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

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TitleAnxiolytic effects and neuroanatomical targets of estrogen receptor-β (ERβ) activation by a selective ERβ agonist in female mice.
Publication TypeJournal Article
Year of Publication2012
AuthorsOyola, MG, Portillo, W, Reyna, A, Foradori, CD, Kudwa, A, Hinds, L, Handa, RJ, Mani, SK
Date Published2012 Feb
Keywords2-Hydroxypropyl-beta-cyclodextrin, Animals, Anti-Anxiety Agents, Anxiety, Behavior, Animal, beta-Cyclodextrins, Estrogen Receptor beta, Female, Gene Expression Regulation, Mice, Mice, Knockout, Mutation, Nitriles, Ovariectomy, Propionates, Stress, Physiological

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, we identified 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 hypothalamo-pituitary-adrenal axis function and behaviors.

Alternate JournalEndocrinology
PubMed ID22186418
PubMed Central IDPMC3275390
Grant ListR01 NS039951 / NS / NINDS NIH HHS / United States
R25 GM069234 / GM / NIGMS NIH HHS / United States
NS039951-11 / NS / NINDS NIH HHS / United States