Progestins have multiple mechanisms of action in the central nervous system that are important for modulating lordosis of female rats. In the ventral tegmental area (VTA), progestins, such as the progesterone metabolite and neurosteroid 5α-pregnan-3α-ol-20-one (3α,5α-THP), regulate lordosis via actions independent of intracellular progestin receptors. We hypothesized that if, in the VTA, dopamine type 1 receptors (D1), G-proteins, and adenosine 3′,5′-monophosphate (cAMP) are downstream effectors of 3α,5α-THP’s actions for lordosis, then pharmacological manipulations of these signaling molecules will produce changes in 3α,5α-THP-facilitated lordosis of estradiol (E2)-primed rats. VTA infusions of 3α,5α-THP (50 ng) or 3α,5α-THP and the D1 agonist SKF38393 (100 ng) increased lordosis of ovariectomized, E2 (10 µg)- primed rats, compared to vehicle. Both 3α,5α-THP- and 3α,5α-THP plus SKF38393-facilitated lordosis was reduced by VTA infusions of the G-protein inhibitor guanosine 5′-O-(2-thiodiphosphate) (GDP-β-S; 50 µM), but not vehicle. Also, in the VTA, blocking D1 with SCH23390 (100 ng) decreased, or increasing cAMP with 8-bromo-cAMP (200 ng) enhanced, 3α,5α-THP-facilitated lordosis of E2-primed rats. Notably, SCH23390’s inhibitory effects on 3α,5α-THP-facilitated lordosis were reversed by 8-bromo-cAMP. Thus, in the VTA, 3α,5α-THP’s actions for lordosis may involve activation of D1 and initiation of the G-protein-mediated second messenger cAMP.

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