Progesterone (P) mediates exploration, anxiety, social and sexual (socio-sexual) behaviors of female rodents in part through actions of its product, 3?-hydroxy-5?-pregnan-20-one (3?,5?-THP). In the ventral tegmental area (VTA), 3?,5?-THP has actions to facilitate socio-sexual behavior through GABAA/Benzodiazepine (GBRs) and/or NMDA type glutamate (NMDARs), rather than via intracellular progestin receptors. 3?,5?-THP levels in the midbrain VTA both facilitate, and are enhanced by, socio-sexual behavior. The pregnane X receptor (PXR) mediates the production of, and/or metabolism to, various neurobiological factors. PXR is localized to the midbrain VTA of rats. Our hypothesis is that PXR-dependent biosynthesis of 3?,5?-THP in the VTA underlies facilitation of, and/or response to, socio-sexual behaviors. Using classic behavioral endocrinology, pharmacology, and radioimmunoassay methods, in conjunction with tools of molecular biology, in a rat model of socio-sexual behaviors, aims will be to investigate. 1) The causal actions of PXR in the midbrain VTA for 3?,5?-THP to facilitate socio-sexual behaviors. 2) The effects of socio-sexual behaviors on PXR-dependent midbrain 3?,5?-THP levels. If PXR and 3?,5?-THP are altered in response to socio-sexual behaviors, and blocking PXR attenuates behavior-induced 3?,5?-THP, then effects of 3?,5?-THP in the midbrain to mediate, and be dynamically altered by, socio-sexual stimuli are PXR-dependent. 3) 3?,5?- THP can be formed in the VTA from metabolism of P produced peripherally by ovaries or adrenals or centrally via biosynthesis in brain. The role of PXR for 3?,5?-THP in the VTA to be produced from central biosynthesis and/or metabolism from peripheral P to facilitate, or be increased by, socio-sexual behaviors will be investigated. 4) 3?,5?-THP may have PXR- dependent actions involving GBRs and/or NMDARs. Whether behavioral effects of 3?,5?- THP, or 3?,5?-THP formation in response to socio-sexual behaviors, are in part due to PXR-dependent effects at GBRs and/or NMDARs, will be examined. Investigating novel behavioral functions of 3?,5?-THP will extend our knowledge of the neurobiology of progestogens, relevant for socio-sexual behaviors, and their connections to systems that regulate emotions. 3?,5?-THP is implicated in stress regulation, pathophysiology and/or treatment of neuropsychiatric disorders. Thus, further understanding of 3?,5?-THP's role and mechanisms to enhance reproduction/social bonds, minimize aggression, influence affective aspects of social behaviors, and to mediate responses to stress, are essential.
Progestogens mediate exploration, anxiety, social and sexual (socio-sexual) behavior in rodents, in part through non-classic actions in the midbrain ventral tegmental area (VTA), and can be enhanced by engaging in socio-sexual behaviors. The role of the pregnane xenobiotic receptor (PXR) in mediating formation of progestogens and their non-traditional actions in the midbrain VTA will be investigated. Elucidation of PXR as a mediating factor in this phenomena will provide greater understanding of the mechanisms of progestogens underlying sex and/or hormonally-mediated effects on social and/or affective processes, and/or the etiology and/or treatment of some stress-sensitive neuropsychiatric disorders. Further understanding of progestogens'effects and mechanisms are vital to provide insight into normative and pathophysiological processes.
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