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

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 mPRα (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 mPRɑ 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.