Progestins mediate the onset and duration of the mating posture, lordosis, in female rodents through actions in the hypothalamus and ventral tegmental area (VTA). In the hypothalamus, progesterone (P) has traditional, """"""""genomic"""""""" actions via intracellular progestin receptors (PRs). In the VTA, 3a-hydroxy-5a-pregnan-20-one (3a,5a-THP) has """"""""non-genomic"""""""" actions independent of PRs to facilitate lordosis that may involve GABA-Benzodiazepine receptors (GBRs) and/or NMDA type glutamate receptors (NMDARs). In addition to lordosis, 3a,5a-THP may influence other social behaviors, as well as exploration and anxiety. Levels of 3a,5a-THP can also change with behavioral and/or environmental stimuli. Thus, experiments will test the hypothesis that rapid biosynthesis of, or metabolism to, 3a,5a-THP and its non-genomic actions at GBRs and/or NMDARs influence social and sexual behaviors (socio-sexual behaviors) and socio-sexual behaviors alter central 3a,5a-THP concentrations via similar mechanisms. Using classic behavioral endocrinology, pharmacology, and radioimmunoassay methods in a model of socio-sexual behaviors, experiments will investigate: 1) the causal effects of 3a,5a-THP in the midbrain VTA to facilitate socio-sexual behaviors. 2) The effects of various socio-sexual behaviors on midbrain 3a,5a-THP levels. If midbrain 3a,5a-THP is altered in response to socio-sexual behaviors, then this will suggest 3a,5a-THP in the midbrain mediates, and can be reflexively altered by, socio-sexual stimuli. 3) 3a,5a-THP can be formed in the VTA from metabolism of progestins produced peripherally by endocrine glands or centrally via biosynthesis in glial cells. The relative importance of 3a,5a-THP in the VTA from central biosynthesis vs metabolism of peripheral progestins to effect, or be increased by, socio-sexual behaviors will be investigated. 4) 3a,5a-THP may have actions at non-genomic substrates, such as GBRs and/or NMDARs. Whether behavioral effects of 3a,5a-THP, or 3a,5a-THP formation in response to socio-sexual behaviors, are in part due to non-genomic actions at these receptors in the VTA will be examined. Together, these experiments will elucidate the function, source, and mechanisms of 3a,5a-THP's actions in the VTA for socio-sexual behaviors and reveal how 3a,5a-THP increases in response to these behaviors. This research, investigating novel behavioral functions of 3a,5a-THP, will extend knowledge of the neurobiology of progestins, relevant for socio-sexual behaviors, and their connections to systems that regulate emotions. 3a,5a-THP is implicated in stress and the pathophysiology and treatment of neuropsychiatric disorders. Thus, 3a,5a-THP's role and actions to enhance reproduction and social bonds, minimize aggression, influence affective aspects of social behaviors, and to mediate responses to behavioral and/or environmental stimuli needs to be understood.

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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Winsky, Lois M
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State University of New York at Albany
Schools of Arts and Sciences
United States
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Porcu, P; Barron, A M; Frye, C A et al. (2016) Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research. J Neuroendocrinol 28:12351
Walf, Alicia A; Koonce, Carolyn J; Frye, Cheryl A (2015) Progestogens' effects and mechanisms for object recognition memory across the lifespan. Behav Brain Res 294:50-61
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, 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
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, 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
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, 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
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
Koonce, Carolyn J; Walf, Alicia A; Frye, Cheryl A (2012) Type 1 5?-reductase may be required for estrous cycle changes in affective behaviors of female mice. Behav Brain Res 226:376-80

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