The Role of Neurosteroids and Nongenomic Effects of Progestins in the Ventral Tegmental Area in Mediating Sexual Receptivity of Rodents

Abstract

Progesterone (P4) in the ventromedial hypothalamus (VMH) and ventral tegmental (VTA) is important for facilitation of lordosis; however, P4's actions in these brain areas are different. Using lordosis in rodents as in vivo experimental models, we have examined the effects progestins exert in the midbrain and hypothalamus. Localization and blocker studies indicate that P4'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 GABAA/benzodiazepine receptor complexes (GBRs) in the VTA alter lordosis, which suggests that progestins may interact with GBRs to facilitate receptivity by enhancing the function of GABAergic neurons. Interfering with P4's metabolism to 5α-pregnan-3α-ol-20-one (3α,5α-THP), the most effective endogenous positive modulator of GBRs, or the biosynthesis of the neurosteroid 3α,5α-THP in the VTA attenuates female sexual behavior in rodents. Stimulation of mitochondrial benzodiazepine receptors (MBRs), which enhance neurosteroid production, by infusions of a MBR agonist to the VTA enhances lordosis. 3α,5α-THP is increased in the midbrain of mated > proestrous > diestrous rodents. These data suggest that 3α,5α-THP has a proximate modulatory role on lordosis. In summary, the actions of P4 in the VTA are different from those in the VMH that involve PRs. In the VTA, P4 may facilitate lordosis following metabolism to and/or biosynthesis of 3α,5α-THP, which may have subsequent actions at GBRs and/or MBRs to acutely modulate female sexual behavior in rodents.