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

• Published in: Journal of endocrinological investigation Vol. 34; no. 7; pp. e188 - e199
• Main Authors: Frye, C. A., Paris, J. J.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.07.2011
• Subjects: Animals; Behavior, Animal - drug effects; Cyclooxygenase Inhibitors - pharmacology; Electronic Contents; Endocrinology; Exploratory Behavior - drug effects; Female; Humans; Indomethacin - pharmacology; Isoquinolines - pharmacology; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Pregnanolone - metabolism; Pregnanolone - pharmacology; Progesterone - metabolism; Random Allocation; Rats; Rats, Long-Evans; Sexual Behavior, Animal - drug effects; Social Behavior; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - metabolism; peripheral benzodiazepine receptor; 18 kDa translocator protein; allopregnanolone; PK11195; indomethacin
• ISSN: 0391-4097; 1720-8386
• DOI: 10.3275/7334

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.