Infusions of 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) to the ventral tegmental area, but not the substantia nigra, enhance exploratory, anti-anxiety, social and sexual behaviours and concomitantly increase 3alpha,5alpha-THP concentrations in the hippocampus, diencephalon and cortex of ovariectomised oestrogen-primed rats.

Sequential actions of 17beta-oestradiol (E2) and progesterone (P4) in the ventromedial hypothalamus (VMH) and ventral tegmental area (VTA) mediate sexual behaviour of female rodents. In the presence of appropriate environmental stimuli, E2 and P4 can facilitate initiation of sex behaviour (i.e. lordosis), in part through classic actions at intracellular progestin receptors in the VMH. However, the effects of P4 in the VTA to modulate lordosis involve its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), which can have paracrine effects in the brain to reduce anxiety and stress. We investigated the effects of 3alpha,5alpha-THP infusions to the VTA, and a control site, the substantia nigra (SN), on exploratory, anti-anxiety, social and sexual behaviours (socio-sexual behaviours) and hormone levels in the midbrain and other regions (hippocampus, diencephalon and cortex) that may mediate these functions. Ovariectomised, rats were E2-primed (10 microg, s.c.) at 0 h and were infused with beta-cyclodextrin vehicle or 3alpha,5alpha-THP to the VTA or SN 44-48 h later. Ten minutes after infusions, rats were tested in the open field, plus maze, partner preference, social interaction and paced mating tasks, or served as nontested controls. Infusions of 3alpha,5alpha-THP to the VTA, but not the SN, increased central entries in the open field, open arm time in the plus maze, time spent in proximity to a male, duration of social interaction, incidence and intensity of lordosis, pacing, proceptivity, and anti-conflict behaviour. 3Alpha,5alpha-THP, but not vehicle, infusions to the VTA (but not the SN) also increased 3alpha,5alpha-THP levels in the midbrain, as well as the hippocampus, diencephalon and cortex. Behavioural testing increased levels of the precursor of 3alpha,5alpha-THP precursor, dihydroprogesterone (DHP). Thus, infusions of 3alpha,5alpha-THP to the VTA enhance socio-sexual behaviours and increase 3alpha,5alpha-THP levels in the hippocampus, diencephalon and cortex, and behavioural testing increases DHP levels in brain areas involved in modulating socio-sexual behaviours.