Abstract
The neurosteroid, 5α-pregnan-3α-ol-20-one (known as “allopregnanolone” or 3α,5α-THP), is produced in the midbrain ventral tegmental area (VTA), independent of peripheral sources of progestogens, where it has potential actions at N-methyl-D-aspartate (NMDA) and GABAA receptors to facilitate rodent sexual behavior. Progestogens can also have anti-anxiety effects, but whether these involve actions of centrally-derived 3α,5α-THP or these receptors to support reproductively-relevant behavior is not well understood. We investigated the extent to which 3α,5α-THP’s actions via NMDA and/or GABAA receptors in the midbrain VTA influence reproductive behaviors. Estradiol-primed, ovariectomized/adrenalectomized (OVX/ADX) rats received midbrain VTA infusions of vehicle, an NMDA receptor blocker (MK-801; 200 ng), or a GABAA receptor blocker (bicuculline; 100 ng) followed by a second infusion of vehicle or 3α,5α-THP (100 ng). Reproductively-relevant behaviors were assessed: sexual (paced mating), anxiety-like (elevated plus maze), and social (partner preference, social interaction) behavior. Compared to vehicle, intra-VTA infusions of MK-801 exerted anxiolytic-like effects on elevated plus maze behavior and enhanced lordosis. Unlike prior observations in gonadally-intact rats, intra-VTA bicuculline had no effect on the behavior of OVX/ADX rats (likely due to a floor effect). Subsequent infusions of 3α,5α-THP reversed effects on lordosis and infusions of bicuculline inhibited 3α,5α-THP-facilitated lordosis. Thus, NMDA and GABAA receptors may act as mediators for reproductive behavioral effects of 3α,5α-THP in the midbrain VTA.
Highlights
Progesterone (P4) plays a key role in the regulation of reproductive behavior in female rodents
Given that the ventral tegmental area (VTA) is largely devoid of progestin receptors, P4 actions in this brain region are mediated by conversion of P4 to its 3α-hydroxy, 5α-reduced metabolite, 5α-pregnan-3α-ol-20-one
Contrasts revealed that OVX/ADX rats infused with MK801/vehicle spent a significantly increased amount of time on the open arms of the elevated plus-maze, compared to rats receiving infusions of bicuculline/vehicle (p = 0.04) or control infusions of vehicle/vehicle (p = 0.046)
Summary
Progesterone (P4) plays a key role in the regulation of reproductive behavior in female rodents. P4 facilitates lordosis, the reflexive posture that allows copulation. In this brain region, P4 actions are mediated by intracellular cognate progestin receptors, which act as nuclear transcription factors to alter RNA transcription and protein synthesis (Meisel and Pfaff, 1985). Given that the VTA is largely devoid of progestin receptors, P4 actions in this brain region are mediated by conversion of P4 to its 3α-hydroxy, 5α-reduced metabolite, 5α-pregnan-3α-ol-20-one (known as ‘‘allopregnanolone’’ or 3α,5α-THP). Blocking 3α,5α-THP formation in the VTA increases anxiety-like behavior and attenuates lordosis of female rats or hamsters (Frye and Vongher, 2001; Petralia et al, 2005; Frye et al, 2008a,b, 2009a,b; Frye and Paris, 2011). The mechanisms of 3α,5α-THP action in this brain region are not well-understood
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