In the Ventral Tegmental Area, Progestins’ Membrane-Mediated Actions for Lordosis of Hamsters and Rats Involve Protein Kinase A

Abstract

Progestin-facilitated lordosis of hamsters and rats is enhanced by activation of dopamine type 1 (D₁) or GABA_A/benzodiazepine receptor complexes (GBRs) in the ventral tegmental area (VTA) and these effects involve G-proteins and second messengers, such as adenosine 3′,5′-monophosphate (cAMP). We examined whether D₁- and/or GBR-mediated increases in progestin-facilitated lordosis of female hamsters and rats involve the cAMP-dependent protein kinase, protein kinase A (PKA), in the VTA. In experiment 1, ovariectomized hamsters, primed with estradiol (E₂; 10 µg at h 0) + progesterone (P; 100 µg at h 45), were first pre-tested for lordosis and motor behavior (h 48) and then infused with the PKA inhibitor, Rp-cAMP (100 ng/side), or vehicle. Thirty minutes later, hamsters were retested and then received infusions of the D₁ agonist, SKF38393 (100 ng/side), the GBR agonist, muscimol (100 ng/side), or vehicle to the VTA. Hamsters were post-tested for lordosis and motor behavior 30 min later. In Experiment 2, ovariectomized rats, primed with E₂ (10 µg at h 0), were first pre-tested for lordosis and then infused with Rp-cAMP (100 ng/side) or vehicle to the VTA at h 44. Immediately after testing, rats received infusions of SKF38393 (100 ng/side), muscimol (100 ng/side), or vehicle and were retested for lordosis. Rats were then infused with the neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP; 100 or 200 ng/side), or β-cyclodextrin vehicle and were post-tested for lordosis and motor behavior 10 and 60 min later. The enhancing effects of progestins or progestins plus D₁ or GBR activation on lordosis of E₂-primed hamsters and rats were blocked by the PKA inhibitor, Rp-cAMP. Thus, in the VTA, progestins’ membrane actions involving D₁ or GBRs are mediated, in part, by PKA.

Infusions of 3α,5α-THP to the VTA enhance exploratory, anti-anxiety, social, and sexual behavior and increase levels of 3α,5α-THP in midbrain, hippocampus, diencephalon, and cortex of female rats

“…The enzymes necessary for P 4 's conversion to 3α,5α-THP, 5α-reductase, and 3α-hydroxysteroid dehydrogenase (3-HSD), have been localized to the midbrain VTA [3] and activity of 5α-reductase, the limiting enzyme in the conversion of P 4 to 3α,5α-THP, is greater in the midbrain tegmentum than other regions of the mouse or rat brain investigated (hypothalamus, hippocampus, and/or cortex; [56,57]). Pharmacologically blocking P 4 's conversion to 3α,5α-THP by means of application of 5α-reductase or 3-HSD inhibitors to the VTA, but not the surrounding regions, inhibits sexual receptivity of rodents [3,[58][59][60]. Although, adequate 3α,5α-THP levels in the midbrain VTA are necessary for mating to occur, 3α,5α-THP concentrations in the midbrain are further increased with exposure to reproductively relevant stimuli [33].…”

Membrane actions of progestins at dopamine type 1-like and GABAA receptors involve downstream signal transduction pathways

“…Second, whether progestins' ability to enhance lordosis via actions at GBRs and/or D 1 in the VTA is dependent upon activation of adenylyl cyclase and PKA was investigated by administering infusions of an adenylyl cyclase (2′,5′-dideoxyadenosine (DDA; 12 microM/side) or PKA (Rp-cAMP (100 ng/side) inhibitor to the VTA. Infusions of DDA or Rp-cAMP, but not vehicle, to the VTA attenuated 3α5α-THP-, muscimol-, and SKF38393-facilitated lordosis [53][54]. Third, whether progestins' ability to enhance lordosis via actions at GBRs and/or D 1 in the VTA is contingent upon activation of PLC and PKC was investigated by administering infusions of a PLC (U73122; 400 nM/side) or PKC (bisindolylmaleimide; 75 nM/side) inhibitor to the VTA.…”

Progesterone Rapidly Attenuates ATP-Evoked Transient Currents in Cultured Rat Dorsal Root Ganglion Neurons

“…In contrast, progesterone rapidly inhibited gallbladder motility via activating the PKA/cAMP pathways [38] . Activation of PKA stimulated the progesterone-induced calcium influx in human sperm exposed to the phosphodiesterase inhibitor papaverine [39] and the membrane-mediated actions of progestins leading to lordosis of hamsters and rats [53] . These discrepancies suggest that the action of progesterone is complex in different species and tissues.…”