RU486 blocks effects of allopregnanolone on the response to restraint stress

Abstract

These experiments were designed to provide information about the potential involvement of progesterone receptors in the ability of allopregnanolone (3α-hydroxy-5α-pregnan-20-one) to reduce the lordosis-inhibiting effects of restraint stress. Ovariectomized Fischer rats were hormonally primed with 10 μg estradiol benzoate and 4 mg/kg allopregnanolone or vehicle. One hr before allopregnanolone, rats were injected with the progesterone receptor antagonist, RU486 (11β-(4-dimethylamino)phenyl-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one), or vehicle. Four hr after allopregnanolone or vehicle, sexual behavior was examined before and after a 5-min restraint stress. Lordosis behavior of rats primed only with estradiol benzoate declined after the 5 min of restraint while allopregnanolone prevented this decline. RU486 attenuated the ability of allopregnanolone to prevent the restraint-induced decline in lordosis behavior. These findings are consistent with earlier suggestions that progesterone receptors are involved in allopregnanolone's ability to reduce the effects of restraint stress.Keywords lordosis behavior; proceptivity; progesterone metabolites; progesterone receptors; female rats IntroductionFemale rat sexual behavior is temporally coordinated with ovulation to maximize reproductive fitness (Blaustein, 2008;Sodersten, 1981). Both estrogens and progestins influence this reproductive synchrony (Auger, 2004;Mani et al., 1997;Pfaff, 1970) so that reproductive behavior abruptly ceases following ovariectomy. However, sexual behavior can be restored in ovariectomized rats by exogenous treatment with gonadal hormones (Auger, 2004;Pfaff, 2005). The full repertoire of female sexual behavior includes appetitive, precopulatory and copulatory activities and gonadal hormones appear to differentially influence these various events (Blaustein, 2008;Erskine, 1989;Frye, 2007). The lordosis reflex (required for copulation) is thought to depend exclusively on estradiol (Auger, 2004;Blaustein, 2008). Progesterone is not required, but the probability and frequency of lordosis © 2012 Elsevier Inc. All rights reserved. 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. behavior can be increased by progesterone; and progesterone may be required for the occurrence of precopulatory activity such as hopping and darting behavior (Erskine, 1989;Frye and Vongher, 1999;Sodersten, 1981). Progesterone also reduces measures of anxiety (Auger and Forbes-Lorman, 2008;Gomez et al., 2002) and we have previously suggested that progesterone's anxiolytic action contributes to its facilitation of female rat...

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

“…Medroxyprogesterone (which is not readily metabolized to progesterone metabolites but does bind to the intracellular progesterone receptor) did mimic effects of progesterone (Hassell et al, 2011). Both RU486 (Hassell et a., 2011) and CDB4124 (Uphouse et al, 2013) did reduce the effect of the exogenous progesterone. However, allopregnanolone was as effective as progesterone but not on a short time scale (e.g.…”

“…However, allopregnanolone was as effective as progesterone but not on a short time scale (e.g. allopregnanolone required at least 30 or more minutes to attenuate the response to restraint) and the effect of allopregnanone was reduced by RU486 or CDB4124 (Miryala et al, 2011; Uphouse et al, 2013; Uphouse and Hiegel, 2014) suggesting an involvement of the intracellular progesterone receptor. Similar studies have not been performed after the protracted EB treatment.…”

Prior hormonal treatment, but not sexual experience, reduces the negative effects of restraint on female sexual behavior

“…Proestrous females have a relatively low response to stress and exhibit less evidence of anxiety [49, 50]. Proestrous females are also resistant to the lordosis-inhibiting effects of the 5 min restraint experience [16] and current evidence implicates a role for intracellular progesterone receptors in this resistance [11, 15, 51]. …”

An antiprogestin, CDB4124, blocks progesterone's attenuation of the negative effects of a mild stress on sexual behavior

“…However, in many studies, progesterone’s anxiolytic effects have been attributed to progesterone metabolites such as allopregnanolone [25–27, 36]. Allopregnanolone can substitute for progesterone in reducing effects of mild restraint [41], but this effect of allopregnanolone was reduced by prior treatment with RU486 [60]. This led to speculation about the role of progesterone receptors in the effect of allopregnanolone and is consistent with suggestions by other investigators that progesterone receptors are important for the antianxiety effects of progesterone [21].…”