17 Beta-estradiol-induced antidepressant-like effect in the forced swim test is absent in estrogen receptor-beta knockout (BERKO) mice.
BACKGROUND
The decrease in levels of estrogens (ER) that occurs in menopause has been correlated with depressive disorders, probably due to ER direct and/or indirect effects in the brain, where these hormones act through both genomic (i.e. interaction as transcription factors with nuclear receptors ER-alpha and ER-beta) and non-genomic (i.e. binding with cell-membrane receptors) mechanisms. With respect to mood related disorders the interaction between ER-beta and the serotonin (5-HT) system is highly relevant. 17beta-Estradiol (E2) induces expression of the enzyme implicated in 5-HT synthesis - tryptophan hydroxylase (TPH), and this effect is mediated through ER-beta located in 5-HT cell bodies of the dorsal raphe nucleus (DRN).


OBJECTIVE
The present studies tested the hypothesis that E2 induces antidepressant-like effects in female ovariectomized (OVX) mice, and that expression of ER-beta is mandatory for such effects.


METHODS
The Forced Swim Test (FST) was used in three experiments to assess (a) dose response effect of E2 in outbred and inbred mouse strains, (b) length of treatment necessary for effect, (c) and role of ER-beta receptors.


RESULTS
E2 (100 or 200 microg/kg), as well as the antidepressant desipramine (DMI), significantly reduced total duration of immobility in the FST in mice from different strains. Four consecutive daily doses (200 microg/kg) were required for such effect, which was absent in mice lacking the gene coding for ER-beta (BERKO mice).


CONCLUSIONS
These data suggest that E2-induced antidepressant-like effects in mice are mediated through activation of ER-beta. They offer preliminary support to the hypothesis that specific compounds acting at ER-beta may influence mood in postmenopausal women.
Rocha
Beatriz A
BA
Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA. beatriz_rocha@merck.com
Fleischer
Rebecca
R
Schaeffer
James M
JM
Rohrer
Susan P
SP
Hickey
Gerry J
GJ
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use*; D047629:Estrogen Receptor beta / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010052:Ovariectomy; D013550:Swimming / Q000523:psychology
D000928:Antidepressive Agents; D047629:Estrogen Receptor beta; D004958:Estradiol