Our long term goal is to understand how sex steroids regulate G protein-coupled receptor mediated neurotransmission that underlies hormonal activation of behavior. We have demonstrated that estrogen activation of ?-opioid receptors (MORs) is necessary for the full display of sexual receptivity. The neural circuit that regulates this behavior involves the hypothalamic arcuate nucleus (ARH) and the medial preoptic nucleus (MPN) and requires the activation of estrogen receptor-a (ERa), neuropeptide Y (NPY)-Y1 receptors and release of ?-endorphin (?-END). Preliminary studies indicate that metabotropic glutamate receptors (mGluR) are involved in estrogen-induced MOR internalization/activation in the MPN and the regulation of lordosis. The present proposal will examine signaling mechanisms through which estrogen activates this ARH-MPN pathway. The general hypothesis tested is that estrogen activation of MOR in the MPN depends on membrane associated ERa interactions with mGluR1a and GABA-B receptors in the ARH. The ER- mGluR interaction mediates GABA-B receptor function, uncoupling the receptor from a G protein-gated inward rectifying potassium (GIRK) channel. The proposal is divided into three Specific Aims: 1. Estrogen-induced MOR internalization in the MPN is due to an interaction of membrane associated ERa with mGluR1a to block GABA-B receptor inhibition of NPY neurons. This is tested through a series of pharmacological studies that systematically block or activate these receptors. 2. ERa, mGluR1a and GABA-B receptors are expressed by NPY neurons in the ARH. Immunohistochemical studies will determine the co-localization of these receptors and co-immunoprecipitation will determine if ERa directly interacts with mGluR1a. To determine the mechanism of estrogen-induced NPY expression, real time RT-PCR will be used to measure the effects of estrogen signaling through the mGluR on NPY mRNA expression. 3. Estrogen-induced lordosis depends on the sequential activation of ERa, mGluR1a and inhibition of GABA-B receptors. Behavioral experiments will test the how activating membrane associated ER and mGluR affect intracellular signaling pathways regulating lordosis. Estrogen is an important but not well understood neuroactive substance. The results from these studies will help design appropriate estrogen therapies to rescue reproductive, feeding and cognitive dysfunctions that rely on estrogen signaling in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013185-09
Application #
7600545
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (02))
Program Officer
Pilotte, Nancy S
Project Start
2001-03-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
9
Fiscal Year
2009
Total Cost
$330,794
Indirect Cost
Name
University of California Los Angeles
Department
Neurosciences
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Micevych, Paul E; Sinchak, Kevin (2018) Extranuclear signaling by ovarian steroids in the regulation of sexual receptivity. Horm Behav :
Micevych, Paul E; Mermelstein, Paul G; Sinchak, Kevin (2017) Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction. Trends Neurosci 40:654-666
Micevych, Paul E; Meisel, Robert L (2017) Integrating Neural Circuits Controlling Female Sexual Behavior. Front Syst Neurosci 11:42
Rudolph, L M; Bentley, G E; Calandra, R S et al. (2016) Peripheral and Central Mechanisms Involved in the Hormonal Control of Male and Female Reproduction. J Neuroendocrinol 28:
Rudolph, Lauren M; Cornil, Charlotte A; Mittelman-Smith, Melinda A et al. (2016) Actions of Steroids: New Neurotransmitters. J Neurosci 36:11449-11458
Xu, Ji; Bernstein, Alexander M; Wong, Angela et al. (2016) P2X4 Receptor Reporter Mice: Sparse Brain Expression and Feeding-Related Presynaptic Facilitation in the Arcuate Nucleus. J Neurosci 36:8902-20
Wong, Angela M; Abrams, Matthew C; Micevych, Paul E (2015) ?-arrestin regulates estradiol membrane-initiated signaling in hypothalamic neurons. PLoS One 10:e0120530
Christensen, Amy; Dewing, Phoebe; Micevych, Pavel (2015) Immediate early gene activity-regulated cytoskeletal-associated protein regulates estradiol-induced lordosis behavior in female rats. J Neurosci Res 93:67-74
Micevych, Paul E; Wong, Angela May; Mittelman-Smith, Melinda Anne (2015) Estradiol Membrane-Initiated Signaling and Female Reproduction. Compr Physiol 5:1211-22
Sinchak, Kevin; Dewing, Phoebe; Ponce, Laura et al. (2013) Modulation of the arcuate nucleus-medial preoptic nucleus lordosis regulating circuit: a role for GABAB receptors. Horm Behav 64:136-43

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