Temporal and Concentration‐Dependent Effects of Oestradiol on Neural Pathways Mediating Sexual Receptivity

Abstract

The acceptance of estradiol signaling through receptors found in the cell membrane, as well as, the nucleus has provided for a re-examination of timing and location of estradiol actions on neural circuits mediating sexual receptivity (lordosis). Estradiol membrane signaling involves the transactivation of metabotropic glutamate receptors (mGluR) that transduce steroid information through PKC signaling cascades producing rapid activation of lordosis regulating circuits. It has been known for some time that estradiol initially produces an inhibition of the medial preoptic nucleus (MPN). We have demonstrated that underlying this inhibition is estradiol acting in the arcuate nucleus to induce β-endorphin release which inhibits the MPN through a μ-opioid receptor mechanism. This transient inhibition is relieved by either subsequent progesterone treatment or longer exposure to higher doses of estradiol to facilitate lordosis behavior. We review recent findings about estradiol membrane signaling inducing dendritic spine formation in the arcuate nucleus that is critical for estradiol induction of sexual receptivity. Moreover, we discuss the evidence that in addition to ERα, several other putative membrane estrogen receptors facilitate lordosis behavior through regulation of the arcuate nucleus. These include the GRP30 and the STX activated Gq-mER. Finally, we report on the importance of GABA acting at GABAB receptors for estradiol membrane signaling that regulates lordosis circuit activation and sexual receptivity.

17β-estradiol rapidly facilitates lordosis through G protein-coupled estrogen receptor 1 (GPER) via deactivation of medial preoptic nucleus μ-opioid receptors in estradiol primed female rats

“…Sexual receptivity can be facilitated in ovariectomized (OVX) rats with estradiol-only treatments that coordinate classical nuclear, and non-classical extra-nuclear, estrogen receptor (ER) signaling mechanisms (reviewed in Micevych and Sinchak, 2013; Sinchak and Wagner, 2012). A single high dose of esterfied 17β-estradiol benzoate (5–50 μg; EB) or multiple sequential lower doses of estradiol can induce sexual receptivity (reviewed in Clemens and Weaver, 1985; Micevych and Sinchak, 2013).…”

“…A single high dose of esterfied 17β-estradiol benzoate (5–50 μg; EB) or multiple sequential lower doses of estradiol can induce sexual receptivity (reviewed in Clemens and Weaver, 1985; Micevych and Sinchak, 2013). The single large EB dose facilitates sexual receptivity approximately 48 hours after the initial treatment (reviewed in Clemens and Weaver, 1985).…”

“…This could be through down regulation of ARH membrane ERα-mGluR1a complexes to reduce β-endorphin release and deactivate MPN MOR (Mahavongtrakul et al, 2013). However, these ER antagonists also activate G protein-coupled estrogen receptor-1 (GPER; aka GPR30 reviewed in Micevych and Sinchak, 2013; Prossnitz et al, 2008; Sinchak and Wagner, 2012). GPER mediates rapid extranuclear estradiol signaling events in many physiological systems and certain cancers of the reproductive system that are estrogen-responsive, but are exacerbated by anti-estrogen therapies, like tamoxifen (Prossnitz et al, 2008; Soltysik and Czekaj, 2013) reviewed in (Sinchak and Wagner, 2012).…”

Orphanin FQ-ORL-1 Regulation of Reproduction and Reproductive Behavior in the Female

“…1; reviewed in Micevych & Sinchak, 2013;Sinchak & Wagner, 2012). All of the steroid priming paradigms that facilitate lordosis converge to regulate the output of ARH β-endorphin (β-END) neurons that project to the MPN (Borgquist et al, 2013(Borgquist et al, , 2014Cheung & Hammer, 1995;Christensen, Dewing, & Micevych, 2011;Christensen & Micevych, 2012Dewing et al, 2007;Dewing, Christensen, Bondar, & Micevych, 2008;Long, Chhorvann, & Sinchak, 2012;Long et al, 2013Long et al, , 2014Micevych, Rissman, Gustafsson, & Sinchak, 2003;Mills, Sohn, & Micevych, 2004;Sanathara et al, 2011Sanathara et al, , 2014Sinchak et al, 2013;Sinchak & Micevych, 2001;Sinchak, Shahedi, Dewing, & Micevych, 2005; Fig.…”

“…The ovarian hormones, estradiol and progesterone, are important signaling molecules that act on neural circuits to regulate reproductive behavior and physiology. Opioid neuropeptide systems are important mediators of ovarian steroid signaling that regulate reproduction in the female (DevorshakHarvey, Bona-Gallo, & Gallo, 1987;Genazzani & Petraglia, 1989;Goodman & Inskeep, 2006;Lado-Abeal et al, 2002;Micevych & Sinchak, 2013;Pfaus & Gorzalka, 1987;. Approximately, 20 years ago, cloning studies revealed the existence of a novel opioid receptor, the opioid receptor-like receptor-1 (ORL-1) (Bunzow et al, 1994;Chen et al, 1994;Fukuda et al, 1994;Lachowicz, Shen, Monsma, & Sibley, 1995;Marchese et al, 1994;Mollereau et al, 1994;Wang et al, 1994;Wick et al, 1994).…”