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.

Abstract

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). 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. 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). 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). 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.