Role of pregnane xenobiotic receptor in the midbrain ventral tegmental area for estradiol- and 3α,5α-THP-facilitated lordosis of female rats

Progesterone and its metabolite, 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP), have actions in the ventral tegmental area (VTA) that are required for lordosis, a characteristic mating posture of female rodents. 17 beta-estradiol (estradiol) co-varies with progestogens over natural cycles, enhances production of 3 alpha,5 alpha-THP, and is required for successful reproductive behavior. A question of interest is the role of pregnane xenobiotic receptor (PXR), a nuclear receptor that regulates enzymes needed for the production of 3 alpha,5 alpha-THP, for estradiol-mediated lordosis. The hypothesis tested was that if PXR is involved in estradiol-mediated biosynthesis of 3 alpha,5 alpha-THP and reproductive behavior, knocking down expression of PXR in the VTA of estradiol-primed, but not vehicle-primed, rats should decrease lordosis and midbrain 3 alpha,5 alpha-THP; effects may be attenuated by 3 alpha,5 alpha-THP administered to the VTA. Ovariectomized rats were administered subcutaneous injections of oil vehicle or estradiol. Rats were then administered PXR antisense oligonucleotides (PXR AS-ODNs; which are expected to locally knock down expression of PXR), or control (saline), infusions to the VTA. Rats were administered 3 alpha,5 alpha-THP or vehicle via infusions to the VTA. Reproductive behavior (paced mating task) of rats was determined in addition to exploratory (open field), affective (elevated plus maze), and pro-social (social interaction task) behavior. Reproductive behavior (i.e., increased lordosis) was enhanced with estradiol-priming and infusions of 3 alpha,5 alpha-THP to the VTA. Infusions of PXR AS-ODNs to the VTA attenuated responses in estradiol-, but not vehicle-, primed rats, compared to control infusions. PXR may be involved in a neuroregulatory response involving biosynthesis of 3 alpha,5 alpha-THP in the midbrain VTA of estradiol-primed rats.