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Progesterone turnover to its 5α-reduced metabolites in the ventral tegmental area of the midbrain is essential for initiating social and affective behavior and progesterone metabolism in female rats

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Abstract

Background: Among women and female rodents, progesterone (P) influences social affiliation and affect. These effects may be partly due to formation of its 5α-reduced, 3α-hydroxylated metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP). Aim: To elucidate whether actions of 3α,5α-THP in the midbrain ventral tegmental area (VTA) are both necessary and sufficient to enhance non-sexual and sexual social behaviors, affect, and central 3α,5α-THP metabolism. Materials and methods: P and 3α,5α-THP formation were unperturbed or blocked in VTA via infusions of vehicle, PK11195 (400 ng), and/or indomethacin (10 µg). Rats then received subsequent infusions of vehicle or 3α,5α-THP (100 ng) and were assessed in a battery of tasks that included open field (exploration), elevated plus maze (anxiety behavior), social interaction (social affiliation), and paced mating (sexual behavior) or were not tested. Metabolic turnover of P to its 5α-reduced metabolites was assessed in plasma, midbrain, hippocampus, frontal cortex, diencephalon, and remaining subcortical tissues (control interbrain). Results: Infusions of any combination of inhibitors significantly reduced social and affective behavior in all tasks compared to vehicle, concomitant with reduced turnover of P to its 5α-reduced metabolites, in midbrain only. Subsequent infusions of 3α,5α-THP significantly reinstated/enhanced anti-anxiety behavior, lordosis, and P turnover to its 5α-reduced metabolites in midbrain, as well as hippocampus, cortex, and diencephalon (but not plasma or interbrain). Conclusions: These data are the first to provide direct evidence that actions of 3α,5α-THP in the VTA are both necessary and sufficient for social and affective behavior, as well as initiation of central 5α-reduction.

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Authors and Affiliations

  1. Department of Psychology, The University at Albany-SUNY, Albany, USA

    C. A. Frye PhD & J. J. Paris

  2. Department of Biological Sciences, The University at Albany-SUNY, Albany, USA

    C. A. Frye PhD

  3. The Center for Neuroscience, The University at Albany-SUNY, Albany, USA

    C. A. Frye PhD

  4. The Center for Life Sciences Research, The University at Albany-SUNY, Albany, USA

    C. A. Frye PhD

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Frye, C.A., Paris, J.J. Progesterone turnover to its 5α-reduced metabolites in the ventral tegmental area of the midbrain is essential for initiating social and affective behavior and progesterone metabolism in female rats. J Endocrinol Invest 34, e188–e199 (2011). https://doi.org/10.3275/7334

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