Anxiolytic Effects and Neuroanatomical Targets of Estrogen Receptor-β (ERβ) Activation by a Selective ERβ Agonist in Female Mice
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Rats and mice treated with an ERbeta selective agonist showed decreased stress-induced ACTH and CORT release compared with vehicle-treated animals.
“Rats88,89 and mice91 treated with an ERβ selective agonist showed decreased stress-induced ACTH and CORT release compared to vehicle-treated animals.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [91]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
Effects of gonadal steroids in women with a history of postpartum depression
Bloch, M., Schmidt, P. J., Danaceau, M., Murphy, J., Nieman, L., & Rubinow, D. R. (2000) · American Journal of Psychiatry · doi:10.1176/appi.ajp.157.6.924 · Cited by 950 · see citing works
Gonadal Steroid Hormone Receptors and Sex Differences in the Hypothalamo-Pituitary-Adrenal Axis
Handa, R. J., Burgess, L. H., Kerr, J. E., & O'Keefe, J. A. (1994) · Hormones and Behavior · doi:10.1006/hbeh.1994.1044 · Cited by 793 · see citing works
Self-citationMarble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety
Thomas, A., Burant, A., Bui, N., Graham, D., Yuva-Paylor, L. A., & Paylor, R. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1466-y · Cited by 698 · see citing works
The use of behavioral test batteries: Effects of training history
McIlwain, K. L., Merriweather, M. Y., Yuva-Paylor, L. A., & Paylor, R. (2001) · Physiology & Behavior · doi:10.1016/s0031-9384(01)00528-5 · Cited by 579 · see citing works
Distribution of estrogen receptor β immunoreactivity in the rat central nervous system
Shughrue, P. J., & Merchenthaler, I. J. (2001) · The Journal of Comparative Neurology · doi:10.1002/cne.1054 · Cited by 490 · see citing works
Evaluation of marble-burying behavior as a model of anxiety
Njung'e, K., & Handley, S. L. (1991) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(91)90590-x · Cited by 487 · see citing works
Ogawa, S., Eng, V., Taylor, J. A., Lubahn, D. B., Korach, K. S., & Pfaff, D. W. (1998) · Endocrinology · doi:10.1210/endo.139.12.6357 · Cited by 487 · see citing works
Burgess, L. H., & Handa, R. J. (1992) · Endocrinology · doi:10.1210/endo.131.3.1324155 · Cited by 445 · see citing works
Self-citationNovel Actions of Estrogen Receptor-β on Anxiety-Related Behaviors
Lund, T. D., Rovis, T., Chung, W. C. J., & Handa, R. J. (2005) · Endocrinology · doi:10.1210/en.2004-1158 · Cited by 436 · cited 6× · see citing works
“Support for ER ’s role in anxiety, stems from the studies on anxiety-related behaviors in female rats, treated with an ER subtype-selective agonist (12).”
BackgroundMethodInfluentialSelf-citationMakino, S., Gold, P. W., & Schulkin, J. (1994) · Brain Research · doi:10.1016/0006-8993(94)91862-7 · Cited by 400 · see citing works
Ogawa, S., Chan, J. S. W., Chester, A. E., Gustafsson, J.-Α., Korach, K. S., & Pfaff, D. W. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.22.12887 · Cited by 399 · see citing works
Shepard, J. D., Barron, K. W., & Myers, D. A. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02019-9 · Cited by 321 · see citing works
Broekkamp, C. L., Rijk, H. W., Joly-Gelouin, D., & Lloyd, K. L. (1986) · European Journal of Pharmacology · doi:10.1016/0014-2999(86)90051-8 · Cited by 286 · see citing works
Increased anxiety and synaptic plasticity in estrogen receptor β-deficient mice
Krężel, W., Dupont, S., Krust, A., Chambon, P., & Chapman, P. F. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.221451898 · Cited by 279 · see citing works
Effects of Estrogen on Activity and Fear-Related Behaviors in Mice
Morgan, M., & Pfaff, D. W. (2001) · Hormones and Behavior · doi:10.1006/hbeh.2001.1716 · Cited by 271 · see citing works
The relevance of differential response to trauma in an animal model of posttraumatic stress disorder
Cohen, H., Zohar, J., & Matar, M. A. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01909-1 · Cited by 268 · see citing works
Oestrogen receptor knockout mice: roles for oestrogen receptors α and β in reproductive tissues
Hewitt, S. C., & Korach, K. S. (2003) · Reproduction · doi:10.1530/rep.0.1250143 · Cited by 261 · see citing works
Cohen, H., Zohar, J., Matar, M. A., Kaplan, Z., Loewenthal, U., & Richter‐Levin, G. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300523 · Cited by 254 · see citing works
Weiser, M. J., & Handa, R. J. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2008.12.058 · Cited by 250 · see citing works
Self-citationThe use of behavioral test batteries, II: Effect of test interval
Paylor, R. E., Spencer, C. M., Yuva‐Paylor, L. A., & Pieke-Dahl, S. (2005) · Physiology & Behavior · doi:10.1016/j.physbeh.2005.09.002 · Cited by 243 · see citing works
Lund, T. D., Hinds, L. R., & Handa, R. J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3777-05.2006 · Cited by 236 · see citing works
Self-citationWalf, A. A., & Frye, C. A. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300713 · Cited by 229 · see citing works
Imwalle, D. B., Gustafsson, J.-Α., & Rissman, E. F. (2004) · Physiology & Behavior · doi:10.1016/j.physbeh.2004.11.002 · Cited by 225 · see citing works
Alves, S. E., López, V., McEwen, B. S., & Weiland, N. G. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.6.3281 · Cited by 217 · see citing works
Hrabovszky, E., Kalló, I., Hajszán, T., Shughrue, P. J., Merchenthaler, I. J., & Liposits, Z. (1998) · Endocrinology · doi:10.1210/endo.139.5.6024 · Cited by 193 · see citing works
Rachman, I. M., Unnerstall, J. R., Pfaff, D. W., & Cohen, R. S. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.23.13941 · Cited by 182 · see citing works
Antidepressant effects of ERβ-selective estrogen receptor modulators in the forced swim test
Walf, A. A., Rhodes, M. E., & Frye, C. A. (2004) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2004.03.023 · Cited by 179 · see citing works
Lund, T. D., Munson, D. J., Haldy, M. E., & Handa, R. J. (2004) · Journal of Neuroendocrinology · doi:10.1111/j.0953-8194.2004.01167.x · Cited by 172 · see citing works
Self-citationPatisaul, H. B., Scordalakes, E. M., Young, L. J., & Rissman, E. F. (2003) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.2003.01061.x · Cited by 160 · see citing works
Walf, A., Koonce, C. J., Manley, K., & Frye, C. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.09.016 · Cited by 153 · see citing works
Jacome, L. F., Gautreaux, C., Inagaki, T., Mohan, G., Alves, S. E., Lubbers, L. S., & Luine, V. N. (2010) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2010.08.016 · Cited by 150 · see citing works
Excitation of neurones in the rat paraventricular nucleus in vitro by vasopressin and oxytocin.
Inenaga, K., & Yamashita, H. (1986) · The Journal of Physiology · doi:10.1113/jphysiol.1986.sp015928 · Cited by 138 · see citing works
Rubino, T., Sala, M., Viganò, D., Braida, D., Castiglioni, C., Limonta, V., Guidali, C., Realini, N., & Parolaro, D. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301330 · Cited by 137 · see citing works
Weiser, M. J., Wu, T. J., & Handa, R. J. (2009) · Endocrinology · doi:10.1210/en.2008-1355 · Cited by 124 · see citing works
Self-citationNomikos, G. G., & Spyraki, C. (1988) · Neuropharmacology · doi:10.1016/0028-3908(88)90077-9 · Cited by 121 · see citing works
Walf, A., Koonce, C. J., & Frye, C. (2008) · Behavioral Neuroscience · doi:10.1037/a0012749 · Cited by 118 · see citing works
Suzuki, S., & Handa, R. J. (2005) · Journal of Comparative Neurology · doi:10.1002/cne.20457 · Cited by 97 · see citing works
Self-citationShughrue, P. J., Dellovade, T., & Merchenthaler, I. J. (2002) · Progress in brain research · doi:10.1016/s0079-6123(02)39004-6 · Cited by 93 · see citing works
Sun, J., Baudry, J. Y., Katzenellenbogen, J. A., & Katzenellenbogen, B. S. (2003) · Molecular Endocrinology · doi:10.1210/me.2002-0341 · Cited by 91 · see citing works
Hughes, Z. A., Liu, F., Platt, B. J., Dwyer, J. M., Pulicicchio, C. M., Zhang, G., Schechter, L. E., Rosenzweig-Lipson, S., & Day, M. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.03.004 · Cited by 88 · cited 1× · see citing works
“Conversely, the activation of ER , using theER selectiveagonists, racemicDPN, WAY-200070, and S-DPN, reduces stress-induced HPA axis reactivity as evidenced by a decrease in CORT and ACTH secretion (12, 19, 21).”
MethodEffect of ER-β gene disruption on estrogenic regulation of anxiety in female mice
Tomihara, K., Soga, T., Nomura, M., Korach, K., Gustafsson, J., Pfaff, D., & Ogawa, S. (2008) · Physiology and Behavior · doi:10.1016/j.physbeh.2008.10.014 · Cited by 76 · see citing works
Animal Models of Obsessive‐Compulsive Disorder
Witkin, J. M. (2008) · Current Protocols in Neuroscience · doi:10.1002/0471142301.ns0930s45 · Cited by 72 · see citing works
Weiser, M. J., Foradori, C. D., & Handa, R. J. (2010) · Brain Research · doi:10.1016/j.brainres.2010.03.098 · Cited by 66 · see citing works
Self-citationThe effect of perinatal exposure to estrogens on the sexually dimorphic response to novelty
Leret, M. L., Molina‐Holgado, F., & González, M. I. (1994) · Physiology & Behavior · doi:10.1016/0031-9384(94)90148-1 · Cited by 62 · see citing works
Estrogens of multiple classes and their role in mental health disease mechanisms
Watson, C. S. (2010) · International Journal of Women s Health · doi:10.2147/ijwh.s6907 · Cited by 52 · see citing works
Carroll, V. M., Jeyakumar, M., Carlson, K. E., & Katzenellenbogen, J. A. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm201436k · Cited by 50 · see citing works
D'Costa, A. P., Prevette, D. M., Houenou, L. J., Wang, S., Zackenfels, K., Rohrer, H., Zapf, J., Caroni, P., & Oppenheim, R. W. (1998) · Journal of Neurobiology · doi:10.1002/(sici)1097-4695(19980905)36:3 · Cited by 49 · see citing works
Gerrits, M., Grootkarijn, A., Bekkering, B. F., Bruinsma, M., den Boer, J. D., & ter Horst, G. T. (2005) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2005.06.021 · Cited by 44 · see citing works
PRIOR‐TREATMENT EFFECTS ON OPEN‐FIELD EMOTIONALITY: THE NEED FOR REPRESENTATIVE DESIGN*
Henderson, N. D. (1969) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1969.tb12984.x · Cited by 30 · see citing works
Effects of agents targeting glutamatergic systems on marble-burying behavior
Iijima, M., Kurosu, S., & Chaki, S. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.12.048 · Cited by 28 · see citing works
Somponpun, S. J., & Sladek, C. D. (2004) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2004.01200.x · Cited by 25 · see citing works
Adamec, R. E., Tóth, M., Haller, J., Halász, J., & Blundell, J. J. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.11.018 · Cited by 25 · see citing works
Identifying Early Behavioral and Molecular Markers of Future Stress Sensitivity
Goel, N., & Bale, T. L. (2007) · Endocrinology · doi:10.1210/en.2007-0479 · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Gonadal steroid hormones and the hypothalamo–pituitary–adrenal axis
Handa, R. J., & Weiser, M. J. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.11.001 · Cited by 408 · see citing works
Self-citationAcevedo‐Rodriguez, A., Kauffman, A. S., Cherrington, B. D., Borges, C. S., Roepke, T. A., & Laconi, M. (2018) · Journal of neuroendocrinology · doi:10.1111/jne.12590 · Cited by 298 · see citing works
You’ve got male: Sex and the microbiota-gut-brain axis across the lifespan
Jaggar, M., Rea, K., Spichak, S., Dinan, T. G., & Cryan, J. F. (2020) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2019.100815 · Cited by 200 · see citing works
Oxytocin and Estrogen Receptor β in the Brain: An Overview
Acevedo-Rodriguez, A., Mani, S. K., & Handa, R. J. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00160 · Cited by 124 · see citing works
Self-citationKudwa, A. E., McGivern, R. F., & Handa, R. J. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.03.004 · Cited by 73 · see citing works
Self-citationOyola, M. G., Thompson, M. K., Handa, A. Z., & Handa, R. J. (2017) · Journal of Comparative Neurology · doi:10.1002/cne.24295 · Cited by 53 · see citing works
Self-citation
- Authors
- Oyola, M. G., Portillo, W., Reyna, A., Foradori, C. D., Kudwa, A., Hinds, L., Handa, R. J., & Mani, S. K.
- Affiliations
- Baylor College of Medicine (US)
- Molecular and Cellular Biology (W.P., A.R., S.K.M.), Houston, Texas 77030
- University of Arizona College of Medicine- Phoenix (US)
- Corresponding author
- Mani, Shaila K.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2012-02-01
- Volume
- 153
- Issue
- 2
- Pages
- 837-846
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC3275390
- OpenAlex
- W2082870934
- Cited by
- 99
- References
- 54
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 10 · 2019: 8 · 2018: 4 · 2017: 7 · 2016: 6 · 2015: 12 · 2014: 11 · 2013: 7 · 2012: 6
- FWCI
- 4.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dartmouth College
- National Institute of General Medical Sciences (R25GM069234)
- National Institute of Neurological Disorders and Stroke (R01NS039951, NS039951-11)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- estrogen receptor beta, anxiolytic effects, estradiol, diarylpropionitrile, anxiety-like behavior, hypothalamic-pituitary-adrenal axis, corticosterone, ACTH, c-fos, bed nucleus of the stria terminalis, paraventricular nucleus, ovariectomy, female mice, ERβ knockout mice
- MeSH terms
- 2-Hydroxypropyl-beta-cyclodextrin, Animals, Anxiety, Behavior, Animal, Female, Gene Expression Regulation, Mutation, Nitriles, Ovariectomy, Propionates, Stress, Physiological, Anti-Anxiety Agents, Mice, Knockout, beta-Cyclodextrins, Estrogen Receptor beta, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
