Mechanisms responsible for progesterone's protection against lordosis-inhibiting effects of restraint

Abstract

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.

Dose-dependent effects of the antiprogestin, RU486, on sexual behavior of naturally cycling Fischer rats

“…In previous experiments [44, 45, 55], we have reported that a mild 5 min restraint reduced lordosis behavior in ovariectomized rats that were hormonally primed with 10 µg estradiol benzoate but not in naturally cycling rats or in ovariectomized rats primed with estradiol benzoate and progesterone. A role for intracellular progesterone receptors in this resistance to the lordosis-inhibiting effects of the restraint was suggested by the ability of both RU486 and of the more selective progesterone receptor antagonist, CDB4124, to block effects of progesterone [44, 56]. In the current experiment, in all treatments with RU486, lordosis behavior was reduced by restraint.…”

“…For example, ovariectomized Fischer female rats may show high sensitivity because a single injection of 10 µg estradiol benzoate to naive ovariectomized females elicits near maximal lordosis behavior (but not proceptivity) in a majority of females [44, 45] while comparable treatment is not reported to elicit high lordosis responding in Sprague Dawley or Wistar females [20, 46]. …”

“…When ovariectomized Fischer rats are hormonally primed with 10 µg estradiol benzoate to elicit high lordosis responding, a brief 5 min restraint stress significantly reduces lordosis behavior [55]. The addition of progesterone priming completely eliminates this effect of restraint and intracellular progesterone receptors may be required [44, 55]. Importantly, restraint does not reduce lordosis behavior in naturally-cycling proestrous rats [55].…”

“…Importantly, restraint does not reduce lordosis behavior in naturally-cycling proestrous rats [55]. Since progesterone reduces the response to the 5 min restraint, we have proposed that this anti-stress effect of progesterone can account, in part, for progesterone’s ability to facilitate low-level lordosis behavior of estrogen-primed ovariectomized rats and may be required for this anti-stress effect [44, 45, 56]. …”

Repeated estradiol benzoate treatment protects against the lordosis-inhibitory effects of restraint and prevents effects of the antiprogestin, RU486

“…When ovariectomized Fischer rats are injected with 10 μg EB, the emergence of lordosis behavior (but not proceptivity) can be as high as observed in rats given EB and 500 μg progesterone, but when these 10 μg EB treated rats are given a brief 5 min restraint experience, lordosis behavior is rapidly reduced. The addition of progesterone completely prevents this restraint-induced decline (Hassell et al, 2011; Miryala et al, 2011; White and Uphouse, 2004) and the antiprogestins, RU486 or CDB4124, reduce progesterone’s ability to attenuate the effect of restraint (Hassell et al, 2011; Uphouse and Hiegel, 2013). However, when rats were given 4 consecutive weeks of treatment with 10 μg EB, the repeated treatment with estradiol benzoate was as effective as the addition of progesterone in reducing the lordosis-inhibiting effect of a 5 min restraint stress (Uphouse et al, 2014).…”