Progesterone (P) mediates exploration, anxiety, social responding of female rodents in part through actions of its product, 3a-hydroxy-5a-pregnan-20-one (3a,5a-THP). In the ventral tegmental area (VTA), 3a,5a-THP has actions to facilitate affective and social behaviors through GABAA/Benzodiazepine (GBRs) and/or NMDA type glutamate (NMDARs), rather than via intracellular progestin receptors. 3a,5a-THP levels in the midbrain VTA both facilitate, and are enhanced by, affective and social 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 3a,5a-THP in the VTA underlies facilitation of, and/or response to, affective and social behavior. Using classic methods of behavioral endocrinology, pharmacology, in conjunction with tools of molecular biology, in a rat model of affective/social behaviors, the following aims will be to investigate. 1) The causal actions of PXR in the midbrain VTA for 3a,5a-THP to facilitate affective/social behaviors. 2) The effects of affective/social behaviors on PXR-dependent midbrain 3a,5a-THP levels. If PXR and 3a,5a-THP are altered in response to affective/social behaviors, and blocking PXR attenuates behavior- induced 3a,5a-THP, then effects of 3a,5a-THP in the midbrain to mediate, and be dynamically altered by, social stimuli are PXR-dependent. 3) 3a,5a-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 3a,5a-THP in the VTA to be produced from central biosynthesis and/or metabolism from peripheral P to facilitate, or be increased by, affective/social behaviors will be investigated. 4) 3a,5a-THP may have PXR-dependent actions involving GBRs and/or NMDARs. Whether behavioral effects of 3a,5a-THP, or 3a,5a-THP formation in response to affective/social behaviors, are in part due to PXR- dependent effects at GBRs and/or NMDARs, will be examined. Investigating novel behavioral functions of 3a,5a-THP will extend our knowledge of the neurobiology of progestogens, relevant for affective/social behaviors, and their connections to systems that regulate emotions. 3a,5a-THP is implicated in stress regulation, pathophysiology and/or treatment of neuropsychiatric disorders. Thus, further understanding of 3a,5a-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.

Public Health Relevance

Progestogens mediate exploration, anxiety, and social responding behavior in rodents, in part through non-classic actions in the midbrain ventral tegmental area (VTA), and can be enhanced by engaging in affective and social 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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Desmond, Nancy L
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University of Alaska Fairbanks
Schools of Arts and Sciences
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Frye, C A; Koonce, C J; Walf, A A (2014) Role of pregnane xenobiotic receptor in the midbrain ventral tegmental area for estradiol- and 3?,5?-THP-facilitated lordosis of female rats. Psychopharmacology (Berl) 231:3365-74
Frye, C A; Koonce, C J; Walf, A A (2014) 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. Psychopharmacology (Berl) 231:3375-90
Koonce, Carolyn J; Frye, Cheryl A (2014) Female mice with deletion of Type One 5?-reductase have reduced reproductive responding during proestrus and after hormone-priming. Pharmacol Biochem Behav 122:20-9
Frye, Cheryl Anne; Koonce, Carolyn J; Walf, Alicia A et al. (2013) Motivated behaviors and levels of 3*,5*-THP in the midbrain are attenuated by knocking down expression of pregnane xenobiotic receptor in the midbrain ventral tegmental area of proestrous rats. J Sex Med 10:1692-706
Frye, Cheryl A; Koonce, Carolyn J; Walf, Alicia A (2013) Progesterone, compared to medroxyprogesterone acetate, to C57BL/6, but not 5*-reductase mutant, mice enhances object recognition and placement memory and is associated with higher BDNF levels in the hippocampus and cortex. Neurosci Lett 551:53-7
Koonce, Carolyn J; Frye, Cheryl A (2013) Progesterone facilitates exploration, affective and social behaviors among wildtype, but not 5*-reductase Type 1 mutant, mice. Behav Brain Res 253:232-9
Frye, C A; Koonce, C J; Walf, A A (2013) Pregnane xenobiotic receptors and membrane progestin receptors: role in neurosteroid-mediated motivated behaviours. J Neuroendocrinol 25:1002-11
Frye, Cheryl A (2011) Progesterone attenuates depressive behavior of younger and older adult C57/BL6, wildtype, and progesterone receptor knockout mice. Pharmacol Biochem Behav 99:525-31
Walf, Alicia A; Paris, Jason J; Rhodes, Madeline E et al. (2011) Divergent mechanisms for trophic actions of estrogens in the brain and peripheral tissues. Brain Res 1379:119-36
Walf, Alicia A; Paris, Jason J; Llaneza, Danielle C et al. (2011) I. Levels of 5?-reduced progesterone metabolite in the midbrain account for variability in reproductive behavior of middle-aged female rats. Brain Res 1379:137-48

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