Chapter Two - Estrogen Receptors Modulation of Anxiety-Like Behavior
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 et al., 2010, Morrill et al., 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 intracellular 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.
Section snippets
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.
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
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
G-Protein-Coupled Estrogen Receptor
Recent research has identified the existence of a novel estrogen receptor known as GPR30 or GPER1 (Filardo et al., 2000, Revankar et al., 2005, Thomas et al., 2005). This receptor has been described as localized both at the membrane (Filardo et al., 2007, Funakoshi et al., 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
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
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.
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
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