title: 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.
authors.affiliation: MRC Brain Metabolism Unit, University Department of Neuroscience, 1 George Square, Edinburgh EH8 9JZ, UK.
authors.forename: B E H
authors.initials: BE
authors.lastname: Sumner
authors.forename: K E
authors.initials: KE
authors.lastname: Grant
authors.forename: R
authors.initials: R
authors.lastname: Rosie
authors.forename: Ch
authors.initials: Ch
authors.lastname: Hegele-Hartung
authors.forename: K-H
authors.initials: KH
authors.lastname: Fritzemeier
authors.forename: G
authors.initials: G
authors.lastname: Fink
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D007986:Luteinizing Hormone / Q000378:metabolism; D019964:Mood Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D050486:Serotonin Plasma Membrane Transport Proteins; D013629:Tamoxifen; D012701:Serotonin; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D007986:Luteinizing Hormone