Ventral tegmental area infusions of inhibitors of the biosynthesis and metabolism of 3alpha,5alpha-THP attenuate lordosis of hormone-primed and behavioural oestrous rats and hamsters.

The importance of progesterone biosynthesis and metabolism to 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), which exerts its effects via GABAA/benzodiazepine receptor complexes (GBRs) rather than intracellular progestin receptors (PRs), was investigated for its effects on sexual receptivity. Epostane, a 3beta-hydroxysteroid dehydrogenase inhibitor, blocks progesterone and 3alpha,5alpha-THP biosynthesis. Finasteride, a 5alpha-reductase inhibitor, blocks the metabolism of progesterone to dihydroprogesterone (DHP), which is subsequently metabolized to 3alpha,5alpha-THP. Indomethacin, a 3alpha-hydroxysteroid oxidoreductase inhibitor, blocks DHP's metabolism to 3alpha,5alpha-THP, and its oxidation to DHP. Epostane, finasteride, indomethacin or vehicle were infused intracranially in the ventral tegmental area (VTA) of hormone-primed or naturally receptive rats and hamsters and sexual behaviour was recorded. Epostane, finasteride and indomethacin to the VTA significantly reduced lordosis, compared to vehicle infusions, in hormone-primed and behavioural oestrous rats and hamsters. Radioimmunoassay revealed that concentrations of midbrain 3alpha,5alpha-THP were reduced following epostane, finasteride or indomethacin infusions that significantly decreased lordosis. Immunocytochemistry for 3alpha,5alpha-THP revealed the number of immunoreactive cells were significantly reduced in the VTA following epostane, finasteride or indomethacin infusion to the VTA, but not other midbrain sites. These data suggest that biosynthesis of progestins, and the metabolism of progesterone to 3alpha,5alpha-THP in the VTA, are important for progestin-facilitated sexual receptivity of rats and hamsters.