Comparison of the effects of estradiol and progesterone on serotonergic function.
BACKGROUND
Ovarian hormones may contribute to the vulnerability to depression, as well as to the response to antidepressants (ADs). Previously, we reported that acute systemic treatment with estradiol or progesterone blocked the ability of the selective serotonin reuptake inhibitor, fluvoxamine, to inhibit serotonin transporter function in ovariectomized rats. In this study, behavioral consequences, as well as receptor mechanisms underlying these hormonal effects, were investigated.


METHODS
Using the forced swimming test, the acute effect of estradiol and/or progesterone on fluvoxamine's AD-like effects was investigated. Using in vivo chronoamperometry, the effect of local application of estradiol or progesterone into the hippocampus of ovariectomized rats on serotonin (5-HT) clearance, as well as on the ability of fluvoxamine to slow 5-HT clearance, were investigated.


RESULTS
The decreased immobility and increased swimming caused by fluvoxamine in the forced swimming test was blocked in rats treated with estradiol and/or progesterone. Local application of estradiol, but not progesterone, slowed 5-HT clearance and both hormones blocked the ability of fluvoxamine to slow 5-HT clearance. Use of hormone receptor agonists and antagonists, revealed that the effects of estradiol are mediated by activation of membrane, as well as nuclear estrogen receptors (ER). The AD-like effect of estradiol involved ER beta and G-protein coupled receptor 30, whereas its blockade of fluvoxamine's effects was ER alpha-mediated. The effects of progesterone occurred solely by activation of intracellular progesterone receptors.


CONCLUSIONS
Targeting of ER beta or G-protein coupled receptor 30 might reveal a strategy to permit beneficial effects of estrogen without its deleterious effect on selective serotonin reuptake inhibitor efficacy.
Department of Pharmacology, University of Texas Health Science Center at San Antonio, 78229-3900, USA. benmansour@uthscsa.edu
Saloua
S
Benmansour
Rami S
RS
Weaver
Amanda K
AK
Barton
Opeyemi S
OS
Adeniji
Alan
A
Frazer
D000818:Animals; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D016666:Fluvoxamine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D008845:Microinjections; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000819:agonists / Q000502:physiology; D011980:Receptors, Progesterone / Q000819:agonists / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D013550:Swimming / Q000502:physiology
D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D012701:Serotonin; D011374:Progesterone; D004958:Estradiol; D016666:Fluvoxamine