The role of neurosteroids and non-genomic effects of progestins and androgens in mediating sexual receptivity of rodents.

Progestins and androgens modulate sexual receptivity in rodents, in part through mechanisms independent of traditional intracellular steroid receptors. Progesterone (PROG) in the ventromedial hypothalamus (VMH) and ventral tegmental (VTA) facilitates lordosis but has different actions in these brain areas. Primarily using lordosis in rodents as an in vivo experimental model, we have examined the effects that progestins exert in the midbrain and hypothalamus. Localization and blocker studies indicate that PROG's actions in the VMH require intracellular progestin receptors (PRs) but in the VTA they do not. Progestins that have rapid, membrane effects, and/or are devoid of affinity for PRs, facilitate lordosis when applied to the VTA. Manipulation of GABA and/or GABA(A)/benzodiazepine receptor complexes (GBRs) in the VTA alters lordosis, which suggests that progestins may interact with GBRs to facilitate receptivity by enhancing the function of GABAergic neurons. Interfering with PROG's metabolism to, or the biosynthesis of, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG or allopregnanolone), the most effective endogenous GBR agonist, in the VTA attenuates female sexual behavior in rodents. Stimulation of mitochondrial benzodiazepine receptors (MBRs), which enhances neurosteroid production, by infusions of an MBR agonist to the VTA enhances lordosis. 3alpha,5alpha-TH PROG is increased in the midbrain of mated>proestrous>diestrous rodents. These data suggest that in the VTA, PROG may facilitate lordosis following metabolism to and/or biosynthesis of 3alpha,5alpha-TH PROG, which may have subsequent actions at GBRs and/or MBRs to acutely modulate female sexual behavior in rodents. The 3alpha-hydroxysteroid oxidoreduced metabolite of dihydrotestosterone (DHT), 5alpha-androstane-3alpha,17beta-diol (3alpha-androstanediol), is important for termination of sexual receptivity in rodents and has these effects in the absence of functional intracellular androgens receptors. As well, altering GBR function in the hypothalamus can influence 3alpha-androstanediol's inhibition of sexual receptivity. Through actions in the hypothalamus that are independent of intracellular androgen receptors but involving GBRs, 3alpha-androstanediol inhibits lordosis. These findings suggest that the PROG metabolite and pregnane neurosteroid, 3alpha,5alpha-TH PROG, and the testosterone metabolite and androstane neurosteroid, 3alpha-androstanediol, can have proximate influences on lordosis that is via nonclassical actions at intracellular steroid receptors.