Anxiolytic effects and neuroanatomical targets of estrogen receptor-β (ERβ) activation by a selective ERβ agonist in female mice

Mario G. Oyola, Wendy Portillo, Andrea Reyna, Chad D. Foradori, Andrea Kudwa, Laura Hinds, Robert J Handa, Shaila K. Mani

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Abstract

The dichotomous anxiogenic and anxiolytic properties of estrogens have been reported to be mediated by two distinct neural estrogen receptors (ER), ERα and ERβ, respectively. Using a combination of pharmacological and genetic approaches, we confirmed that the anxiolytic actions of estradiol are mediated by ERβ and extended and these observations to demonstrate the neuroanatomical targets involved in ERβ activation in these behavioral responses. We examined the effects of the biologically active S-enantiomer of diarylpropionitrile (S-DPN) on anxiety-related behavioral measures, the corresponding stress hormonal response to hypothalamo-pituitary-adrenal axis reactivity, and potential sites of neuronal activation in mutant female mice carrying a null mutation for ERβ gene (βERKO). S-DPN administration significantly reduced anxiety-like behaviors in the open field, light-dark exploration, and the elevated plus maze (EPM) in ovariectomized wild-type (WT) mice, but not in their βERKO littermates. Stress-induced corticosterone (CORT) and ACTH were also attenuated by S-DPN in the WT mice but not in the βERKO mice. Using c-fos induction after elevated plus maze, as a marker of stress-induced neuronal activation,weidentified the anterodorsal medial amygdala and bed nucleus of the stria terminalis as the neuronal targets of S-DPN action. Both areas showed elevated c-fos mRNA expression with S-DPN treatment in the WT but not βERKO females. These studies provide compelling evidence for anxiolytic effects mediated by ERβ, and its neuroanatomical targets, that send or receive projections to/from the paraventricular nucleus, providing potential indirect mode of action for the control of hypothalamopituitary- adrenal axis function and behaviors.

Original languageEnglish (US)
Pages (from-to)837-846
Number of pages10
JournalEndocrinology
Volume153
Issue number2
DOIs
StatePublished - Feb 2012

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Anti-Anxiety Agents
Estrogen Receptors
Estrogens
Anxiety
Septal Nuclei
Paraventricular Hypothalamic Nucleus
Sensory Receptor Cells
Corticosterone
Amygdala
Adrenocorticotropic Hormone
Estradiol
diarylpropionitrile
Pharmacology
Light
Messenger RNA
Mutation
Genes

ASJC Scopus subject areas

  • Endocrinology

Cite this

Oyola, M. G., Portillo, W., Reyna, A., Foradori, C. D., Kudwa, A., Hinds, L., ... Mani, S. K. (2012). Anxiolytic effects and neuroanatomical targets of estrogen receptor-β (ERβ) activation by a selective ERβ agonist in female mice. Endocrinology, 153(2), 837-846. https://doi.org/10.1210/en.2011-1674

Anxiolytic effects and neuroanatomical targets of estrogen receptor-β (ERβ) activation by a selective ERβ agonist in female mice. / Oyola, Mario G.; Portillo, Wendy; Reyna, Andrea; Foradori, Chad D.; Kudwa, Andrea; Hinds, Laura; Handa, Robert J; Mani, Shaila K.

In: Endocrinology, Vol. 153, No. 2, 02.2012, p. 837-846.

Research output: Contribution to journalArticle

Oyola, Mario G. ; Portillo, Wendy ; Reyna, Andrea ; Foradori, Chad D. ; Kudwa, Andrea ; Hinds, Laura ; Handa, Robert J ; Mani, Shaila K. / Anxiolytic effects and neuroanatomical targets of estrogen receptor-β (ERβ) activation by a selective ERβ agonist in female mice. In: Endocrinology. 2012 ; Vol. 153, No. 2. pp. 837-846.
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