Abstract
In humans, sex differences in mood disorders emerge during adolescence, with prevalence rates being consistently higher in females than males. It has been hypothesised that exposure to endogenous ovarian hormones during adolescence enhances the susceptibility of females to mood disorders from this stage of life onwards. However, experimental evidence in favour of this hypothesis is lacking. In the present study, we examined the long-term effects of suppressing adolescent gonadal hormone levels in a group of female Lister-hooded rats via administration of a gonadotrophin-releasing hormone antagonist (Antide; administered on postnatal day [PND] 28 and 42) compared to control females and males (n=14 per group). We predicted that, in adulthood, Antide-treated female rats would exhibit more male-like behaviour than control females in novel environments (elevated-plus maze, open field and light-dark box), in response to novel objects and novel social partners, and in an acoustic startle task. Progesterone and luteinising hormone assays (which were conducted on blood samples collected on PND 55/56 and 69/70) confirmed that the hypothalamic-pituitary-gonadal axis was temporarily suppressed by Antide treatment. In addition, Antide-treated females were found to exhibit a modest pubertal delay, as measured by vaginal opening, which was comparable in length to the pubertal delay that has been induced by adolescent exposure to alcohol or stress in previous studies of female rats. However, Antide-treated females did not substantially differ from control females on any of the behavioural tests, despite the evidence for predicted sex differences in some measures. Following the acoustic startle response task, all subjects were culled and perfused, and c-Fos staining was conducted in the medial and basolateral amygdala, with the results showing no significant differences in cell counts between the groups. These findings suggest that ovarian hormone exposure during adolescence does not have long-term effects on anxiety-related responses in female rats.
Highlights
In humans, the prevalence of mood disorders is consistently reported to be higher in women than in men,[1,2,3] and this sex difference in prevalence emerges during adolescence.[4,5,6] These observations have led to hypothesis that the fluctuations in ovarian hormone levels that accompany puberty increase the susceptibility to mood disorders amongst adolescent girls.[7]
The results of the present study indicate that treatment of adolescent female rats with the gonadotropin-releasing hormone (GnRH) antagonist, Antide, successfully suppressed the HPG axis and delayed pubertal development, as measured by reproductive hormone levels and the timing of Vaginal opening (VO), and Antide-treated and control females exhibited comparable levels of social behaviour during adolescence
Contrary to our predictions, Antide-treated females did not differ from control females in behavioural tests involving exploration of novel environments, novel objects or novel social partners, or immobilisation responses to negative acoustic stimuli, in adulthood
Summary
The prevalence of mood disorders is consistently reported to be higher in women than in men,[1,2,3] and this sex difference in prevalence emerges during adolescence.[4,5,6] These observations have led to hypothesis that the fluctuations in ovarian hormone levels that accompany puberty increase the susceptibility to mood disorders amongst adolescent girls.[7]. We examined the effects of suppressing ovarian hormones during adolescence using a GnRH peptide antagonist (Antide), and the goal was to delay pubertal gonadal hormone exposure to a similar extent as seen with adolescent exposure to alcohol or stress, both of which can interfere with HPG functioning during this period of life.[20,57] We predicted that, in adulthood, Antide-treated female rats would exhibit more male-like behaviour than control females in novel environments (elevated-plus maze, open field and light-dark box), in response to novel objects and novel social partners, and in an acoustic startle task. Previous studies have reported behavioural sex differences in these tasks[58]; for example, on average, female rats usually spend more time than males in the exposed sections of the elevated-plus maze and light-dark box,[18,19,20] and male rats exhibit stronger acoustic startle responses than females.[59,60] We postulated that c-fos activation in the amygdala following the acoustic startle task would be greater in Antide-treated females than in control females
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