Estrogen receptor beta activation prevents glucocorticoid receptor-dependent effects of the central nucleus of the amygdala on behavior and neuroendocrine function
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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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Peripheral administration of ERβ agonist R-DPN prevents increased HPA axis reactivity and increased anxiety-like behaviors in female rats in response to GR agonist implant adjacent to the central nucleus of the amygdala.
“Peripheral administration of the estrogen receptor β agonist, R-DPN, prevented the increased HPA axis reactivity and increased anxiety-like behaviors in female rats in response to the implantation of a wax pellet containing a GR agonist, adjacent to the central nucleus of the amygdala (Weiser, Foradori, & Handa, 2010).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Weiser, Foradori, & Handa, 2010
The Results (§2) report that peripheral S-DPN blocked the anxiety-like behaviors and increased stress-induced corticosterone associated with RU28362 implants. But the claim names R-DPN. Drug treatments (§4; page not provided) explicitly states that only the S-enantiomer was tested. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredEstradiol inhibits HPA axis reactivity through ERβ.
“Together, such data suggest a possible mechanism for estradiol actions in inhibiting HPA axis reactivity through estrogen receptor β.”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Weiser, Foradori, & Handa, 2010
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- Authors
- Weiser, M. J., Foradori, C. D., & Handa, R. J.
- Affiliations
- Colorado State University (US)
- University of Arizona (US)
- Corresponding author
- Handa, Robert J.
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 1336
- Pages
- 78-88
- ISSN
- 0006-8993 (ISSN-L)
- PMC
- PMC2879480
- OpenAlex
- W2067978273
- Cited by
- 66
- References
- 85
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 5 · 2022: 4 · 2021: 5 · 2019: 6 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 6 · 2013: 6 · 2012: 9
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS039951)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- estrogen receptor beta, glucocorticoid receptor, central amygdala, anxiety-like behavior, hypothalamic-pituitary-adrenal axis, estradiol, corticosterone, stress reactivity, neuroendocrine function, anxiolytic effects
- MeSH terms
- Amygdala, Animals, Anxiety, Behavior, Animal, Female, Hypothalamo-Hypophyseal System, Immunohistochemistry, Neurosecretory Systems, Ovariectomy, Pituitary-Adrenal System, Receptors, Glucocorticoid, Stress, Psychological, Rats, Sprague-Dawley, Estradiol Congeners, Estrogen Receptor beta, Rats
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