Elsevier

Physiology & Behavior

Volume 96, Issue 2, 16 February 2009, Pages 300-306
Physiology & Behavior

Effect of ER-β gene disruption on estrogenic regulation of anxiety in female mice

https://doi.org/10.1016/j.physbeh.2008.10.014Get rights and content

Abstract

It has been shown that long-term estrogen treatment in gonadectomized female mice increases anxiety levels. On the other hand, a recent study has reported that estrogen may down-regulate the levels of anxiety by acting through estrogen receptor (ER) β. In the present study, we investigated the role of ER-β in the regulation of anxiety levels in female mice after long-term estrogen treatment. Gonadectomized ER-β knockout (βERKO) female mice and their wild type (βWT) littermates were implanted several different doses (experiment 1: 2.0 μg/day, experiment 2: 1.0, 0.4, 0.2 or 0.1 μg/day) of an estradiol benzoate (EB) or placebo pellet. Ten days after pellet implant, behavioral tests commenced to measure the anxiety levels (experiment 1: light–dark transition test (LDT), experiment 2: LDT, elevated plus maze test (EPM) and social investigation test (SIT)). We found that, at higher-doses, long-term treatment of EB had anxiogenic effects in both βWT and βERKO mice as indicated by a decrease of the time spent in the light side and the number of transitions between two sides during LDT. In contrast, several behavioral measurements indicated that the lower-doses treatment of EB might reduce the anxiety levels possibly through ER-β. Particularly, the anxiolytic effects of EB in the SIT were more pronounced in βWT mice than βERKO mice. Together, the findings in the present study suggest that estrogen may have both anxiolytic and anxiogenic effects in female mice, and that ER-β gene disruption did not affect anxiogenic regulation by estrogen in female mice, but partially affected anxiolytic regulation.

Section snippets

Mice

βERKO female mice and their wild type (βWT) littermates were used. They were obtained from the βERKO breeding colonies maintained at the Rockefeller University by mating heterozygous male and female mice. Original breeding pairs (in C57BL/6J background) were obtained from the National Institute of Environmental Health Sciences [21]. From weaning to 10 days before the first behavioral tests, subjects were housed with same-sex littermates in plastic cages (30 × 20 × 12 cm). At the age of 9–17 weeks,

Experiment 1

Overall, there were no main effects of genotype in any measurements during the LDT tests; the time spent in the light compartment (Fig. 1a), the number of transitions between two compartments (Fig. 1b), and the latency to the first emerge to the light compartment (Fig. 1c). EB treatment at the dose of 2.0 μg/day similarly affected these behavioral measurements in βWT and βERKO mice. Both the time spent in the light compartment [F(1, 44) = 8.75, P < 0.01] and the number of transitions [F(1, 44) = 

Discussion

In the present study, we examined the effects of estrogen on the levels of anxiety in both non-social (LDT and EPM) and social (SIT) situations. In experiment 1, we tested animals in the LDT apparatus and found that EB treatment at the dose of 2.0 μg/day decreased the time spent in the light side and the number of transitions between the dark and light sides. These results indicate that long-term EB treatment at a relatively high-dose, among the treatment dose used in this study, increases the

Acknowledgments

This work was supported by the Overseas Research Grant of the Ministry of Education, Culture, Sports, Science and Technology of Japan to K. T. and the National Institute of Mental Health Grants MH-62147 to S. O. We thank Ms. Lee Holmes and Mr. Walter Chan for their assistance.

References (40)

  • M. Nomura et al.

    Estrogen receptor-beta regulates transcript levels for oxytocin and arginine vasopressin in the hypothalamic paraventricular nucleus of male mice

    Brain Res Mol Brain Res

    (2002)
  • M.M. McCarthy et al.

    An anxiolytic action of oxytocin is enhanced by estrogen in the mouse

    Physiol Behav

    (1996)
  • L.M. Sena et al.

    The dorsal raphe nucleus exerts opposed control on generalized anxiety and panic-related defensive responses in rats

    Behav Brain Res

    (2003)
  • A.A. Walf et al.

    Administration of estrogen receptor beta-specific selective estrogen receptor modulators to the hippocampus decrease anxiety and depressive behavior of ovariectomized rats

    Pharmacol Biochem Behav

    (2007)
  • U. Halbreich

    Role of estrogen in postmenopausal depression

    Neurology

    (1997)
  • J. Slater et al.

    A reevaluation of the relation between estrogen and emotionality in female rats

    J Comp Physiol Psychol

    (1976)
  • C.A. Frye et al.

    Estrogen and/or progesterone administered systemically or to the amygdala can have anxiety-, fear-, and pain-reducing effects in ovariectomized rats

    Behav Neurosci

    (2004)
  • P.A. Newhouse et al.

    Estrogen administration negatively alters mood following monoaminergic depletion and psychosocial stress in postmenopausal women

    Neuropsychopharmacology

    (2008)
  • S.E. File et al.

    Trough oestradiol levels associated with cognitive impairment in post-menopausal women after 10 years of oestradiol implants

    Psychopharmacology (Berl)

    (2002)
  • J.L. Payne

    The role of estrogen in mood disorders in women

    Int Rev Psychiatry

    (2003)

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