of yawning already seen in control rats. It is possible, however, that female sexual hormones play a role in the dynamics of the systems involved with yawning behavior, masking the receptor sensitization induced by PSD.
Chromodacryorrhea results from the activation of muscarinic peripheral mechanisms. Studies investigating the relationship between the effects of PSD and cholinergic drugs in males show that PSD inhibits the shedding of bloody tears. Our study showed the same results in females, suggesting that peripheral mechanisms involved in this phenomenon are similar for both genders. Finally, our results of colonic temperature in females are in agreement with studies investigating the relationship between sleep and thermoregulation in male rats, which report hyperthennia induced by PSD .
Taken together, the results of the present study indicate that female sexual hormones may have a modulatory role on the dopaminergic and cholinergic systems. Because the results in females partly replicate those in males, we propose that this class of hormones does not alter the neurotransmission per se, but the expression of behaviors mediated by these systems.
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