Pregnane xenobiotic receptors and membrane progestin receptors: role in neurosteroid-mediated motivated behaviours.

Progestogens have actions in the midbrain ventral tegmental area (VTA) to mediate motivated behaviours, such as those involved in reproductive processes, among female rodents. In the VTA, the formation and actions of one progestogen, 5α-pregnan-3α-ol-20-one (3α,5α-THP), are necessary and sufficient to facilitate sexual responding (measured by lordosis) of female rodents. Although 3α,5α-THP can be produced after metabolism of ovarian progesterone, 3α,5α-THP is also a neurosteroid produced de novo in brain regions, such as the VTA. There can be dynamic changes in 3α,5α-THP production associated with behavioural experience, such as mating. Questions of interest are the sources and targets of 3α,5α-THP. Regarding sources, the pregnane xenobiotic receptor (PXR) may be a novel factor involved in 3α,5α-THP metabolism in the VTA (as well as a direct target of 3α,5α-THP). We have identified PXR in the midbrain of female rats, and manipulating PXR in this region reduces 3α,5α-THP synthesis and alters lordosis, as well as affective and social behaviours. Regarding targets, recent studies have focused on the role of membrane progestin receptors (mPRs). We have analysed the expression of two of the common forms of these receptors (mPRα/paqr7 and mPRβ/paqr8) in female rats. The expression of mPRα was observed in peripheral tissues and brain areas, including the hypothalamus and midbrain. The expression of mPRβ was only observed in brain tissues and was abundant in the midbrain and hypothalamus. To our knowledge, studies of these receptors in mammalian models have been limited to expression and regulation, instead of function. One question that was addressed was the functional effects of progestogens via mPRα and mPRβ in the midbrain of hormone-primed rats for lordosis. Studies to date suggest that mPRβ may be an important target of progestogens in the VTA for lordosis. Taken together, the result of these studies demonstrate that PXR is involved in the production of 3α,5α-THP in the midbrain VTA. Moreover, mPRs may be a target for the actions of progestogens in the VTA for lordosis.