Estrogen is necessary for 5α-pregnan-3α-ol-20-one (3α,5α-THP) infusion to the ventral tegmental area to facilitate social and sexual, but neither exploratory nor affective behavior of ovariectomized rats

The progesterone metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP, allopregnanolone), acts in the ventral tegmental area (VTA) to facilitate exploratory, anti-anxiety, and socio-sexual behavior among ovariectomized (OVX), estrogen (E2)-primed rats and gonadally-intact rats with high (proestrus) or low (diestrus) endogenous E2 levels. The extent to which E2 is required for these effects of 3α,5α-THP is not known. OVX rats were primed with systemic 17β-estradiol (10 µg) or oil vehicle and were infused 44 h later with 3α,5α-THP (100 ng) or β-cyclodextrin vehicle to the VTA, substantia nigra (SN), or central grey (CG). Rats were assessed in a battery of exploratory (open field), anxiety (elevated plus maze), social (partner preference, social interaction), and sexual (paced mating) tasks. E2-priming was necessary for 3α,5α-THP infusions to facilitate social interaction and mating and midbrain 3α,5α-THP levels were higher among E2-compared to vehicle-primed rats. Irrespective of E2-priming, rats infused with 3α,5α-THP to the VTA, but not SN or CG, demonstrated increased exploration in an open field, anti-anxiety behavior on an elevated plus maze, and preference for a male. Thus, actions of 3α,5α-THP in the VTA to enhance social and sexual behaviors were reliant on E2 but increases in exploratory and anti-anxiety behavior were not.