Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2018 Feb 16.
Published in final edited form as: Vitam Horm. 2016 Oct 13;103:27–52. doi: 10.1016/bs.vh.2016.08.004

Estrogen Receptors Modulation of Anxiety-Like Behavior

AP Borrow 1, RJ Handa 1,1
PMCID: PMC5815294  NIHMSID: NIHMS941110  PMID: 28061972

Abstract

Estrogens exert profound effects on the expression of anxiety in humans and rodents; however, the directionality of these effects varies considerably within both clinical and preclinical literature. It is believed that discrepancies regarding the nature of estrogens’ effects on anxiety are attributable to the differential effects of specific estrogen receptor (ER) subtypes. In this chapter we will discuss the relative impact on anxiety and anxiety-like behavior of each of the three main ERs: ERα, which has a generally anxiogenic effect, ERβ, which has a generally anxiolytic effect, and the G-protein-coupled ER known as GPR30, which has been found to both increase and decrease anxiety-like behavior. In addition, we will describe the known mechanisms by which these receptor subtypes exert their influence on emotional responses, focusing on the hypothalamic–pituitary–adrenal axis and the oxytocinergic and serotonergic systems. The impact of estrogens on the expression of anxiety is likely the result of their combined effects on all of these neurobiological systems.

1. INTRODUCTION

Changes in circulating estrogen levels across the reproductive lifespan have long been associated with changes in the incidence of anxiety in women. The risk of developing an anxiety disorder is elevated at menarche (Patton et al., 1996), a developmental period characterized by an increase in circulating estradiol from prepubertal to adult levels (Ojeda & Bilger, 2000). By contrast, an increase in anxiety symptoms has also been noted when estradiol levels drop, such as following surgical menopause (Rocca et al., 2008) and in postmenopausal women (Sahingoz, Uguz, & Gezginc, 2011). Moreover, toward the end of the luteal phase of the menstrual cycle, which is characterized by a dramatic decline in circulating estradiol levels, there is an increase in symptoms of anxiety in patients with anxiety disorders (Cameron, Kuttesch, McPhee, & Curtis, 1988), as well as in patients with premenstrual disorders (Yonkers, O’Brien, & Eriksson, 2008).

While the association between anxiety symptoms and low endogenous estradiol levels might suggest a therapeutic effect of estrogens, both clinical and preclinical studies have reported that treatment with estradiol yields contradictory results. For example, in postmenopausal women, anxiety levels have been reported to either decrease (Gleason et al., 2015) or remain unaffected (Demetrio et al., 2011) following estrogen therapy. Using rodent models, studies have shown that the effect of estradiol on anxiety-like behavior may be dependent on both the dose administered and the behavioral testing paradigm. A recent study by Kastenberger, Lutsch, and Schwarzer (2012) conducted in ovariectomized mice found that a high dose of estradiol (0.25 mg/kg) but not a low dose (0.025 mg/kg) decreased anxiety-like behavior in the elevated plus maze. In contrast, only the low dose of estradiol increased anxiety-like behavior in the open field test (Kastenberger et al., 2012). A different group also noted that a low dose of estradiol (2.0 μg/day) increased anxiety in ovariectomized mice in the light/dark test, while a dose that was even lower (0.2 μg/day) instead decreased anxiety-like behavior (Tomihara et al., 2009). Other studies have reported either anxiogenic (Mora, Dussaubat, & Diaz-Véliz, 1996), anxiolytic (Tian et al., 2013), or null (Walf & Frye, 2008) effects of estradiol in a variety of rodent models. Consequently, the conflicting effects of estradiol on anxiety and anxiety-like behavior have been proposed to be the result of diverging roles for estrogen receptor subtypes (Kastenberger et al., 2012).

Currently, researchers are aware of at least three types of estrogen receptors. The classic estrogen receptors, ERα and ERβ, are highly homologous in structure and belong to one subclass of a large superfamily of nuclear hormone receptors (Burris et al., 2013) which also include the receptors for androgens, glucocorticoids, mineralocorticoids, thyroid hormone, and retinoic acid, to name but a few. A more complete examination of these receptor proteins can be found in several recent reviews (Huang, Chandra, & Rastinejad, 2010; Morrill, Kostellow, & Gupta, 2015), and their distributions into the various subclasses of receptors, specific receptor-related transcriptomics, and reagents are now cataloged online at the nuclear receptor signaling atlas website (www.nursa.org). It is classically thought that the nuclear receptors influence gene expression both directly, as ligand-activated transcription factors, and perhaps indirectly, through the membrane localization of the classical receptors which can rapidly impact intra-cellular signaling cascades (Edwards, 2005). A third, more recently identified receptor, the G-protein-coupled estrogen receptor (GPR30 or GPER1), is not related to the nuclear hormone receptors and exerts its effects through both rapid signaling events and, to a lesser extent, direct transcriptional activation (Prossnitz & Arterburn, 2015). Additionally, receptors such as the STX-sensitive receptor, a membrane-associated receptor which can mediate some of the actions of estradiol (Smith, Bosch, Wagner, Rønnekleiv, & Kelly, 2013), and ER-X, a putative membrane receptor for 17α estradiol (Toran-Allerand et al., 2002), have recently been described, although our understanding of their effects is currently, at best, very limited. In this chapter, we will discuss the contribution of each of the major estrogen receptors to anxiety and anxiety-like behavior, and their potential roles as therapeutic targets for anxiety disorders.

2. NUCLEAR ESTROGEN RECEPTOR FORM AND FUNCTION

ERα and ERβ show a number of similarities, both in their modular structure (Ascenzi, Bocedi, & Marino, 2006) as well as in homology within the central DNA binding domain (Pettersson, Grandien, Kuiper, & Gustafsson, 1997). The two ERs arose from a single duplication event approximately 450 million years ago (Kelley & Thackray, 1999). Since then, they have undergone a parallel evolution resulting in substantial sequence homology, yet they exhibit unique roles in regulated mammalian physiology. The generation of transgenic mouse lines that are null for ERα (Antonson, Omoto, Humire, & Gustafsson, 2012; Dupont et al., 2000), ERβ (Dupont et al., 2000; Krege et al., 1998), or both (Dupont et al., 2000; Kudwa & Rissman, 2003), has helped to determine the function of the nuclear estrogen receptors. These receptors influence expression of target genes through both genomic and nongenomic mechanisms (Björnström & Sjöberg, 2005) (Fig. 1). Classically, it has been shown that ligand binding to nuclear ERs results in receptor dimerization, followed by binding to promoter regions of target genes at sites known as estrogen response elements, ultimately attracting coregulatory proteins to these areas which can positively or negatively influence gene transcription. In addition, nuclear ERs are able to indirectly influence gene expression via tethering to other transcription factors, as well as through modulating the synthesis of various second messenger proteins (Björnström & Sjöberg, 2005). Despite

Fig. 1.

Fig. 1

Open in a new tab

A simplified description of known estrogen receptor signaling pathways. Classically, ligand-activated estrogen receptors (ER) α and β bind directly to promoter regions at estrogen response element (ERE) sites, attracting coregulatory proteins, which influence gene transcription (1). ERα and β can also indirectly affect gene transcription by influencing the activity of other transcription factors (TF) (2) and by mediating the synthesis of second messenger proteins such as Src kinase (3). Ligand binding to GPR30 initiates several second messenger signaling cascades, including the activation of adenylyl cyclase which increases the production of cAMP, ultimately activating the transcription factor cAMP response element-binding protein (CREB) (4), and the recruitment of Src kinase, which activates epidermal growth factor receptors (EGFRs), resulting in the activation of mitogen-activated protein kinases (MAPKs) ERK1/2 and phosphatidylinositol 3-kinases (PI3Ks), ultimately leading to the activation of proteins that regulate transcription factors (5). See Björnström and Sjöbergg (2005), Maggiolini and Picard (2010), and Prossnitz et al. (2008) for review. the marked similarities between ERα and ERβ, these receptors differ significantly in tissue distribution (Shughrue, Lane, & Merchenthaler, 1997) and function, particularly in brain.

3. ESTROGEN RECEPTOR ALPHA

ERα is the original ER to be cloned and characterized and has long been thought of as the ER that is essential for regulating reproductive physiology and behaviors. Knockout models of ERα consistently show impaired reproductive hormone secretion, physiology, and behaviors (Antonson et al., 2012; Dupont et al., 2000; McDevitt et al., 2007). In regard to the regulation of nonreproductive behaviors, the activation of ERα is largely associated with an increase in anxiety-like behavior in the rodent. For example, downregulation of ERα within the medial preoptic area and the posterodorsal amygdala of ovariectomized rats following infusion of an adeno-associated viral vector encoding for a small hairpin RNA (shRNA) targeting the ERα gene produced a decrease in anxiety-like behavior in the light–dark box and open field test (Spiteri et al., 2010; Spiteri, Ogawa, Musatov, Pfaff, & Ågmo, 2012). It is important to note that not all studies have observed effects of ERα on anxiety-like behavior. In ERα knockout mice, there were no observable changes in anxiety-like behavior in the elevated plus maze or open field tests (Kre¸żel, Dupont, Krust, Chambon, & Chapman, 2001). Additionally, some researchers have observed no effects ( Jacome et al., 2010; Walf & Frye, 2005) or mild effects (Lund, Rovis, Chung, & Handa, 2005) of the selective ERα agonist propylpyrazole triol (PPT) on anxiety-like behaviors when tested in the open field and elevated plus maze in rat models. Thus, it is possible that the effects of ERα on anxiety are context or species dependent, and further work is required to tease out the subtleties of this response.

While ERα’s effects appear mostly anxiogenic in the rodent, recent research has suggested an opposing effect of ERα on anxiety-like behavior in female animals following reproductive experience. Expression of ERα in the medial amygdala may change during the postpartum period, demonstrating a downregulation at 3 weeks postpartum, followed by an upregulation at 5 weeks (Furuta et al., 2013). Studies of primiparous rats have shown a decrease in anxiety-like behavior in the elevated plus maze following treatment with PPT at 3 weeks (albeit, not as effectively as estradiol treatment) (Furuta et al., 2013) or at 7 weeks (Byrnes, Casey, & Bridges, 2012; Byrnes, Casey, Carini, & Bridges, 2013) postpartum. It is unknown whether this temporal change in ERα’s effects is the result of hormonal changes during pregnancy and the postnatal period, maternal experience, or some combination of these two factors.

To date, only a small number of studies have considered a link between single nucleotide polymorphisms (SNPs) of the ERα gene (ESR1) and the occurrence of anxiety disorders. A study of adult men in treatment for substance abuse noted an association between symptoms of anxiety and dinucleotide polymorphisms (Comings, Muhleman, Johnson, & MacMurray, 1999). In an elderly human population, a study investigating SNPs found that, in women only, ESR1 haplotypes consisting of the T allele of rs2234693 and the A allele of rs9340799 were correlated with an increased likelihood of anxiety disorders (Tiemeier et al., 2005). More recently, a study by Ryan et al. noted that these same haplotypes were linked to an increase in panic disorder in elderly women, and that this association was mediated by the use of hormone therapy (Ryan et al., 2011). While further verification in a younger female population is still needed, these studies suggest that specific ESR1 polymorphisms may result in an increased vulnerability to the development of anxiety disorders.

4. ESTROGEN RECEPTOR BETA

ERβ was first described in 1996, after being cloned from a rat prostate cDNA library (Kuiper, Enmark, Pelto-Huikko, Nilsson, & Gustafsson, 1996). While studies in the prostate have demonstrated a role for ERβ in activating apoptosis and limiting prostate growth, studies utilizing ERβ knockout models have suggested that in brain, this receptor is a major component of estradiol’s anxiolytic-like effects in the rodent. A number of studies have reported increased anxiety-like behaviors in female ERβ knockout mice (Imwalle, Gustafsson, & Rissman, 2005; Kre¸żel et al., 2001; Walf, Koonce, & Frye, 2008), as well as higher levels of plasma corticosterone (Walf, Koonce, Manley, & Frye, 2009). Further evidence supporting an anxiolytic-like effect of ERβ can be found in pharmacological studies utilizing selective ERβ agonists. The most commonly used ERβ agonist, the selective estrogen receptor modulator (SERM) diarylpropionitrile (DPN), causes decreased anxiety-like behavior in rats and mice in a number of tests, including the open field test (Lund et al., 2005; Oyola et al., 2012; Walf et al., 2008), elevated zero maze test (Walf et al., 2008), elevated plus maze test (Lund et al., 2005; Oyola et al., 2012), and light–dark box test (Lund et al., 2005; Oyola et al., 2012). Administration of a different ERβ agonist, WAY-200070, increased anxiolytic-like responding in the open field, the elevated plus maze (Weiser, Wu, & Handa, 2009), the four-plate test, which “punishes” exploration of a novel environment with mild foot shock, and in a test of stress-induced hypothermia (Hughes et al., 2008). Furthermore, DPN administration to the paraventricular nucleus (PVN) decreased restraint stress-induced c-fos mRNA levels within the PVN and decreased the plasma adrenocorticotropic hormone (ACTH) response to in the male rat (Lund, Hinds, & Handa, 2006), suggesting a central site for ERβ action. This mechanism also holds true for mice, since peripheral DPN administration decreased stress-induced plasma corticosterone and ACTH in ovariectomized mice (Oyola et al., 2012). Despite all of the evidence suggesting an anxiolytic-like effect of ERβ activation, an influence of this receptor on anxiety-like behavior has not always been observed (Jacome et al., 2010; Patisaul, Burke, Hinkle, Adewale, & Shea, 2009). The absence of effects of ERβ agonists on anxiolytic behaviors in some studies may be due to dose or timing phenomena since the selectivity of ERβ agonists is rather modest and, therefore, too high or too low a dose may negate its actions by interactions with ERα (at higher doses) or by failing to activate ERβ (at lower doses). Nonetheless, there remains strong support for ERβ as an inhibitor of rodent anxiety.

Of importance, the activation of ERβ is not restricted to estrogens or selective ERβ agonists. Naturally occurring metabolites of androgens have been recently described that can also bind and activate ERβ and consequently can modulate physiology and behaviors. The two best described androgen metabolites that functionally impact ERβ signaling pathways are 5-androsten-3β,17β-diol (ADIOL), a metabolite of the adrenal androgen dehydroepiandrosterone (Saijo, Collier, Li, Katzenellenbogen, & Glass, 2011), and 5α-androstane-3β,17β-diol (3β-diol) (Weihua, Lathe, Warner, & Gustafsson, 2002), a metabolite of the potent nonaromatizable androgen, dihydrotestosterone. Both of these androgens have been shown to be antiinflammatory (Saijo et al., 2011; Zuloaga, O’Connor, Handa, & Gonzales, 2012), and the effects of 3β-diol have been described in regulating anxiety-like behaviors. Treatment of rats with 3β-diol dipropionate reduces anxiety in the elevated plus maze (Handa, Pak, Kudwa, Lund, & Hinds, 2008) and reduces the acute neuroendocrine response to restraint stress (Handa et al., 2008; Lund et al., 2006). Moreover, 3β-diol has been shown to act through ERβ to regulate promoter activity of several neuropeptides, including oxytocin and vasopressin (Hiroi et al., 2013; Pak, Chung, Hinds, & Handa, 2007; Pak et al., 2005).

Unfortunately, despite the large body of literature describing ERβ’s effects in the rodent, research regarding the influence of ERβ on anxiety in humans is currently very limited. A recent study noted that, for the ERβ gene ESR2, the SNP rs1256049 was associated with a greater incidence of generalized anxiety disorder in older women (Ryan et al., 2011). It is unknown if this correlation is observable in younger women or in men. Given the compelling data from preclinical models, further investigation into the role of ERβ in human anxiety disorders is critically needed.

5. G-PROTEIN-COUPLED ESTROGEN RECEPTOR

Recent research has identified the existence of a novel estrogen receptor known as GPR30 or GPER1 (Filardo, Quinn, Bland, & Frackelton, 2000; Revankar, Cimino, Sklar, Arterburn, & Prossnitz, 2005; Thomas, Pang, Filardo, & Dong, 2005). This receptor has been described as localized both at the membrane (Filardo et al., 2007; Funakoshi, Yanai, Shinoda, Kawano, & Mizukami, 2006; Thomas et al., 2005) as well as within several intracellular structures, including endoplasmic reticulum (Revankar et al., 2005) and cytokeratin intermediate filaments (Sandén et al., 2011). GPR30 exhibits a widespread distribution across the rodent brain, with high levels of immunoreactivity noted in regions implicated in affective behavior, such as the cortex, hippocampus, hypothalamus, and brainstem (Brailoiu et al., 2007; Hazell et al., 2009). In addition, GPR30 immunoreactivity is increased following acute stress in the basolateral amygdala of ovariectomized mice, which is accompanied by increased inhibitory synaptic transmission in the basolateral amygdala (Tian et al., 2013), suggesting a role in the rodent stress response.

GPR30 is capable of influencing gene expression through several known mechanisms, resulting in both short-term and long-term effects on transcription (see Fig. 1). Agonist binding to GPR30 can cause the activation of adenylyl cyclase, stimulating the production of cAMP, which ultimately activates the transcription factor cAMP response element-binding protein (CREB). Additionally, in vitro activation of GPR30 has been found to recruit second messengers such as Src kinase, producing downstream trans-activation of epidermal growth factor receptors (EGFRs), leading to the activation of mitogen-activated protein kinases (MAPKs) ERK1/2, and the activation of phosphatidylinositol 3-kinases (PI3Ks), ultimately resulting in the activation of proteins that regulate transcription factors (for review, see Maggiolini & Picard, 2010; Prossnitz et al., 2008).

Although several recent studies have implicated GPR30 in modulating the expression of anxiety-like behaviors in the mouse, there are conflicting reports as to the nature of this receptor’s effects. Importantly, the impact of this receptor on anxiety-like behavior may be sex dependent and may vary depending on the behavioral testing paradigm employed. For example, following an acute stressor, administration of the GPR30 agonist G-1 to the basolateral amygdala prevented an increase in anxiety-like behavior in ovariectomized mice in the open field test and elevated plus maze (Tian et al., 2013). Peripheral administration of G-1 produced a decrease in anxiety-like behavior in the elevated plus maze in gonadectomized male mice, while ovariectomized subjects were unaffected by treatment (Hart et al., 2014). Conversely, G-1 treatment led to an increase in anxiety-like behavior in ovariectomized mice and intact male mice in the elevated plus maze and open field test (Kastenberger et al., 2012). All told, it is possible that this discrepancy in the effects of G-1 on behavior may result from differences in dose of G-1, as well as differences in the timing of G-1 administration relative to behavioral testing.

While little is known about the nature of GPR30’s influence on anxiety-like behavior, even less is known about the potential mechanisms responsible for GPR30’s effects on this behavior. Activation of GPR30 increases inhibitory synaptic transmission within the basolateral amygdala of ovariectomized mice (Tian et al., 2013). Based on an observed high level of colocalization of GPR30 with both GABAergic interneurons and glutamatergic pyramidal neurons, coupled with GPR30’s prevention of stress-induced downregulation of GABAA receptor expression and upregulation of glutamate receptors, Tian et al. (2013) have proposed that GPR30 mediates anxiety-like behavior by altering the balance between GABAergic and glutamatergic signaling within the basolateral amygdala (Tian et al., 2013). This receptor’s effects may not be the result of activation of the ERK signaling pathway, as two studies investigating anxiety-like behavior following G-1 administration found no changes in phosphorylated ERK in the hippocampus of gonadectomized male (Hart et al., 2014) and female (Anchan, Clark, Pollard, & Vasudevan, 2014) mice. However, potential changes in phosphorylated ERK were not assessed in other regions implicated in regulating anxiety-like behavior that also express GPR30, thereby currently limiting conclusions about the ERK signaling pathway.

6. CROSS TALK BETWEEN ESTROGEN RECEPTORS

The above discussion has focused on the individual contribution of each estrogen receptor in anxiety and anxiety-like behavior. However, evidence suggests that these receptor subtypes are capable of interacting with one another. One such example is the relation between ERα and ERβ. Male ERα knockout mice show decreased expression of ERβ protein within the medial preoptic area and increased expression within the bed nucleus of the stria terminalis, suggesting that ERβ expression can be modulated by ERα. This observation can be coupled with a relative insensitivity to estradiol’s effects on ERβ expression, as assessed through gonadectomy and estradiol replacement (Nomura, Korach, Pfaff, & Ogawa, 2003) although this lack of effect may be brain region dependent (Patisaul, Whitten, & Young, 1999). GPR30 and ERα have also shown some interdependence. A recent study by Hart et al. (2014) found that GPR30’s agonist G-1 increased protein expression of hippocampal phosphorylated ERα in male mice (Hart et al., 2014). In addition, an in vitro study using ovarian cancer cells reported that both GPR30 and ERα were required for either estradiol or G-1 to induce an upregulation in expression of the oncogene c-fos (Albanito et al., 2007). The relation between ERβ and GPR30 has not yet been assessed. In sum, these findings demonstrate that estrogen receptors do not function entirely independently of one another, which likely has implications for estrogen receptors’ mediation of anxiety.

7. MECHANISMS FOR ESTROGEN RECEPTOR EFFECTS ON ANXIETY

Researchers are continuing to investigate the pathways by which estrogen receptors influence anxiety and anxiety-like behavior. The most well-described mechanisms, discussed later, demonstrate that estrogen receptors are capable of mediating a diverse range of neural systems. Importantly, these systems do not operate in isolation; therefore, estrogen receptor effects on anxiety are likely the result of a number of interactions between pathways.

7.1 Effects on the Hypothalamo-Pituitary-Adrenal Axis

In response to a stressor, neurons within the PVN of the hypothalamus secrete the peptides corticotropin-releasing hormone (CRH) and vasopressin, which act in concert to stimulate the release of ACTH from the anterior pituitary into the peripheral circulation (Fig. 2). Moreover, ACTH acts upon the cortex of the adrenal gland, causing the upregulation of enzymes involved in steroidogenesis and ultimately the enhanced secretion of glucocorticoids. Glucocorticoids then act to prevent further activity of this system through a long-loop negative feedback mechanism that can involve the hippocampus, hypothalamus, and pituitary gland. This neuroendocrine system, known as the hypothalamo-pituitary-adrenal (HPA) axis, is one of the primary ways in which an organism is capable of reacting to a stressor (Herman & Cullinan, 1997) and maintaining homeostasis. Of importance for the current discussion, estrogen receptors have been shown to impact neuroendocrine stress responsivity at several different levels of this axis.

Fig. 2.

Fig. 2

Open in a new tab

Diagrammatic representation of the hypothalamo-pituitary-adrenal (HPA) axis and a summary of the effects of estrogen receptor agonists.

ERα may mediate anxiety-like behavior through its actions on HPA axis function. Glucocorticoids have long been known to activate brain regions that are involved in mediating anxiety and fear responses in rodents. In particular, the central nucleus of the amygdala has been shown to express glucocorticoid receptors, and neurons in this brain area respond to glucocorticoids to enhance anxiety-like behaviors. Thus, increases in glucocorticoid secretion can directly influence behaviors such as anxiety (Shepard, Barron, & Myers, 2003; Weiser, Foradori, & Handa, 2010) and correspondingly, factors that influence HPA activity can have similar actions on anxiety. Administration of estradiol, PPT, or the ERα-selective agonist, moxestrol, to the PVN augmented the ACTH response to restraint stress in the male rat (Lund et al., 2006), which correlated with an elevation in c-fos mRNA levels within this brain region (Lund et al., 2006). Interestingly, ERα is expressed at only low levels within the rat PVN (Shughrue et al., 1997), suggesting an alternative route for the effects of these ERα agonists on behavior. It has been proposed that the activation of the ERα-containing GABAergic neurons surrounding the PVN may inhibit GABAergic inhibition of the PVN, resulting in an increase in HPA activity. Correspondingly, increased stressor-induced C-fos immunoreactivity has been shown in CRH neurons following administration of PPT to ovariectomized rats (Thammacharoen, Geary, Lutz, Ogawa, & Asarian, 2009). Furthermore, as shown in vitro by Lalmansingh and Uht (2008) using an amygdaloid cell line, ERα may regulate CRH gene (crh) expression through histone acetylation in the cAMP regulatory element region of the crh promoter (Lalmansingh & Uht, 2008). This molecular regulation provides another pathway for ERα’s anxiogenic effects.

Substantial evidence for ERβ influencing anxiety through HPA axis mediation has also been shown. Peripheral administration of the ERβ agonist DPN causes decreased stress-induced plasma corticosterone and ACTH levels in the ovariectomized mouse (Oyola et al., 2012). In contrast to ERα, ERβ is robustly expressed within both the rat and mouse (Fig. 3) PVN. A possible target for ERβ in the HPA axis is a direct action on a population of neuro-secretory cells in the PVN that produce CRH. Neuroendocrine CRH neurons in the rat PVN express ERβ in a subregion-dependent fashion (13–60%) (Laflamme, Nappi, Drolet, Labrie, & Rivest, 1998; Suzuki & Handa, 2005). These CRH-expressing neurons initiate the HPA axis response to stress, ultimately increasing circulating glucocorticoid levels (Herman & Cullinan, 1997). Similar to peripheral DPN injection, implantation of a DPN-containing pellet near the male rat PVN has produced a decrease in stress-induced plasma corticosterone and ACTH (Lund et al., 2006). Thus, ERβ may mediate HPA axis activity by actions directly on PVN neurons. It has been proposed that this receptor subtype also regulates crh expression through histone acetylation in the cAMP regulatory element region of the crh promoter. Unlike ERα, ERβ may have a more indirect influence on expression, acting by attracting the cAMP-binding protein-binding protein (CBP) to the CRE element in the crh promoter (Lalmansingh & Uht, 2008).

Fig. 3.

Fig. 3

Open in a new tab

Confocal microscopic image showing distribution of immunofluorescent labeling of estrogen receptors α (A) and β (B) in the mouse paraventricular nucleus. ERα was detected by standard immunofluorescent techniques using an AlexaFluor 594-labeled secondary antibody, and ERβ-expressing neurons were detected in the same brain section by examining endogenous ERβ-EGFP expression in a transgenic mouse model. 3V, 3rd ventricle.

7.2 Effects on the Serotonergic System

The serotonergic system has long been implicated in modulating anxiety in humans and rodent models (Handley, McBlane, Critchley, & Njung’e, 1993; Naughton, Mulrooney, & Leonard, 2000). Estrogens have potent effects on this system, causing changes in levels of serotonin, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), the serotonin transporter, and serotonin receptors (Borrow & Cameron, 2014). These effects may be driven by the actions of ERβ and GPR30.

The estrogen receptor that has received the most attention as a facilitator of estradiol’s effects on the serotonergic system is ERβ. Treatment of male mice with the ERβ agonist WAY-200070 has resulted in increased levels of serotonin within the striatum (Hughes et al., 2008), while DPN treatment caused increased levels of 5-HIAA in OVX rats (Jacome et al., 2010). Male ERβ knockout mice have been reported to have decreased levels of 5-hydroxytryptophan, the precursor of serotonin, within the frontal cortex (Hughes et al., 2008), while it has been shown that female ERβ knockout mice have lower levels of serotonin within the hippocampus, bed nucleus of the stria terminalis, and the preoptic area (Imwalle et al., 2005). These findings suggest that estrogens may mediate serotonin synthesis through ERβ.

One way in which ERβ may influence anxiety-like behavior through the serotonergic system is by mediating expression of tryptophan hydroxylase, the rate-limiting enzyme required for the synthesis of serotonin. Knockdown of this enzyme within the caudal dorsal raphe nucleus of OVX rats removes the anxiolytic-like effects of estradiol in the open field test (Hiroi, McDevitt, Morcos, Clark, & Neumaier, 2011). Correspondingly, both male and female ERβ-null mice have decreased expression of tryptophan hydroxylase. In addition, OVX decreased the number of tryptophan hydroxylase-positive neurons within the DRN, which was rescued following treatment with estradiol or the ERβ agonist LY3201 (Suzuki et al., 2013). Similarly, our laboratory has shown an upregulation in tryptophan hydroxylase 2 in OVX rats following systemic or local treatment with DPN (Donner & Handa, 2009). However, despite evidence implicating ERβ as a mediator of anxiety-like behavior through its effects on the serotonergic system, ERβ may not act directly on DRN neurons to influence anxiety-like behavior. We have previously reported that direct administration of DPN to this region did not alter anxiety-like behavior in the open field or elevated plus maze in OVX rats (Donner & Handa, 2009). Furthermore, rats may not express ERβ within the DRN (Sheng et al., 2004). This suggests an alternative site of action for ERβ’s effects on anxiety through serotonergic modulation.

Another potential site for ERβ’s effects on the serotonergic system is the amygdala. Kre¸żel et al. (2001) reported that ERβ knockout mice showed an enhanced induction of long-term potentiation within the amygdala relative to wild-type controls. The authors also noted an increase in the receptor 5-HT1A within the medial amygdala of ERβ knockout female animals. When coupled with an observed potentiation of synaptic response following GABAergic inhibition and the known effects of serotonin on amygdala GABAergic tone (Koyama, Kubo, Rhee, & Akaike, 1999), this led them to hypothesize that enhanced 5-HT1A receptor activation might mediate long-term potentiation within the amygdala through the inhibition of GABA release (Kre¸żel et al., 2001). Direct confirmation of changes in anxiety-like behavior as a result of ERβ’s effects on the serotonergic system within the amygdala is still needed.

Despite the large body of data implicating ERβ in estrogens’ mediation of anxiety-like behavior through the serotonergic system, it has recently been proposed that GPR30, not ERβ, is the estrogen receptor responsible for some of estrogens’ effects. In the female rat PVN, a desensitization of 5-HT1A receptors following administration of estradiol was found to be the result of GPR30 expression, and not of ERβ (McAllister, Creech, Kimball, Muma, & Li, 2012). GPR30 is also colocalized with 5-HT1A receptors within the PVN, and administration of the agonist G-1 has attenuated 5-HT1A receptor signaling within this region (Xu et al., 2009). Thus, at least within the PVN, which shows an absence of ERα in the rat (Shughrue et al., 1997), estrogens may influence serotonergic signaling through GPR30 activation.

7.3 Effects on the Oxytocinergic System

Oxytocin (OT) is a nonapeptide produced primarily by magnocellular neurons within the PVN and the supraoptic nucleus of the hypothalamus. Its function has classically been associated with regulation of parturition and lactation, although more recent studies indicate that oxytocin can have a variety of effects on the central nervous system (CNS) to regulate such behaviors as reproductive and parental behavior, anxiety, social bonding, and social recognition (for review, see Borrow & Cameron, 2012; Lee, Macbeth, Pagani, & Young, 2009; Neumann, 2008). OT is secreted by three known methods: release into the peripheral circulation via activation of the neurohypophyseal system, local dendritic release followed by diffusion into local brain structures, and release into regions such as the hippocampus and amygdala by axonal projections from OT neurons within the PVN (Murgatroyd et al., 2004). Following its release, OT acts on its receptors (OTR), which are widely expressed throughout the brain and periphery. OT is an important mediator of anxiety symptoms in both humans and rodents. Plasma OT levels are negatively correlated with anxiety symptoms in depressed patients (Scantamburlo et al., 2007), and intranasal OT administration attenuates emotional fear reactivity in patients with social anxiety disorder (Labuschagne et al., 2010). Furthermore, an SNP within the oxytocin receptor gene, rs2254298, has been correlated with anxiety symptoms in women and adolescent girls (Chen & Johnson, 2012; Thompson, Parker, Hallmayer, Waugh, & Gotlib, 2011). In the rodent, central administration of OT or an OTR agonist decreases anxiety-like behavior and suppresses HPA axis activation in response to stress (Mak, Broussard, Vacy, & Broadbear, 2012; Sabihi, Durosko, Dong, & Leuner, 2014; Windle, Shanks, Lightman, & Ingram, 1997). Estradiol has been found to increase levels of plasma OT (Amico, Seif, & Robinson, 1981; Yamaguchi, Akaishi, & Negoro, 1979), OT mRNA (Hiroi et al., 2013; Nomura, McKenna, Korach, Pfaff, & Ogawa, 2002; Sharma, Handa, & Uht, 2012), and OTR binding (Krege et al., 1998), presenting an additional mechanism by which estrogens are capable of mediating anxiety.

The receptor primarily implicated in the effects of estradiol on OT is ERβ. OT and ERβ are highly colocalized within the PVN in the female rat (Hrabovszky et al., 2004; Suzuki & Handa, 2005), and colocalization of ERβ and OT has also been reported in the human PVN (Hrabovszky et al., 2004). ERβ knockout mice do not show the increase in OT mRNA following estradiol administration observed in wild-type controls (Nomura et al., 2002). Administration of the ERβ ligand 5α-androstane-3β,17β-diol (3β-diol) increased OT mRNA in a mouse hypothalamic cell line (Hiroi et al., 2013; Sharma et al., 2012) and in ovariectomized rats (Hiroi et al., 2013). Finally, the anxiolytic effects of the ERβ agonist DPN are blocked in the rat following treatment with an OT antagonist (Kudwa, McGivern, & Handa, 2014). Recent in vitro evidence suggests that ERβ regulates OT expression by binding to the composite hormone response element of the Ot gene promoter, inducing the recruitment of the coactivators cAMP response element-binding protein (CREB) and steroid receptor coactivator (SRC-1) to the promoter site, resulting in an increase in histone H4 acetylation, ultimately leading to an increase in Ot gene transcription (Hiroi et al., 2013; Sharma et al., 2012).

Research investigating the regulation of OT by ERα and GPR30 is more limited, but bears mentioning. ERα knockout mice do not show an increase in OT receptor binding following estradiol treatment (Krege et al., 1998). Moreover, OT receptors have been shown to be estrogen regulated (de Kloet, Voorhuis, Boschma, & Elands, 1986). Such data indicate that the OT receptor is under estrogenic control, through ERα but not ERβ, whereas oxytocin may be differentially regulated by ERβ and not ERα. Finally, GPR30 is colocalized with OT neurons within the rat PVN (Sakamoto et al., 2007), but the influence of GPR30 on OT is currently unknown, and warrants further investigation.

8. CONCLUSIONS

There is compelling evidence demonstrating that estrogens influence anxiety and anxiety-like behaviors in both humans and rodents. The nature of this influence differs based on the subtype of estrogen receptor utilized (Table 1). While animal models suggest that activation of ERβ may serve to generate anxiolytic-like effects, ERα appears to have largely anxiogenic-like properties. The more recently discovered membrane estrogen receptor, GPR30, has also been implicated in the rodent anxiety response, although, at present, the extent of its participation is not clear. Given the importance of receptor subtype in modulating anxiety, SERMs demonstrate great potential as novel therapeutic agents in the treatment of anxiety disorders. SERMs that target ERβ may be particularly effective in patients with specific polymorphisms of ESR1 and ESR2, and in patients with anxiety symptoms temporally associated with declining estrogen levels, such as during the premenstrual period or menopause.

Table 1.

The Effect of Estrogen Receptor Subtypes on Anxiety-Like Behavior in the Rodent

Receptor Method Species References Effect
ERα
Agonists PPT s.c., 1 mg/kg Femalea and male mice Kastenberger et al. (2012) No effect in EPM, LD, OFT
PPT s.c., 1 mg/kg for 4 days Female and male ratsa Lund et al. (2005) ↑ Anxiety in EPM
PPT s.c., 10 μg Female ratsa Walf and Frye (2005) No effect in DFT, EPM, ET, OFT, VT
PPT s.c., 3 or 5 mg/kg for 2 days Female ratsa Jacome et al. (2010) No effect in EPM
PPT s.c., 1 mg/kg for 7 days Female ratsa Weiser et al. (2009) No effect in EPM, OFT
PPT s.c., 1 mg/kg for 3 days Male rats Patisaul et al. (2009) No effect in LD
PPT s.c., 1 mg/kg for 4 days Female ratsa Byrnes et al. (2012) ↓ Anxiety in primiparous females in EPM
PPT s.c., 1 mg/kg Female ratsa Byrnes et al. (2013) ↑ Anxiety in nulliparous females, ↓ anxiety in primiparous females in EPM
PPT s.c., 1 mg/kg Primiparous female rats Furuta et al. (2013) ↓ Anxiety in EPM
Genetic models shRNA targeting ERα intra-MPOA, estradiol s.c., 18 μg/kg Female ratsa Spiteri et al. (2012) ↓ Anxiety in LD, OFT
shRNA targeting ERα intra-meAMYG, estradiol s.c., 18 μg/kg Female ratsa Spiteri et al. (2010) ↓ Anxiety in LD
ERα knockout mice Female and male mice Kre¸żel et al. (2001) No effect in EPM or OFT
ERβ
Agonists DPN s.c., 1 mg/kg Femalea and male mice Kastenberger et al. (2012) No effect in EPM, LD, OFT
DPN s.c., 1 mg/kg for 4 days Female and male ratsa Lund et al. (2005) ↓ Anxiety in EPM, LD (only females tested), and OFT (only females tested)
DPN s.c., 3 mg/kg for 2 days Female ratsa Jacome et al. (2010) No effect in EPM
DPN s.c., 10 μg Female ratsa Walf and Frye (2005) ↓ Anxiety in DFT, EPM, ET, OFT, VT
DPN s.c., 1 mg/kg for 4 days Female ratsa Byrnes et al. (2012) No effect in EPM
DPN s.c., 0.5 or 2 mg/kg for 4 days, 1 mg/kg for 3 days Male rats Patisaul et al. (2009) No effect in EPM or LD
DPN s.c., 1 mg/kg Primiparous female rats Furuta et al. (2013) No effect in EPM
DPN s.c., 0.1 mg/kg Female micea Walf et al. (2008) ↓ Anxiety in EPM, EZM, OFT, SIT
S-DPN s.c., 1 mg/kg Female micea Oyola et al. (2012) ↓ Anxiety in EPM, LD, OFT, no effect in MBT
DPN or S-DPN s.c., 2 mg/kg for 7 days Females ratsa Weiser et al. (2009) ↓ Anxiety in EPM, OFT
Coumestrol s.c., 10 μg Female ratsa Walf and Frye (2005) ↓ Anxiety in DFT, EPM, ET, OFT, VT
WAY-200070 s.c., 30 mg/kg Male mice Hughes et al. (2008) ↓ Anxiety in 4PT, SIH
WAY-200070 s.c., 2 mg/kg for 7 days Female ratsa Weiser et al. (2009) ↓ Anxiety in EPM, OFT
Genetic models ERβ knockout mice Female micea Oyola et al. (2012) No effect in EPM, LD, MBT, OFT
ERβ knockout mice Female and male mice Kre¸żel et al. (2001) ↑ Anxiety in EPM, OFT (females only)
ERβ knockout mice, s.c. estradiol (85–100 pg/mL) Female micea Imwalle et al. (2005) ↑ Anxiety in EPM
ERβ knockout mice, s.c. DPN 0.1 mg/kg Female micea Walf et al. (2008) ↑ Anxiety in EPM, EZM, OFT, SIT
GPR30
Agonists (G-1) s.c., 0.3 μg Female and male micea Hart et al. (2014) ↓ Anxiety in EPM (males only), no effect in OFT
(G-1) s.c., 1 mg/kg Femalea and male mice Kastenberger et al. (2012) ↑ Anxiety in EPM, LD (males only), OFT
(G-1) intra-BLA, 0.5 μM Female micea Tian et al. (2013) ↓ Anxiety in EPM, OFT
Genetic models GPR30 knockout mice Female and male mice Kastenberger and Schwarzer (2014) ↓ Anxiety in EPM (males only) and LD (males only), no effect in OFT
Open in a new tab
a

Gonadectomized subjects.

Note: 4PT, four-plate test; BLA, basolateral amygdala; DFT, defensive freezing test; EPM, elevated plus maze test; ET, emergence test; EZM, elevated zero maze test; LD, light–dark box; MBT, marble burying test; meAMYG, medial amygdala; MPOA, medial preoptic area; OFT, open field test; SIH, stress-induced hypothermia; SIT, social interaction test; VT, Vogel test.

References

  1. Albanito L, Madeo A, Lappano R, Vivacqua A, Rago V, Carpino A, … Maggiolini M. G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17β-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Research. 2007;67(4):1859–1866. doi: 10.1158/0008-5472.CAN-06-2909. [DOI] [PubMed] [Google Scholar]
  2. Amico JA, Seif SM, Robinson AG. Oxytocin in human plasma: Correlation with neurophysin and stimulation with estrogen. The Journal of Clinical Endocrinology and Metabolism. 1981;52(5):988–993. doi: 10.1210/jcem-52-5-988. [DOI] [PubMed] [Google Scholar]
  3. Anchan D, Clark S, Pollard K, Vasudevan N. GPR30 activation decreases anxiety in the open field test but not in the elevated plus maze test in female mice. Brain and Behavior. 2014;4(1):51–59. doi: 10.1002/brb3.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Antonson P, Omoto Y, Humire P, Gustafsson JA. Generation of ERalpha-floxed and knockout mice using the Cre/LoxP system. Biochemical and Biophysical Research Communications. 2012;424(4):710–716. doi: 10.1016/j.bbrc.2012.07.016. [DOI] [PubMed] [Google Scholar]
  5. Ascenzi P, Bocedi A, Marino M. Structure–function relationship of estrogen receptor α and β: Impact on human health. Molecular Aspects of Medicine. 2006;27(4):299–402. doi: 10.1016/j.mam.2006.07.001. [DOI] [PubMed] [Google Scholar]
  6. Björnström L, Sjöberg M. Mechanisms of estrogen receptor signaling: Convergence of genomic and nongenomic actions on target genes. Molecular Endocrinology. 2005;19(4):833–842. doi: 10.1210/me.2004-0486. [DOI] [PubMed] [Google Scholar]
  7. Borrow AP, Cameron NM. The role of oxytocin in mating and pregnancy. Hormones and Behavior. 2012;61(3):266–276. doi: 10.1016/j.yhbeh.2011.11.001. [DOI] [PubMed] [Google Scholar]
  8. Borrow AP, Cameron NM. Estrogenic mediation of serotonergic and neurotrophic systems: Implications for female mood disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2014;54:13–25. doi: 10.1016/j.pnpbp.2014.05.009. [DOI] [PubMed] [Google Scholar]
  9. Brailoiu E, Dun SL, Brailoiu GC, Mizuo K, Sklar LA, Oprea TI, … Dun NJ. Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system. Journal of Endocrinology. 2007;193(2):311–321. doi: 10.1677/JOE-07-0017. [DOI] [PubMed] [Google Scholar]
  10. Burris TP, Solt LA, Wang Y, Crumbley C, Banerjee S, Griffett K, … Kojetin DJ. Nuclear receptors and their selective pharmacologic modulators. Pharmacological Reviews. 2013;65(2):710–778. doi: 10.1124/pr.112.006833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Byrnes EM, Casey K, Bridges RS. Reproductive experience modifies the effects of estrogen receptor alpha activity on anxiety-like behavior and corticotropin releasing hormone mRNA expression. Hormones and Behavior. 2012;61(1):44–49. doi: 10.1016/j.yhbeh.2011.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Byrnes EM, Casey K, Carini LM, Bridges RS. Reproductive experience alters neural and behavioural responses to acute oestrogen receptor alpha activation. Journal of Neuroendocrinology. 2013;25(12):1280–1289. doi: 10.1111/jne.12113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cameron OG, Kuttesch D, McPhee K, Curtis GC. Menstrual fluctuation in the symptoms of panic anxiety. Journal of Affective Disorders. 1988;15(2):169–174. doi: 10.1016/0165-0327(88)90086-9. [DOI] [PubMed] [Google Scholar]
  14. Chen FS, Johnson SC. An oxytocin receptor gene variant predicts attachment anxiety in females and autism-spectrum traits in males. Social Psychological and Personality Science. 2012;3:93–99. [Google Scholar]
  15. Comings DE, Muhleman D, Johnson P, MacMurray JP. Potential role of the estrogen receptor gene (ESR1) in anxiety. Molecular Psychiatry. 1999;4(4):374–377. doi: 10.1038/sj.mp.4000503. [DOI] [PubMed] [Google Scholar]
  16. de Kloet ER, Voorhuis DA, Boschma Y, Elands J. Estradiol modulates density of putative ‘oxytocin receptors’ in discrete rat brain regions. Neuroendocrinology. 1986;44(4):415–421. doi: 10.1159/000124680. [DOI] [PubMed] [Google Scholar]
  17. Demetrio FN, Rennó J, Jr, Gianfaldoni A, Gonçalves M, Halbe HW, Filho AH, Gorenstein C. Effect of estrogen replacement therapy on symptoms of depression and anxiety in non-depressive menopausal women: A randomized double-blind, controlled study. Archives of Women’s Mental Health. 2011;14(6):479–486. doi: 10.1007/s00737-011-0241-3. [DOI] [PubMed] [Google Scholar]
  18. Donner N, Handa RJ. Estrogen receptor beta regulates the expression of tryptophan-hydroxylase 2 mRNA within serotonergic neurons of the rat dorsal raphe nuclei. Neuroscience. 2009;163(2):705–718. doi: 10.1016/j.neuroscience.2009.06.046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development. 2000;127(19):4277–4291. doi: 10.1242/dev.127.19.4277. [DOI] [PubMed] [Google Scholar]
  20. Edwards DP. Regulation of signal transduction pathways by estrogen and progesterone. Annual Review of Physiology. 2005;67:335–376. doi: 10.1146/annurev.physiol.67.040403.120151. [DOI] [PubMed] [Google Scholar]
  21. Filardo EJ, Quinn JA, Bland KI, Frackelton AR., Jr Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Molecular Endocrinology. 2000;14(10):1649–1660. doi: 10.1210/mend.14.10.0532. [DOI] [PubMed] [Google Scholar]
  22. Filardo E, Quinn J, Pang Y, Graeber C, Shaw S, Dong J, Thomas P. Activation of the novel estrogen receptor G protein-coupled receptor 30 (GPR30) at the plasma membrane. Endocrinology. 2007;148(7):3236–3245. doi: 10.1210/en.2006-1605. [DOI] [PubMed] [Google Scholar]
  23. Funakoshi T, Yanai A, Shinoda K, Kawano MM, Mizukami Y. G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane. Biochemical and Biophysical Research Communications. 2006;346(3):904–910. doi: 10.1016/j.bbrc.2006.05.191. [DOI] [PubMed] [Google Scholar]
  24. Furuta M, Numakawa T, Chiba S, Ninomiya M, Kajiyama Y, Adachi N, … Kunugi H. Estrogen, predominantly via estrogen receptor α, attenuates postpartum-induced anxiety- and depression-like behaviors in female rats. Endocrinology. 2013;154(10):3807–3816. doi: 10.1210/en.2012-2136. [DOI] [PubMed] [Google Scholar]
  25. Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, … Asthana S. Effects of hormone therapy on cognition and mood in recently postmenopausal women: Findings from the randomized, controlled KEEPS–cognitive and affective study. PLoS Medicine. 2015;12(6):e1001833. doi: 10.1371/journal.pmed.1001833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Handa RJ, Pak TR, Kudwa AE, Lund TD, Hinds L. An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5alpha-androstane-3beta,17beta-diol. Hormones and Behavior. 2008;53(5):741–752. doi: 10.1016/j.yhbeh.2007.09.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Handley SL, McBlane JW, Critchley MA, Njung’e K. Multiple serotonin mechanisms in animal models of anxiety: Environmental, emotional and cognitive factors. Behavioural Brain Research. 1993;58(1–2):203–210. doi: 10.1016/0166-4328(93)90104-x. [DOI] [PubMed] [Google Scholar]
  28. Hart D, Nilges M, Pollard K, Lynn T, Patsos O, Shiel C, … Vasudevan N. Activation of the G-protein coupled receptor 30 (GPR30) has different effects on anxiety in male and female mice. Steroids. 2014;81:49–56. doi: 10.1016/j.steroids.2013.11.004. [DOI] [PubMed] [Google Scholar]
  29. Hazell GG, Yao ST, Roper JA, Prossnitz ER, O’Carroll AM, Lolait SJ. Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. Journal of Endocrinology. 2009;202(2):223–236. doi: 10.1677/JOE-09-0066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Herman JP, Cullinan WE. Neurocircuitry of stress: Central control of the hypothalamo–pituitary–adrenocortical axis. Trends in Neurosciences. 1997;20(2):78–84. doi: 10.1016/s0166-2236(96)10069-2. [DOI] [PubMed] [Google Scholar]
  31. Hiroi R, Lacagnina AF, Hinds LR, Carbone DG, Uht RM, Handa RJ. The androgen metabolite, 5alpha-androstane-3beta,17beta-diol (3beta-diol), activates the oxytocin promoter through an estrogen receptor-beta pathway. Endocrinology. 2013;154(5):1802–1812. doi: 10.1210/en.2012-2253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Hiroi R, McDevitt RA, Morcos PA, Clark MS, Neumaier JF. Over-expression or knockdown of rat tryptophan hyroxylase-2 has opposing effects on anxiety behavior in an estrogen-dependent manner. Neuroscience. 2011;176:120–131. doi: 10.1016/j.neuroscience.2010.12.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Hrabovszky E, Kalló I, Steinhauser A, Merchenthaler I, Coen CW, Petersen SL, Liposits Z. Estrogen receptor-beta in oxytocin and vasopressin neurons of the rat and human hypothalamus: Immunocytochemical and in situ hybridization studies. The Journal of Comparative Neurology. 2004;473(3):315–333. doi: 10.1002/cne.20127. [DOI] [PubMed] [Google Scholar]
  34. Huang P, Chandra V, Rastinejad F. Structural overview of the nuclear receptor superfamily: Insights into physiology and therapeutics. Annual Review of Physiology. 2010;72:247–272. doi: 10.1146/annurev-physiol-021909-135917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Hughes ZA, Liu F, Platt BJ, Dwyer JM, Pulicicchio CM, Zhang G, … Day M. WAY-200070, a selective agonist of estrogen receptor beta as a potential novel anxiolytic/antidepressant agent. Neuropharmacology. 2008;54(7):1136–1142. doi: 10.1016/j.neuropharm.2008.03.004. [DOI] [PubMed] [Google Scholar]
  36. Imwalle DB, Gustafsson J-Å, Rissman EF. Lack of functional estrogen receptor β influences anxiety behavior and serotonin content in female mice. Physiology & Behavior. 2005;84(1):157–163. doi: 10.1016/j.physbeh.2004.11.002. [DOI] [PubMed] [Google Scholar]
  37. Jacome LF, Gautreaux C, Inagaki T, Mohan G, Alves S, Lubbers LS, Luine V. Estradiol and ERβ agonists enhance recognition memory, and DPN, an ERβ agonist, alters brain monoamines. Neurobiology of Learning and Memory. 2010;94(4):488–498. doi: 10.1016/j.nlm.2010.08.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kastenberger I, Lutsch C, Schwarzer C. Activation of the G-protein-coupled receptor GPR30 induces anxiogenic effects in mice, similar to oestradiol. Psychopharmacology. 2012;221(3):527–535. doi: 10.1007/s00213-011-2599-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Kastenberger I, Schwarzer C. GPER1 (GPR30) knockout mice display reduced anxiety and altered stress response in a sex and paradigm dependent manner. Hormones and Behavior. 2014;66:628–636. doi: 10.1016/j.yhbeh.2014.09.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Kelley ST, Thackray VG. Phylogenetic analyses reveal ancient duplication of estrogen receptor isoforms. Journal of Molecular Evolution. 1999;49(5):609–614. doi: 10.1007/pl00006582. [DOI] [PubMed] [Google Scholar]
  41. Koyama S, Kubo C, Rhee JS, Akaike N. Presynaptic serotonergic inhibition of GABAergic synaptic transmission in mechanically dissociated rat basolateral amygdala neurons. The Journal of Physiology. 1999;518(2):525–538. doi: 10.1111/j.1469-7793.1999.0525p.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, … Smithies O. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(26):15677–15682. doi: 10.1073/pnas.95.26.15677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Kre¸żel W, Dupont S, Krust A, Chambon P, Chapman PF. Increased anxiety and synaptic plasticity in estrogen receptor β-deficient mice. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(21):12278–12282. doi: 10.1073/pnas.221451898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Kudwa AE, McGivern RF, Handa RJ. Estrogen receptor beta and oxytocin interact to modulate anxiety-like behavior and neuroendocrine stress reactivity in adult male and female rats. Physiology and Behavior. 2014;129:287–296. doi: 10.1016/j.physbeh.2014.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Kudwa AE, Rissman EF. Double oestrogen receptor alpha and beta knockout mice reveal differences in neural oestrogen-mediated progestin receptor induction and female sexual behaviour. Journal of Neuroendocrinology. 2003;15(10):978–983. doi: 10.1046/j.1365-2826.2003.01089.x. [DOI] [PubMed] [Google Scholar]
  46. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(12):5925–5930. doi: 10.1073/pnas.93.12.5925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Labuschagne I, Phan KL, Wood A, Angstadt M, Chua P, Heinrichs M, … Nathan PJ. Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. Neuropsychopharmacology. 2010;35(12):2403–2413. doi: 10.1038/npp.2010.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Laflamme N, Nappi RE, Drolet G, Labrie C, Rivest S. Expression and neuropeptidergic characterization of estrogen receptors (ERalpha and ERbeta) throughout the rat brain: Anatomical evidence of distinct roles of each subtype. Journal of Neurobiology. 1998;36(3):357–378. doi: 10.1002/(sici)1097-4695(19980905)36:3<357::aid-neu5>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  49. Lalmansingh AS, Uht RM. Estradiol regulates corticotropin-releasing hormone gene (crh) expression in a rapid and phasic manner that parallels estrogen receptor-α and -β recruitment to a 3′,5′-cyclic adenosine 5′-monophosphate regulatory region of the proximal crh promoter. Endocrinology. 2008;149(1):346–357. doi: 10.1210/en.2007-0372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Lee HJ, Macbeth AH, Pagani JH, Young WS., 3rd Oxytocin: The great facilitator of life. Progress in Neurobiology. 2009;88(2):127–151. doi: 10.1016/j.pneurobio.2009.04.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Lund TD, Hinds LR, Handa RJ. The androgen 5α-dihydrotestosterone and its metabolite 5α-androstan-3β, 17β-diol inhibit the hypothalamo–pituitary–adrenal response to stress by acting through estrogen receptor β-expressing neurons in the hypothalamus. The Journal of Neuroscience. 2006;26(5):1448–1456. doi: 10.1523/JNEUROSCI.3777-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Lund TD, Rovis T, Chung WCJ, Handa RJ. Novel actions of estrogen receptor-β on anxiety-related behaviors. Endocrinology. 2005;146(2):797–807. doi: 10.1210/en.2004-1158. [DOI] [PubMed] [Google Scholar]
  53. Maggiolini M, Picard D. The unfolding stories of GPR30, a new membrane-bound estrogen receptor. Journal of Endocrinology. 2010;204(2):105–114. doi: 10.1677/JOE-09-0242. [DOI] [PubMed] [Google Scholar]
  54. Mak P, Broussard C, Vacy K, Broadbear JH. Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat. Journal of Psychopharmacology. 2012;26(4):532–542. doi: 10.1177/0269881111416687. [DOI] [PubMed] [Google Scholar]
  55. McAllister C, Creech R, Kimball P, Muma N, Li Q. GPR30 is necessary for estradiol-induced desensitization of 5-HT 1A receptor signaling in the paraventricular nucleus of the rat hypothalamus. Psychoneuroendocrinology. 2012;37(8):1248–1260. doi: 10.1016/j.psyneuen.2011.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. McDevitt MA, Glidewell-Kenney C, Weiss J, Chambon P, Jameson JL, Levine JE. Estrogen response element-independent estrogen receptor (ER)-alpha signaling does not rescue sexual behavior but restores normal testosterone secretion in male ERalpha knockout mice. Endocrinology. 2007;148(11):5288–5294. doi: 10.1210/en.2007-0673. [DOI] [PubMed] [Google Scholar]
  57. Mora S, Dussaubat N, Diaz-Véliz G. Effects of the estrous cycle and ovarian hormones on behavioral indices of anxiety in female rats. Psychoneuroendocrinology. 1996;21(7):609–620. doi: 10.1016/s0306-4530(96)00015-7. [DOI] [PubMed] [Google Scholar]
  58. Morrill GA, Kostellow AB, Gupta RK. Transmembrane helices in “classical” nuclear reproductive steroid receptors: A perspective. Nuclear Receptor Signaling. 2015;13:e003. doi: 10.1621/nrs.13003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Murgatroyd C, Wigger A, Frank E, Singewald N, Bunck M, Holsboer F, … Spengler D. Impaired repression at a vasopressin promoter polymorphism underlies overexpression of vasopressin in a rat model of trait anxiety. Journal of Neuroscience. 2004;24(35):7762–7770. doi: 10.1523/JNEUROSCI.1614-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Naughton M, Mulrooney JB, Leonard BE. A review of the role of serotonin receptors in psychiatric disorders. Human Psychopharmacology. 2000;15(6):397–415. doi: 10.1002/1099-1077(200008)15:6<397::AID-HUP212>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
  61. Neumann ID. Brain oxytocin: A key regulator of emotional and social behaviours in both females and males. Journal of Neuroendocrinology. 2008;20(6):858–865. doi: 10.1111/j.1365-2826.2008.01726.x. [DOI] [PubMed] [Google Scholar]
  62. Nomura M, Korach KS, Pfaff DW, Ogawa S. Estrogen receptor beta (ERbeta) protein levels in neurons depend on estrogen receptor alpha (ERalpha) gene expression and on its ligand in a brain region-specific manner. Molecular Brain Research. 2003;110(1):7–14. doi: 10.1016/s0169-328x(02)00544-2. [DOI] [PubMed] [Google Scholar]
  63. Nomura M, McKenna E, Korach KS, Pfaff DW, Ogawa S. Estrogen receptor-beta regulates transcript levels for oxytocin and arginine vasopressin in the hypothalamic paraventricular nucleus of male mice. Molecular Brain Research. 2002;109(1–2):84–94. doi: 10.1016/s0169-328x(02)00525-9. [DOI] [PubMed] [Google Scholar]
  64. Ojeda SR, Bilger M. Neuroendocrine regulation of puberty. In: Michael PM, Freeman ME, editors. Neuroendocrinology in physiology and medicine. New York: Springer Science+Business Media, LLC; 2000. pp. 197–224. [Google Scholar]
  65. Oyola MG, Portillo W, Reyna A, Foradori CD, Kudwa A, Hinds L, … Mani SK. Anxiolytic effects and neuroanatomical targets of estrogen receptor-β (ERβ) activation by a selective ERβ agonist in female mice. Endocrinology. 2012;153(2):837–846. doi: 10.1210/en.2011-1674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Pak TR, Chung WC, Hinds LR, Handa RJ. Estrogen receptor-beta mediates dihydrotestosterone-induced stimulation of the arginine vasopressin promoter in neuronal cells. Endocrinology. 2007;148(7):3371–3382. doi: 10.1210/en.2007-0086. [DOI] [PubMed] [Google Scholar]
  67. Pak TR, Chung WC, Lund TD, Hinds LR, Clay CM, Handa RJ. The androgen metabolite, 5alpha-androstane-3beta, 17beta-diol, is a potent modulator of estrogen receptor-beta1-mediated gene transcription in neuronal cells. Endocrinology. 2005;146(1):147–155. doi: 10.1210/en.2004-0871. [DOI] [PubMed] [Google Scholar]
  68. Patisaul HB, Burke KT, Hinkle RE, Adewale HB, Shea D. Systemic administration of diarylpropionitrile (DPN) or phytoestrogens does not affect anxiety-related behaviors in gonadally intact male rats. Hormones and Behavior. 2009;55(2):319–328. doi: 10.1016/j.yhbeh.2008.11.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Patisaul HB, Whitten PL, Young LJ. Regulation of estrogen receptor beta mRNA in the brain: Opposite effects of 17beta-estradiol and the phytoestrogen, coumestrol. Molecular Brain Research. 1999;67(1):165–171. doi: 10.1016/s0169-328x(99)00058-3. [DOI] [PubMed] [Google Scholar]
  70. Patton G, Hibbert M, Carlin J, Shao Q, Rosier M, Caust J, Bowes G. Menarche and the onset of depression and anxiety in Victoria, Australia. Journal of Epidemiology and Community Health. 1996;50(6):661–666. doi: 10.1136/jech.50.6.661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Pettersson K, Grandien K, Kuiper GG, Gustafsson JA. Mouse estrogen receptor β forms estrogen response element-binding heterodimers with estrogen receptor α. Molecular Endocrinology. 1997;11(10):1486–1496. doi: 10.1210/mend.11.10.9989. [DOI] [PubMed] [Google Scholar]
  72. Prossnitz ER, Arterburn JB. International union of basic and clinical pharmacology. XCVII. G protein-coupled estrogen receptor and its pharmacologic modulators. Pharmacological Reviews. 2015;67(3):505–540. doi: 10.1124/pr.114.009712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Prossnitz ER, Arterburn JB, Smith HO, Oprea TI, Sklar LA, Hathaway HJ. Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annual Review of Physiology. 2008;70:165–190. doi: 10.1146/annurev.physiol.70.113006.100518. [DOI] [PubMed] [Google Scholar]
  74. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005;307(5715):1625–1630. doi: 10.1126/science.1106943. [DOI] [PubMed] [Google Scholar]
  75. Rocca WA, Grossardt BR, Geda YE, Gostout BS, Bower JH, Maraganore DM, … Melton LJ., 3rd Long-term risk of depressive and anxiety symptoms after early bilateral oophorectomy. Menopause. 2008;15(6):1050–1059. doi: 10.1097/gme.0b013e318174f155. [DOI] [PubMed] [Google Scholar]
  76. Ryan J, Scali J, Carrière I, Scarabin PY, Ritchie K, Ancelin ML. Estrogen receptor gene variants are associated with anxiety disorders in older women. Psychoneuroendocrinology. 2011;36(10):1582–1586. doi: 10.1016/j.psyneuen.2011.04.011. [DOI] [PubMed] [Google Scholar]
  77. Sabihi S, Durosko NE, Dong SM, Leuner B. Oxytocin in the prelimbic medial prefrontal cortex reduces anxiety-like behavior in female and male rats. Psychoneuroendocrinology. 2014;45:31–42. doi: 10.1016/j.psyneuen.2014.03.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Sahingoz M, Uguz F, Gezginc K. Prevalence and related factors of mood and anxiety disorders in a clinical sample of postmenopausal women. Perspectives in Psychiatric Care. 2011;47(4):213–219. doi: 10.1111/j.1744-6163.2010.00296.x. [DOI] [PubMed] [Google Scholar]
  79. Saijo K, Collier JG, Li AC, Katzenellenbogen JA, Glass CK. An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell. 2011;145(4):584–595. doi: 10.1016/j.cell.2011.03.050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Sakamoto H, Matsuda K, Hosokawa K, Nishi M, Morris JF, Prossnitz ER, Kawata M. Expression of G protein-coupled receptor-30, a G protein-coupled membrane estrogen receptor, in oxytocin neurons of the rat paraventricular and supra-optic nuclei. Endocrinology. 2007;148(12):5842–5850. doi: 10.1210/en.2007-0436. [DOI] [PubMed] [Google Scholar]
  81. Sandén C, Broselid S, Cornmark L, Andersson K, Daszkiewicz-Nilsson J, Martensson UE, … Leeb-Lundberg LM. G protein-coupled estrogen receptor 1/G protein-coupled receptor 30 localizes in the plasma membrane and traffics intracellularly on cytokeratin intermediate filaments. Molecular Pharmacology. 2011;79(3):400–410. doi: 10.1124/mol.110.069500. [DOI] [PubMed] [Google Scholar]
  82. Scantamburlo G, Hansenne M, Fuchs S, Pitchot W, Maréchal P, Pequeux C, … Legros JJ. Plasma oxytocin levels and anxiety in patients with major depression. Psychoneuroendocrinology. 2007;32(4):407–410. doi: 10.1016/j.psyneuen.2007.01.009. [DOI] [PubMed] [Google Scholar]
  83. Sharma D, Handa RJ, Uht RM. The ERβ ligand 5α-androstane, 3β,17β-diol (3β-diol) regulates hypothalamic oxytocin (Oxt) gene expression. Endocrinology. 2012;153(5):2353–2361. doi: 10.1210/en.2011-1002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Sheng Z, Kawano J, Yanai A, Fujinaga R, Tanaka M, Watanabe Y, Shinoda K. Expression of estrogen receptors (alpha, beta) and androgen receptor in serotonin neurons of the rat and mouse dorsal raphe nuclei; sex and species differences. Neuroscience Research. 2004;49(2):185–196. doi: 10.1016/j.neures.2004.02.011. [DOI] [PubMed] [Google Scholar]
  85. Shepard JD, Barron KW, Myers DA. Stereotaxic localization of corticosterone to the amygdala enhances hypothalamo-pituitary-adrenal responses to behavioral stress. Brain Research. 2003;963(1–2):203–213. doi: 10.1016/s0006-8993(02)03978-1. [DOI] [PubMed] [Google Scholar]
  86. Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. The Journal of Comparative Neurology. 1997;388(4):507–525. doi: 10.1002/(sici)1096-9861(19971201)388:4<507::aid-cne1>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  87. Smith AW, Bosch MA, Wagner EJ, Rønnekleiv OK, Kelly MJ. The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: Role in mediating the anorexigenic effects of 17beta-estradiol. American Journal of Physiology. Endocrinology and Metabolism. 2013;305(5):E632–E640. doi: 10.1152/ajpendo.00281.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Spiteri T, Musatov S, Ogawa S, Ribeiro A, Pfaff DW, Ågmo A. The role of the estrogen receptor α in the medial amygdala and ventromedial nucleus of the hypothalamus in social recognition, anxiety and aggression. Behavioural Brain Research. 2010;210(2):211–220. doi: 10.1016/j.bbr.2010.02.033. [DOI] [PubMed] [Google Scholar]
  89. Spiteri T, Ogawa S, Musatov S, Pfaff DW, Ågmo A. The role of the estrogen receptor α in the medial preoptic area in sexual incentive motivation, proceptivity and receptivity, anxiety, and wheel running in female rats. Behavioural Brain Research. 2012;230(1):11–20. doi: 10.1016/j.bbr.2012.01.048. [DOI] [PubMed] [Google Scholar]
  90. Suzuki H, Barros RP, Sugiyama N, Krishnan V, Yaden BC, Kim HJ, … Gustafsson JA. Involvement of estrogen receptor β in maintenance of serotonergic neurons of the dorsal raphe. Molecular Psychiatry. 2013;18(6):674–680. doi: 10.1038/mp.2012.62. [DOI] [PubMed] [Google Scholar]
  91. Suzuki S, Handa RJ. Estrogen receptor-β, but not estrogen receptor-α, is expressed in prolactin neurons of the female rat paraventricular and supraoptic nuclei: Comparison with other neuropeptides. The Journal of Comparative Neurology. 2005;484(1):28–42. doi: 10.1002/cne.20457. [DOI] [PubMed] [Google Scholar]
  92. Thammacharoen S, Geary N, Lutz TA, Ogawa S, Asarian L. Divergent effects of estradiol and the estrogen receptor-α agonist PPT on eating and activation of PVN CRH neurons in ovariectomized rats and mice. Brain Research. 2009;1268:88–96. doi: 10.1016/j.brainres.2009.02.067. [DOI] [PubMed] [Google Scholar]
  93. Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology. 2005;146(2):624–632. doi: 10.1210/en.2004-1064. [DOI] [PubMed] [Google Scholar]
  94. Thompson RJ, Parker KJ, Hallmayer JF, Waugh CE, Gotlib IH. Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls. Psychoneuroendocrinology. 2011;36(1):144–147. doi: 10.1016/j.psyneuen.2010.07.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Tian Z, Wang Y, Zhang N, Guo YY, Feng B, Liu SB, Zhao MG. Estrogen receptor GPR30 exerts anxiolytic effects by maintaining the balance between GABAergic and glutamatergic transmission in the basolateral amygdala of ovariectomized mice after stress. Psychoneuroendocrinology. 2013;38(10):2218–2233. doi: 10.1016/j.psyneuen.2013.04.011. [DOI] [PubMed] [Google Scholar]
  96. Tiemeier H, Schuit SCE, den Heijer T, van Meurs JB, van Tuijl HR, Hofman A, … Uitterlinden AG. Estrogen receptor α gene polymorphisms and anxiety disorder in an elderly population. Molecular Psychiatry. 2005;10(9):806–807. doi: 10.1038/sj.mp.4001697. [DOI] [PubMed] [Google Scholar]
  97. Tomihara K, Soga T, Nomura M, Korach KS, Gustafsson J-Å, Pfaff DW, Ogawa S. Effect of ER-β gene disruption on estrogenic regulation of anxiety in female mice. Physiology & Behavior. 2009;96(2):300–306. doi: 10.1016/j.physbeh.2008.10.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Toran-Allerand CD, Guan X, MacLusky NJ, Horvath TL, Diano S, Singh M, … Tinnikov AA. ER-X: A novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. Journal of Neuroscience. 2002;22(19):8391–8401. doi: 10.1523/JNEUROSCI.22-19-08391.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Walf AA, Frye CA. ERβ-selective estrogen receptor modulators produce anti-anxiety behavior when administered systemically to ovariectomized rats. Neuropsychopharmacology. 2005;30(9):1598–1609. doi: 10.1038/sj.npp.1300713. [DOI] [PubMed] [Google Scholar]
  100. Walf AA, Frye CA. Parity and estrogen-administration alter affective behavior of ovariectomized rats. Physiology & Behavior. 2008;93(1):351–356. doi: 10.1016/j.physbeh.2007.09.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Walf AA, Koonce CJ, Frye CA. Estradiol or diarylpropionitrile decrease anxiety-like behavior of wildtype, but not estrogen receptor beta knockout, mice. Behavioral Neuroscience. 2008;122(5):974–981. doi: 10.1037/a0012749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Walf AA, Koonce C, Manley K, Frye CA. Proestrous compared to diestrous wildtype, but not estrogen receptor beta knockout, mice have better performance in the spontaneous alternation and object recognition tasks and reduced anxiety-like behavior in the elevated plus and mirror maze. Behavioural Brain Research. 2009;196(2):254–260. doi: 10.1016/j.bbr.2008.09.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Weihua Z, Lathe R, Warner M, Gustafsson JA. An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(21):13589–13594. doi: 10.1073/pnas.162477299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Weiser MJ, Foradori CD, Handa RJ. Estrogen receptor beta activation prevents glucocorticoid receptor-dependent effects of the central nucleus of the amygdala on behavior and neuroendocrine function. Brain Research. 2010;1336:78–88. doi: 10.1016/j.brainres.2010.03.098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Weiser MJ, Wu TJ, Handa RJ. Estrogen receptor-beta agonist diarylpropionitrile: Biological activities of R- and S- enantiomers on behavior and hormonal response to stress. Endocrinology. 2009;150(4):1817–1825. doi: 10.1210/en.2008-1355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Windle RJ, Shanks N, Lightman SL, Ingram CD. Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats. Endocrinology. 1997;138(7):2829–2834. doi: 10.1210/endo.138.7.5255. [DOI] [PubMed] [Google Scholar]
  107. Xu H, Qin S, Carrasco GA, Dai Y, Filardo EJ, Prossnitz ER, … Muma NA. Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus. Neuroscience. 2009;158(4):1599–1607. doi: 10.1016/j.neuroscience.2008.11.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Yamaguchi K, Akaishi T, Negoro H. Effect of estrogen treatment on plasma oxytocin and vasopressin in ovariectomized rats. Endocrinologia Japonica. 1979;26(2):197–205. doi: 10.1507/endocrj1954.26.197. [DOI] [PubMed] [Google Scholar]
  109. Yonkers KA, O’Brien PMS, Eriksson E. Premenstrual syndrome. Lancet. 2008;371(9619):1200–1210. doi: 10.1016/S0140-6736(08)60527-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Zuloaga KL, O’Connor DT, Handa RJ, Gonzales RJ. Estrogen receptor beta dependent attenuation of cytokine-induced cyclooxygenase-2 by androgens in human brain vascular smooth muscle cells and rat mesenteric arteries. Steroids. 2012;77(8–9):835–844. doi: 10.1016/j.steroids.2012.04.013. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES