Raloxifene blocks estradiol induction of the serotonin transporter and 5-hydroxytryptamine2A receptor in female rat brain.

Abstract:

:Sex steroids have potent effects on mood, mental state and cognition. Our previous findings and those of others suggest that these effects may be due at least in part to estradiol actions on central serotonergic mechanisms. Specifically, estradiol-17beta in its acute positive feedback mode for gonadotropin release in the female rat induces expression of the genes for the 5-hydroxytryptamine(2A) receptor (5-HT(2A)R) and the serotonin transporter (SERT) in the dorsal raphe nucleus (DRN). This is accompanied by an increase in the densities of 5-HT(2A)R and the SERT in forebrain regions which in the human are concerned with the control of mood, mental state, cognition and emotion. Here we report that raloxifene, a benzothiophene and selective estrogen receptor modulator (SERM), completely blocked estradiol stimulation of brain 5-HT(2A)R and SERT expression in acutely ovariectomized rats. Raloxifene also blocked the estrogen-induced surge of luteinizing hormone. Treatment of acutely ovariectomized rats with raloxifene alone increased the density of SERT sites in the mid-frontal cortex and decreased the density of 5-HT(2A)R in the posterior olfactory tubercle. The inhibitory effects of raloxifene on acute estrogen-induction of central serotonergic mechanisms were similar to those of tamoxifen even though there are major differences between the two SERMs in their affinity for the two estrogen receptor subtypes and their actions on the uterus. These findings provide robust evidence that estradiol induction of the 5-HT(2A)R and the SERT in brain is mediated by nuclear estrogen receptors. Our data may provide the basis for obtaining a better understanding of the effects of sex steroids on mood and mental state in the human and the possible rational development of congeners of sex steroids for the treatment of mental disorders.

journal_name

Neurosci Lett

journal_title

Neuroscience letters

authors

Sumner BE,Grant KE,Rosie R,Hegele-Hartung Ch,Fritzemeier KH,Fink G

doi

10.1016/j.neulet.2007.02.039

subject

Has Abstract

pub_date

2007-04-24 00:00:00

pages

95-9

issue

1

eissn

0304-3940

issn

1872-7972

pii

S0304-3940(07)00196-6

journal_volume

417

pub_type

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