Progestins' non-genomic actions for socio-sexual behavior

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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.