Our long term goal is to understand how gonadal (sex) steroids regulate G protein-coupled receptor mediated neurotransmission that underlies hormonal activation of behavior. Among the best studied steroid-responsive circuits are those in the hypothalamus that regulate the female reproductive behavior, lordosis. Preliminary results suggest that estrogen and progesterone have differential effects on mu-opioid receptors (MOR) and opioid receptor-like orphanin receptor (OFQR). The present proposal will examine mechanisms through which estrogen and progesterone shift the functional balance of a hypothalamic circuit from inhibition to facilitation of lordosis by sequentially activating MOR and then OFQR. Specifically, the proposed experiments will test a general hypothesis: estrogen increases transmission at MOR and progesterone attenuates the inhibitory MOR activation and increases transmission at OFQR resulting in lordosis. The proposal is divided into three specific aims. First, preliminary studies indicate estrogen acts at intracellular receptors to cause endogenous opioid release resulting in MOR activation. Because there are two estrogen receptors, ER-alpha and ER-beta, a fundamental question is which receptor mediates estrogen-induced effects. In the ER-alpha 'knock-out' (ERKO-alpha) mouse, immunocytochemistry will be used to monitor MOR activation. In situ hybridization will be used to monitor OFQR mRNA levels. These experiments will determine the role of specific estrogen receptors underlying MOR activation and OFQR expression and may provide clues about steroid regulation of opioid receptors in other circuits. Second, steroids may uncouple opioid receptors from intracellular signaling cascades altering the physiologic balance between MOR and OFQR. [35S]-GTPgS binding will be used to determine the temporal and site-specific sex steroid regulation of MOR and ORQR coupling to G proteins. This will provide a measure of functional coupling of the opioid receptors. Third, several endogenous opioid peptides activate MOR, including: enkephalins, beta-endorphin and endomorphins. Only one endogenous ligand has been described for OFQR, orphanin FQ/nociceptin, but OFQR may also have several ligands. To determine which endogenous opioids regulate lordosis, passive immunoneutralization and behavioral analysis will examine whether OFQR is only activated by orphanin FQ/nociceptin, and whether MOR is principally activated by endomorphins or other endogenous opioids. Such experiments will functionally define the interaction of steroids and opioids modulating lordosis, and demonstrate a category of analyses that compare patterns of receptor activation and behavioral output of specific circuits.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013185-05
Application #
6868948
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Thadani, Pushpa
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
5
Fiscal Year
2005
Total Cost
$343,125
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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