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

Abstract

The progesterone metabolite and neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-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 3α,5α-THP formation, as well as 3α,5α-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 3α,5α-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 3α,5α-THP formation decreased exploratory, anti-anxiety, social, and sexual behavior, as well as midbrain 3α,5α-THP levels. Infusions of FGIN 1-27 following 3α,5α-THP inhibition restored these behaviors and midbrain 3α,5α-THP levels to those commensurate with control rats that had not been administered inhibitors. These findings suggest that 3α,5α-THP formation in the midbrain VTA may influence appetitive, as well as consummatory, aspects of mating behavior.