%0 Journal Article
%T The pregnane xenobiotic receptor, a prominent liver factor, has actions in the midbrain for neurosteroid synthesis and behavioral/neural plasticity of female rats
%A Cheryl A. Frye
%A Carolyn J. Koonce
%A Alicia A. Walf
%J Frontiers in Systems Neuroscience
%D 2014
%I Frontiers Media
%R 10.3389/fnsys.2014.00060
%X A novel factor of interest for growth/plasticity in the brain is pregnane xenobiotic receptor (PXR). PXR is a liver factor known for its role in xenobiotic clearance and cholesterol metabolism. It is expressed in the brain, suggesting a potential role for plasticity, particularly involving cholesterol-based steroids and neurosteroids. Mating induces synthesis of neurosteroids in the midbrain Ventral Tegmental Area (VTA) of female rodents, as well as other ¡®plastic¡¯ regions of the brain, including the hippocampus, that may be involved in the consolidation of the mating experience. Reducing PXR in the VTA attenuates mating-induced biosynthesis of the neurosteroid, 5¦Á-pregnan-3¦Á-ol-20-one (3¦Á,5¦Á-THP). The 18kDA translocator protein (TSPO) is one rate-limiting factor for 3¦Á,5¦Á-THP neurosteroidogenesis. The hypothesis tested was that PXR is an upstream factor of TSPO for neurosteroidogenesis of 3¦Á,5¦Á-THP in the VTA for lordosis, independent of peripheral glands. First, proestrous rats were administered a TSPO blocker (PK11195) and/or 3¦Á,5¦Á-THP following infusions of PXR antisense oligonucleotides (AS-ODNs) or vehicle to the VTA. Inhibiting TSPO with PK11195 reduced 3¦Á,5¦Á-THP levels in the midbrain and lordosis, an effect that could be reversed with 3¦Á,5¦Á-THP administration, but not AS-ODN+3¦Á,5¦Á-THP. Second, proestrous, ovariectomized (OVX), or ovariectomized/adrenalectomized (OVX/ADX) rats were infused with a TSPO enhancer (FGIN 1-27) subsequent to AS-ODNs or vehicle to the VTA. PXR AS-ODNs blocked actions of FGIN 1-27 for lordosis and 3¦Á,5¦Á-THP levels among proestrous> OVX> OVX/ADX rats. Thus, PXR may be upstream of TSPO, involved in neurosteroidogenesis of 3¦Á,5¦Á-THP in the brain for plasticity. This novel finding of a liver factor involved in behavioral/neural plasticity substantiates future studies investigating factors known for their prominent actions in the peripheral organs, such as the liver, for modulating brain function and its augmentation.
%K midbrain ventral tegmental area
%K Allopregnanolone
%K Progesterone
%K Cognition
%K Reproduction
%U http://www.frontiersin.org/Journal/10.3389/fnsys.2014.00060/abstract