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

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          Progestin-facilitated lordosis of hamsters and rats is enhanced by activation of dopamine type 1 (D<sub>1</sub>) or GABA<sub>A</sub>/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 D<sub>1</sub>- 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 (E<sub>2</sub>; 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 D<sub>1</sub> 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 E<sub>2</sub> (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 D<sub>1</sub> or GBR activation on lordosis of E<sub>2</sub>-primed hamsters and rats were blocked by the PKA inhibitor, Rp-cAMP. Thus, in the VTA, progestins’ membrane actions involving D<sub>1</sub> or GBRs are mediated, in part, by PKA.

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          Most cited references 58

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          Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum.

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            Ovarian hormones elicit phosphorylation of Akt and extracellular-signal regulated kinase in explants of the cerebral cortex.

            Estradiol and progesterone both have been demonstrated to afford neuroprotection against various insults. In an attempt to identify potential mechanisms underlying these neuroprotective effects, two key elements within signal transduction pathways linked to neuroprotection were evaluated. In mouse cerebral cortical explants, both estradiol and progesterone elicited the phosphorylation of Akt, a downstream effector of the phosphoinositide-3 (PI-3) kinase pathway. Progesterone also elicited the phosphorylation of extracellular-signal regulated kinase (ERK), a component of the mitogen-activated protein kinase (MAPK) pathway. These effects were not inhibited by the progesterone receptor antagonist, RU486. However, inhibition of either MAPK/ERK kinase with PD98059 or PI-3 kinase with LY294002 successfully inhibited progesterone's actions on ERK and Akt, respectively. Collectively, the data offer novel mechanisms for both progesterone and estrogen action in the central nervous system, demonstrating the functional and mechanistic diversity of gonadal hormones and supporting their neuroprotective potential for such neurodegenerative disorders as Alzheimer disease.
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              Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases.

              In the mammalian central nervous system, receptors for excitatory amino acid neurotransmitters such as the alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA)-kainate receptor mediate a large fraction of excitatory transmission. Currents induced by activation of the AMPA-kainate receptor were potentiated by agents that specifically stimulate adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase A (PKA) activity or were supported by intracellular application of the catalytic subunit of PKA by itself or in combination with cAMP. Furthermore, depression of these currents by a competitive inhibitor of PKA indicates that AMPA-kainate receptors are regulated by endogenous PKA. Endogenous protein phosphatases also regulate these receptors because an inhibitor of cellular phosphates enhanced kainate currents. Modulation of PKA and phosphatases may regulate the function of these receptors and thus contribute to synaptic plasticity in hippocampal neurons.

                Author and article information

                S. Karger AG
                March 2007
                30 March 2007
                : 84
                : 6
                : 405-414
                Departments of aPsychology and bBiological Sciences, and The Centers for cNeuroscience and dLife Sciences Research, The University at Albany, SUNY, Albany, N.Y., USA
                100510 Neuroendocrinology 2006;84:405–414
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 4, References: 68, Pages: 10
                Hormone Actions in the Brain


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