Progestins and antiprogestins are widely used therapeutic agents in humans. In many cases, these are indicated for the treatment of reproductive activites. However, progesterone has widespread physiological effects including a reduction of the response to stress. We have reported that 5 min of restraint reduced lordosis behavior of ovariectomized rats hormonally primed with estradiol benzoate. When ovariectomized rats received both estradiol benzoate and progesterone priming, restraint had minimal effects on lordosis. Progesterone influences behavior through classical intracellular progesterone receptor-mediated nuclear events as well as extranuclear events. How these multiple events contribute to the response to stress are unclear. The current project was designed to initiate examination of the mechanisms responsible for progesterone’s ability to protect against the effects of the restraint. In the first experiment, ovariectomized rats, primed with 10 µg estradiol benzoate, received 500 µg progesterone 4 hr, 1 hr, or 30 min before restraint. When progesterone was injected 4 hr before restraint, progesterone eliminated the effects of restraint. In contrast, progesterone 30 min before restraint offered no protection. Effects of progesterone 1 hr before restraint were equivocal allowing the suggestion that less than 4 hr of progesterone priming might be sufficient. In the second experiment, the synthetic progestin, medroxyprogesterone, was shown to mimic effects of progesterone in preventing effects of restraint. Finally, the progesterone receptor antagonist, RU486, attenuated progesterone’s protection against restraint. These findings offer evidence that ligand-activated progesterone receptor mechanisms contribute to the maintenance of lordosis behavior in the presence of mild stress.

These experiments were designed to evaluate the hypothesis that fluoxetine-induced sexual dysfunction in female rats derived from disruption of neuroendocrine events that normally facilitate sexual behavior. If so, exogenous hormonal priming to ovariectomized rats should eliminate fluoxetine's effect. Ovariectomized rats were subchronically treated with 10 mg/kg fluoxetine or distilled/deionized water vehicle for 9 consecutive days. On the 8 th day of treatment, rats were primed with 10 μg estradiol benzoate followed 48 hr later with 500 μg progesterone. In a pretest for sexual behavior on the 10 th day, there was no difference between subchronic treatments. Sexual receptivity was again monitored 30 min after injection on the 10 th day (acute treatment) with distilled/deionized water, 10 mg/kg fluoxetine or 20 mg/kg fluoxetine. Thereafter, the female's behavior was monitored for 20 min in a male preference procedure. After the acute treatment in rats subchronically treated with water, fluoxetine (10 or 20 mg/kg) significantly reduced both lordosis frequency and quality and reduced (but not significantly) time spent with the male. In rats subchronically treated with fluoxetine, the lordosis-inhibiting effect of an acute injection with fluoxetine was significantly attenuated relative to that of the subchronically water-treated rats. In contrast to expectation, subchronic treatment with fluoxetine increased, rather than reduced, the relative time females spent near the male. Activity, as measured by center crossings, and grooming were also reduced by subchronic treatment with fluoxetine. KeywordsSSRI; sexual motivation; lordosis; subchronic IntroductionFluoxetine (Prozac®) is frequently prescribed for depression as well as for a variety of other disorders such as premenstrual dysphoria, anxiety, anorexia and bulemia which are more prevalent in females than in males [4,19,22,33]. A reported undesirable side effect of fluoxetine, as well as other selective serotonin reuptake inhibitors (SSRIs), is a high incidence of sexual dysfunction [8,15,28]. Although such sexual dysfunction occurs in both genders, more experimental emphasis has been placed on identifying the responsible mechanisms in males than in females [17]. Yet, as much as 32% of female patients may experience SSRI-*Corresponding author Department of Biology, Texas Woman's University, Denton, TX 76204, Phone: 940-898-2356, FAX: 940-898-2382.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [32]. The mechanisms responsible for such drug-induced sexual dysfunction in females have been difficult to identify,...

No abstract

When ovariectomized Fischer female rats are hormonally primed with 10 μg estradiol benzoate, a 5 min restraint experience rapidly inhibits lordosis behavior. Addition of progesterone to the hormonal priming prevents this restraint-induced inhibition. In prior work, we reported evidence that progesterone receptors (PR) may contribute to this protective effect of progesterone. In the current manuscript, we provide evidence that progesterone metabolites may also contribute to progesterone’s ability to reduce the effects of restraint. Ovariectomized female rats were hormonally primed with 10 μg estradiol benzoate followed 2 days later with 4.0 mg/kg of the progesterone metabolite, allopregnanolone. Allopregnanolone, administered either 4 hr or 2 hr before the restraint experience, was as effective as progesterone in reducing the lordosis-inhibitory effects of restraint. In the second experiment, progesterone metabolism was blocked with 50 mg/kg of the 5α-reductase inhibitor, finasteride. Surprisingly, finasteride did not prevent progesterone from reducing the effects of restraint. In a third experiment, we tested the possibility that allopregnanolone acted through metabolism to dihydroprogesterone. Rats were treated with allopregnanolone or with allopregnanolone plus the 3α-hydroxysteroid dehydrogenase inhibitor, indomethacin. Indomethacin did not prevent allopregnanolone from reducing the effects of restraint. Mechanisms are discussed whereby cross-talk between PR-mediated and metabolite-mediated events may converge in producing progesterone’s attenuation of the effect of restraint.

No abstract