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

Abstract

Rationale Progesterone and its metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), have actions in the ventral tegmental area (VTA) that are required for lordosis, a characteristic mating posture of female rodents. 17β-estradiol (estradiol) co-varies with progestogens over natural cycles, enhances production of 3α,5α-THP, is required for successful reproductive behavior. Objectives A question of interest is the role of pregnane xenobiotic receptor (PXR), a nuclear receptor that regulates enzymes needed for the production of 3α,5α-THP, for estradiol-mediated lordosis. The hypothesis tested was that if PXR is involved in estradiol-mediated biosynthesis of 3α,5α-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 3α,5α-THP; effects may be attenuated by 3α,5α-THP administered to the VTA. Methods 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 3α,5α-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), pro-social (social interaction task) behavior. Results Reproductive behavior (i.e. increased lordosis) was enhanced with estradiol-priming and infusions of 3α,5α-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. Conclusions PXR may be involved in a neuroregulatory response involving biosynthesis of 3α,5α-THP in the midbrain VTA of estradiol-primed rats.

Involvement of pregnane xenobiotic receptor in mating-induced allopregnanolone formation in the midbrain and hippocampus and brain-derived neurotrophic factor in the hippocampus among female rats

“…When they regained consciousness, rats were administered a loading dose of analgesic (ibuprofen). Post-operative analgesic (ibuprofen) was provided in water bottles ad libitum for 5 days post-surgery and recovery from surgery (neurological exams and body weight gain) was assessed daily for subjects (Frye et al, 2014). All rats passed neurological evaluations and gained weight following surgery and were included in the experiment.…”

“…Rats were infused with 1 μl control (sterile saline vehicle) or PXR AS-ODN (purchased from Invitrogen Life Technologies, Carlsbad, CA; as described in Frye et al, 2014). …”

“…Standard methods were utilized for open field, elevated plus maze, social interaction task, and paced mating (described in more detail in Frye et al, 2014). For standard mating, testing was conducted in clear glass chamber (37.5×75×30cm), containing bedding with a sexually-experienced male that had been acclimated to the testing chamber before the experimental subject is introduced.…”

“…2008). Additional evidence that is may be involved in a homeostatic mechanism involving neurosteroids is that knocking down its expression specifically in the midbrain reduces formation of 3α,5α-THP in this region over the estrous cycle as well as attenuates the response to 3α,5α-THP administration to the midbrain for reproductive behavior of female rats (Frye et al, 2013a; 2014). These experiments suggested the role of PXR in the midbrain VTA that is required for 3α,5α-THP’s effects on reproductive and reproduction-relevant behaviors among female rats, but they did not address whether engaging in these behaviors may alter 3α,5α-THP levels in the brain due to actions involving PXR.…”

“…The present experiments compared effects of PXR manipulations in the midbrain VTA of proestrous rats exposed to different behavioral manipulations, in the complete or partial battery of tasks that has been previously utilized to assess the role of 3α,5α-THP and PXR (Frye et al, 2013a; 2014). Mating is characterized by exploration and affiliations, social behaviors that bring individuals together, as well as inhibition of anxiety and aggressive behaviors that keep individuals apart.…”