Naloxone and initial estrogen action to induce lordosis in ovariectomized rats: the effect of a cut between the septum and preoptic area

doi:10.1016/0304-3940(95)11809-B

Neuroscience Letters

Volume 195, Issue 3, 11 August 1995, Pages 167-170

https://doi.org/10.1016/0304-3940(95)11809-B Get rights and content

Abstract

The effects of intra-third-ventricular (ITV) injection of naloxone (NLX), an opioid receptor antagonist, on lordosis behavior were studied in ovariectomized female rats given a horizontal half-circle cut located just above the anterior commissure (ARD) and subcutaneously (s.c.) treated with estradiol benzoate (EB) and progesterone (Frog). In ARD-sham control animals, lordosis quotient (LQ) was 78.8 ± 4.2% (SE, n = 8). LQ (48.3 ± 7.2%, SE, n = 8) in the ARD-sham rats significantly decreased with the ITV injection of NLX at the time of s.c. EB-priming. In contrast, lordosis reflex in the ARD-operated animals was maximally facilitated (sham versus ARD, P < 0.01). LQ in the ARD-operated rats did not decrease with the ITV injection of NLX at the s.c. EB-priming. The present results suggest that the opioidergic systems modulate an initial phase of estrogen action to induce lordosis and play a part in neural input from the forebrain structures to regulate female sexual receptivity.

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Extranuclear signaling by ovarian steroids in the regulation of sexual receptivity
2018, Hormones and Behavior
Citation Excerpt :
The ARH is an important integrative center for energy balance, cardiovascular regulation, GnRH secretion, temperature regulation, and female reproduction (Coppari et al., 2005; Mittelman-Smith et al., 2016; Mittelman-Smith et al., 2012; Mittelman-Smith et al., 2017; Rance et al., 2013; Voogt et al., 2001). Counterintuitively, without the opioid inhibition in the MPN, full sexual receptivity is not reached, even with sufficient doses of estradiol and progesterone that in control animals induce maximal lordosis behavior (Torii and Kubo, 1994; Torii et al., 1995, 1996, 1999). Sexual receptivity was also reduced in estradiol- and progesterone-primed MOR knock-out mice (Sinchak et al., 2005).
Tamoxifen and ICI 182,780 activate hypothalamic G protein-coupled estrogen receptor 1 to rapidly facilitate lordosis in female rats
2017, Hormones and Behavior
Citation Excerpt :
If the initial actions of estradiol are blocked by treating with a selective estrogen receptor modulator (SERM), tamoxifen (TAM), then sexual receptivity is not facilitated (Etgen and Shamamian, 1986). Likewise, if opioid activity in the region of the MPN is blocked at the time of estradiol priming, then subsequent facilitation of sexual receptivity does not occur (Torii et al., 1995, 1996, 1997, 1999). Finally, in our model system, if the initial mERα-mGluR1a signaling that rapidly activates MPN MOP is blocked by mGluR1a antagonists, the animals are nonreceptive (Dewing et al., 2007).
In the female rat, sexual receptivity (lordosis) can be facilitated by sequential activation of estrogen receptor (ER) α and G protein-coupled estrogen receptor 1 (GPER) by estradiol. In the estradiol benzoate (EB) primed ovariectomized (OVX) rat, EB initially binds to ERα in the plasma membrane that complexes with and transactivates metabotropic glutamate receptor 1a to activate β-endorphin neurons in the arcuate nucleus of the hypothalamus (ARH) that project to the medial preoptic nucleus (MPN). This activates MPN μ-opioid receptors (MOP), inhibiting lordosis. Infusion of non-esterified 17β-estradiol into the ARH rapidly reduces MPN MOP activation and facilitates lordosis via GPER. Tamoxifen (TAM) and ICI 182,780 (ICI) are selective estrogen receptor modulators that activate GPER. Therefore, we tested the hypothesis that TAM and ICI rapidly facilitate lordosis via activation of GPER in the ARH. Our first experiment demonstrated that injection of TAM intraperitoneal, or ICI into the lateral ventricle, deactivated MPN MOP and facilitated lordosis in EB-primed rats. We then tested whether TAM and ICI were acting rapidly through a GPER dependent pathway in the ARH. In EB-primed rats, ARH infusion of either TAM or ICI facilitated lordosis and reduced MPN MOP activation within 30 min compared to controls. These effects were blocked by pretreatment with the GPER antagonist, G15. Our findings demonstrate that TAM and ICI deactivate MPN MOP and facilitate lordosis in a GPER dependent manner. Thus, TAM and ICI may activate GPER in the CNS to produce estrogenic actions in neural circuits that modulate physiology and behavior.
Modulation of the arcuate nucleus-medial preoptic nucleus lordosis regulating circuit: A role for GABA<inf>B</inf> receptors
2013, Hormones and Behavior
Citation Excerpt :
However, knockdown of the synthetic enzymes for GABA, GAD 65 and 67, in the VMH blocked the ability of estradiol and progesterone priming to induce sexual receptivity, suggesting that GABA transmission mediates steroid priming important for the facilitation of lordosis behavior (McCarthy et al., 1994). The need for GABA neurotransmission for the facilitation of lordosis is similar to the requirement for opioid activation during the initial exposure to estradiol for the ultimate facilitation of lordosis behavior (Torii and Kubo, 1994; Torii et al., 1995, 1996, 1999), and may be related to activation of specific GABA receptors. Although GABA actions have been attributed to the VMH, GABAB receptor activity in the ARH POMC neurons is modified by steroids (Kelly and Wagner, 1999; Kelly et al., 1992; for review see Micevych and Kelly, 2012).
Estradiol rapidly activates a microcircuit in the arcuate nucleus of the hypothalamus (ARH) that is needed for maximal female sexual receptivity. Membrane estrogen receptor-α complexes with and signals through the metabotropic glutamate receptor-1a stimulating NPY release within the ARH activating proopiomelanocortin (POMC) neurons. These POMC neurons project to the medial preoptic nucleus (MPN) and release β-endorphin. Estradiol treatment induces activation/internalization of MPN μ-opioid receptors (MOR) to inhibit lordosis. Estradiol membrane action modulates ARH gamma-aminobutyric acid receptor-B (GABA_B) activity. We tested the hypothesis that ARH GABA_B receptors mediate estradiol-induced MOR activation and facilitation of sexual receptivity. Double-label immunohistochemistry revealed expression of GABA_B receptors in NPY, ERα and POMC expressing ARH neurons. Approximately 70% of POMC neurons expressed GABA_B receptors. Because estradiol initially activates an inhibitory circuit and maintains activation of this circuit, the effects of blocking GABA_B receptors were evaluated before estradiol benzoate (EB) treatment and after at the time of lordosis testing. Bilateral infusions of the GABA_B receptor antagonist, CGP52432, into the ARH prior to EB treatment of ovariectomized rats prevented estradiol-induced activation/internalization of MPN MOR, and the rats remained unreceptive. However, in EB-treated rats, bilateral CGP52432 infusions 30 min before behavior testing attenuated MOR internalization and facilitated lordosis. These results indicated that GABA_B receptors were located within the lordosis-regulating ARH microcircuit and are necessary for activation and maintenance of the estradiol inhibition of lordosis behavior. Although GABA_B receptors positively influence estradiol signaling, they negatively regulate lordosis behavior since GABA_B activity maintains the estradiol-induced inhibition.
Membrane-initiated estradiol actions mediate structural plasticity and reproduction
2012, Frontiers in Neuroendocrinology
Citation Excerpt :
The time course of MOR activation is such that nuclear estradiol action was thought not to be involved; MOR is activated within 30 min of estradiol treatment. A membrane constrained estradiol construct, E-biotin, microinjected into the ARH internalized MOR (Dewing et al., 2007), a circuit-activating event tied to the full display of sexual receptivity (Sinchak et al., 2005; Torii et al., 1996, 1995). These results suggested that EMS preceded a nuclear action of estradiol.
Over the years, our ideas about estrogen signaling have greatly expanded. In addition to estradiol having direct nuclear actions that mediate transcription and translation, more recent experiments have demonstrated membrane-initiated signaling. Both direct nuclear and estradiol membrane signaling can be mediated by the classical estrogen receptors, ERα and ERβ, which are two of the numerous putative membrane estrogen receptors. Thus far, however, only ERα has been shown to play a prominent role in regulating female reproduction and sexual behavior. Because ERα is a ligand-gated transcription factor and not a typical membrane receptor, trafficking to the cell membrane requires post-translational modifications. Two necessary modifications are palmitoylation and association with caveolins, a family of scaffolding proteins. In addition to their role in trafficking, caveolin proteins also serve to determine ERα interactions with metabotropic glutamate receptors (mGluRs). It is through these complexes that ERα, which cannot by itself activate G proteins, is able to initiate intracellular signaling. Various combinations of ERα–mGluR interactions have been demonstrated throughout the nervous system from hippocampus to striatum to hypothalamus to dorsal root ganglion (DRG) in both neurons and astrocytes. These combinations of ER and mGluR allow estradiol to have both facilitative and inhibitory actions in neurons. In hypothalamic astrocytes, the estradiol-mediated release of intracellular calcium stores regulating neurosteroid synthesis requires ERα–mGluR1a interaction. In terms of estradiol regulation of female sexual receptivity, activation of ERα–mGluR1a signaling complex leads to the release of neurotransmitters and alteration of neuronal morphology. This review will examine estradiol membrane signaling (EMS) activating a limbic-hypothalamic lordosis regulating circuit, which involves ERα trafficking, internalization, and modifications of neuronal morphology in a circuit that underlies female sexual receptivity.
Estradiol signaling in the regulation of reproduction and energy balance
2012, Frontiers in Neuroendocrinology
Citation Excerpt :
Progesterone treatment must be delayed about 24 h after estradiol priming to facilitate lordosis (Sinchak and Micevych, 2001) to allow for the expression of progesterone receptors through the “priming” actions of estradiol through direct genomic actions of ERα, ERβ (Alves et al., 2000; Shughrue et al., 1997) and possibly through mER interactions that ultimately modulate transcription. For example, blocking classical opioid receptors with naloxone at the time of estradiol injection decreases the ability of progesterone 48 h later to facilitate lordosis (Torii and Kubo, 1994; Torii et al., 1995, 1996, 1999). The activation of μ-opioid receptors in the medial preoptic nucleus are driven by estradiol binding mERα that complex and transactivate mGluR1a mERα-mGluR1a actions in the ARH (Eckersell et al., 1998) indicating the potential for an alternative indirect mechanism for estradiol to induce progesterone receptor expression that is initiated through mERα.
Our knowledge of membrane estrogenic signaling mechanisms and their interactions that regulate physiology and behavior has grown rapidly over the past three decades. The discovery of novel membrane estrogen receptors and their signaling mechanisms has started to reveal the complex timing and interactions of these various signaling mechanisms with classical genomic steroid actions within the nervous system to regulate physiology and behavior. The activation of the various estrogenic signaling mechanisms is site specific and differs across the estrous cycle acting through both classical genomic mechanisms and rapid membrane-initiated signaling to coordinate reproductive behavior and physiology. This review focuses on our current understanding of estrogenic signaling mechanisms to promote: (1) sexual receptivity within the arcuate nucleus of the hypothalamus, (2) estrogen positive feedback that stimulates de novo neuroprogesterone synthesis to trigger the luteinizing hormone surge important for ovulation and estrous cyclicity, and (3) alterations in energy balance.
Energy balance and reproduction
2004, Physiology and Behavior
The physiological mechanisms that control energy balance are reciprocally linked to those that control reproduction, and together, these mechanisms optimize reproductive success under fluctuating metabolic conditions. Thus, it is difficult to understand the physiology of energy balance without understanding its link to reproductive success. The metabolic sensory stimuli, hormonal mediators and modulators, and central neuropeptides that control reproduction also influence energy balance. In general, those that increase ingestive behavior inhibit reproductive processes, with a few exceptions. Reproductive processes, including the hypothalamic–pituitary–gonadal (HPG) system and the mechanisms that control sex behavior are most proximally sensitive to the availability of oxidizable metabolic fuels. The role of hormones, such as insulin and leptin, are not understood, but there are two possible ways they might control food intake and reproduction. They either mediate the effects of energy metabolism on reproduction or they modulate the availability of metabolic fuels in the brain or periphery. This review examines the neural pathways from fuel detectors to the central effector system emphasizing the following points: first, metabolic stimuli can directly influence the effector systems independently from the hormones that bind to these central effector systems. For example, in some cases, excess energy storage in adipose tissue causes deficits in the pool of oxidizable fuels available for the reproductive system. Thus, in such cases, reproduction is inhibited despite a high body fat content and high plasma concentrations of hormones that are thought to stimulate reproductive processes. The deficit in fuels creates a primary sensory stimulus that is inhibitory to the reproductive system, despite high concentrations of hormones, such as insulin and leptin. Second, hormones might influence the central effector systems [including gonadotropin-releasing hormone (GnRH) secretion and sex behavior] indirectly by modulating the metabolic stimulus. Third, the critical neural circuitry involves extrahypothalamic sites, such as the caudal brain stem, and projections from the brain stem to the forebrain. Catecholamines, neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) are probably involved. Fourth, the metabolic stimuli and chemical messengers affect the motivation to engage in ingestive and sex behaviors instead of, or in addition to, affecting the ability to perform these behaviors. Finally, it is important to study these metabolic events and chemical messengers in a wider variety of species under natural or seminatural circumstances.

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Naloxone and initial estrogen action to induce lordosis in ovariectomized rats: the effect of a cut between the septum and preoptic area

Abstract

Brain Res.

Trends Neurosci.

Neurosci. Biobehav. Rev.

Physiol. Behav.

Physiol. Behav.

Brain Res.

Physiol. Behav.

Overview of the endogenous opioid systems: anatomical, biochemical and functional issues

Effect of anti-estrogen on steroid induced sexual receptivity in ovariectomized rats

Physiol. Behav.

Cuts between the septum and preoptic area increase ultrasound production, lordosis, and body weight in female hamsters

Physiol. Behav.