Increasing 3 alpha,5 alpha-THP following inhibition of neurosteroid biosynthesis in the ventral tegmental area reinstates anti-anxiety, social, and sexual behavior of naturally receptive rats

The progesterone metabolite and neurosteroid, 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP), has actions in the midbrain ventral tegmental area (VTA) to modulate lordosis, but its effects on other reproductively relevant behaviors are not well understood. Effects on exploration, anxiety, and social behavior resulting from inhibition of 3 alpha,5 alpha-THP formation, as well as 3 alpha,5 alpha-THP enhancement, were investigated in the midbrain VTA. Naturally sexually receptive, female rats (n = 8-10/group) received infusions aimed at the midbrain VTA of vehicle, PK11195 (an inhibitor of neurosteroidogenesis), and/or indomethacin (an inhibitor of 3 alpha,5 alpha-THP formation from prohormones), and were subsequently infused with vehicle or FGIN 1-27 (a neurosteroidogenesis enhancer). The rats were then assessed in a behavioral battery that examined exploration (open field), anxiety (elevated plus maze), social (social interaction), and sexual (paced mating) behavior. Inhibition of 3 alpha,5 alpha-THP formation decreased exploratory, anti-anxiety, social, and sexual behavior, as well as midbrain 3 alpha,5 alpha-THP levels. Infusionsof FGIN 1-27 following 3 alpha,5 alpha-THP inhibition restored these behaviors and midbrain 3 alpha,5 alpha-THP levels to those commensurate with control rats that had not been administered inhibitors. These findings suggest that 3 alpha,5 alpha-THP formation in the midbrain VTA may influence appetitive, as well as consummatory, aspects of mating behavior.