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 Res 1336: 78-88

Department of Biomedical Sciences, Neuroscience Division, Colorado State University, Fort Collins, CO, USA.
Brain research (Impact Factor: 2.84). 04/2010; 1336:78-88. DOI: 10.1016/j.brainres.2010.03.098
Source: PubMed


Neuropsychiatric disorders such as anxiety and depression have formidable economic and societal impacts. A dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis leading to elevated endogenous glucocorticoid levels is often associated with such disorders. Chronically high glucocorticoid levels may act upon the central nucleus of the amygdala (CeA) to alter normally adaptive responses into those that are maladaptive and detrimental. In addition to glucocorticoids, other steroid hormones such as estradiol and androgens can also modify hormonal and behavioral responses to threatening stimuli. In particular, estrogen receptor beta (ERbeta) agonists have been shown to be anxiolytic. Consequently, these experiments addressed the hypothesis that the selective stimulation of glucocorticoid receptor (GR) in the CeA would increase anxiety-like behaviors and HPA axis reactivity to stress, and further, that an ERbeta agonist could modulate these effects. Young adult female Sprague-Dawley rats were ovariectomized and bilaterally implanted via stereotaxic surgery with a wax pellet containing the selective GR agonist RU28362 or a blank pellet, to a region just dorsal to the CeA. Four days later, animals were administered the ERbeta agonist S-DPN or vehicle (with four daily sc injections). Anxiety-type behaviors were measured using the elevated plus maze (EPM). Central RU28362 implants caused significantly higher anxiety-type behaviors in the EPM and greater plasma CORT levels than controls given a blank central implant. Moreover, S-DPN treated animals, regardless of type of central implant, displayed significantly lower anxiety-type behaviors and post-EPM plasma CORT levels than vehicle treated controls or vehicle treated animals implanted with RU28362. These results indicate that selective activation of GR within the CeA is anxiogenic, and peripheral administration of an ERbeta agonist can overcome this effect. These data suggest that estradiol signaling via ERbeta prevents glucocorticoid-dependent effects of the CeA on behavior and neuroendocrine function.

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    • "Therefore, the significant reduction in testosterone seen in female R6/1 mice may reflect significantly reduced 3β-diol levels and reduced ERβ signalling. The ERβ agonist DPN infused into the central nucleus of the amygdala of rats reduced anxiety-like behaviour and stress-induced corticosterone levels, counteracting the anxiogenic effects of GR agonism of the same area (Weiser et al., 2010). A recent study found that two ERβ agonists, selective oestrogen receptor modulator (SERM)-beta1 and SERM-beta2, are both able to reduce depression-like behaviour in the FST in mice as well as increase neurogenesis in rats (Clark et al., 2012). "
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    • "Low-dose, short-term estradiol administration can inhibit HPA axis reactivity (Redei et al., 1994; Young et al., 2001; Dayas et al., 2000; Komesaroff et al., 1998), while higher doses and long-term administration can enhance HPA axis responses (Burgess and Handa, 1992; Carey et al., 1995; Viau and Meaney, 1991; Rubinow and Schmidt, 2009). Further, estradiol may have opposing effects on HPA axis reactivity depending on the ER subtype being targeted, with excitatory effects of the steroid hormone at ERα and inhibitory effects at ERβ (Lund et al., 2005; Lund et al., 2006 Oyola et al., 2012, Weiser et al., 2010). Our findings build on this literature by using functional neuroimaging to demonstrate that estradiol modulates the activity of brain regions responsible for regulating HPA axis activity. "
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    • "In the amygdala, estradiol acts to reduce anxiety-like behavior (Lund et al., 2005; Weiser et al., 2010) and glutamate activity is thought to promote anxiety (Wu et al., 2008). Estradiol treatment decreased GluA1 levels at 0.5 h, preceding the increase in phospho-cofilin at 1.0 h. "
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