Progesterone-facilitated lordosis of estradiol-primed mice is attenuated by knocking down expression of membrane progestin receptors in the midbrain

Abstract

Evidence is emerging of the role of membrane progestin receptors (referred to as mPRs herein: members of Progestin and AdipoQ Receptor (Paqr) family) as a novel brain target in mammals, such as rats. In the present study, the role of mPRs in mice was assessed to further elucidate the conservation of this mechanism across species. The brain target investigated was the midbrain ventral tegmental area (VTA) given its described role for rapid actions of progestins for reproduction. Studies tested the hypothesis that if mPRs are required for progestin-facilitated lordosis through actions in the VTA, then knockdown of mPRs in the VTA will attenuate lordosis. Ovariectomized (OVX) mice were subcutaneously injected with estradiol (E2) and progesterone (P4), and infused with antisense oligodeoxynucleotides (AS-ODNs) to mPRαs (Paqr7) and/or mPRβ (Paqr8) or vehicle to the lateral ventricle or VTA. Mice were assessed for reproductive behavior (lordosis and aggression/rejection quotients) in a standard mating task. Results supported our hypothesis. E2 + P4-facilitated lordosis was significantly reduced, and aggression/rejection increased, with infusions of mPRα, mPRβ, or mPRαβ AS-ODNs to the lateral ventricle, compared to vehicle. E2 + P4-facilitated lordosis was significantly decreased, and aggression/rejection increased, with mPRβ or mPRαβ AS-ODNs to the VTA of C57/BL6 mice. Both mPRα and mPRβ AS-ODNs reduced lordosis, and increased aggression/rejection, of wildtype (C57/BL6x129) mice, but not nuclear PR knockout mice. Thus, mPRs may be a novel target of progestins for reproductive behavior of mice.

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

“…Alternatively, proceptivity and resistance to stress may be especially dependent on intracellular progesterone receptors while facilitation of lordosis behavior may allow a greater participation of membrane progesterone receptors that are not antagonized by RU486 [18, 66, 67]. Although classical intracellular progesterone receptors within the ventromedial nucleus have been clearly implicated in lordosis behavior [25, 67–69]; in other brain areas such as the medial preoptic area and ventral tegmental area, membrane progesterone receptors and/or neurotransmitter receptors such as GABA A may be sufficient to facilitate the behavior following progesterone treatment [18, 70, 71].…”

“…Although classical intracellular progesterone receptors within the ventromedial nucleus have been clearly implicated in lordosis behavior [25, 67–69]; in other brain areas such as the medial preoptic area and ventral tegmental area, membrane progesterone receptors and/or neurotransmitter receptors such as GABA A may be sufficient to facilitate the behavior following progesterone treatment [18, 70, 71]. …”

“…Progesterone regulates reproductive function by binding to its intracellular cognate receptors [13–15], by binding to membrane progesterone receptors [16–18], and through progesterone metabolites such as allopregnanolone [19, 20]. Several lines of evidence allow the suggestion that intracellular progesterone receptors play an important role in progesterone’s ability to facilitate lordosis behavior [21–24].…”

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

“…In addition to its action at intracellular progesterone receptors, progesterone also influences sexual behavior by binding to membrane progesterone receptors (Frye et al, 2013) and by metabolism to compounds such as allopregnanolone (Frye and Vongher, 1999). Either or both of these mechanisms could have contributed to the current findings.…”

“…Progesterone enhances sexual behavior through binding to intracellular progesterone receptors and membrane progesterone receptors as well as through progesterone metabolites (Blaustein, 2008; Conneely et al, 2003; Frye et al, 1998; Frye et al, 2013; Mani et al, 1997; Pluchino et al, 2009). For lordosis behavior, involvement of intracellular progesterone receptors has been inferred from the lordosis-inhibitory effects of the antiprogestin, RU486 (11β-(4-dimethylamino)phenyl-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one), (Beyer et al, 1995; Blaustein et al, 1987; Brown et al, 1987), from the failure of progesterone to enhance lordosis behavior in progesterone receptor knock-out mice (Lydon et al, 1995; Mani et al, 1997; Mani et al, 2006), and from the inhibitory effect of antisense oligonucleotides to the intracellular progesterone receptor (Mani et al, 1994a; Mani et al, 1994b).…”