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.