title: Signaling mechanisms involved in the acute effects of estradiol on 5-HT clearance.
abstract: Estradiol was found previously to have an antidepressant-like effect and to block the ability of selective serotonin reuptake inhibitors (SSRIs) to have an antidepressant-like effect. The antidepressant-like effect of estradiol was due to estrogen receptor β (ERβ) and/or GPR30 activation, whereas estradiol's blockade of the effect of an SSRI was mediated by ERα. This study focuses on investigating signaling pathways as well as interacting receptors associated with these two effects of estradiol. In vivo chronoamperometry was used to measure serotonin transporter (SERT) function. The effect of local application of estradiol or selective agonists for ERα (PPT) or ERβ (DPN) into the CA3 region of the hippocampus of ovariectomized (OVX) rats on 5-hydroxytryptamine (5-HT) clearance as well as on the ability of fluvoxamine to slow 5-HT clearance was examined after selective blockade of signaling pathways or that of interacting receptors. Estradiol- or DPN-induced slowing of 5-HT clearance mediated by ERβ was blocked after inhibition of MAPK/ERK1/2 but not of PI3K/Akt signaling pathways. This effect also involved interactions with TrkB, and IGF-1 receptors. Estradiol's or PPT's inhibition of the fluvoxamine-induced slowing of 5-HT clearance mediated by ERα, was blocked after inhibition of either MAPK/ERK1/2 or PI3K/Akt signaling pathways. This effect involved interactions with the IGF-1 receptor and with the metabotropic glutamate receptor 1, but not with TrkB. This study illustrates some of the signaling pathways required for the effects of estradiol on SERT function, and particularly shows that ER subtypes elicit different as well as common signaling pathways for their actions.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas 78229, USA.
authors.forename: Saloua
authors.initials: S
authors.lastname: Benmansour
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas 78229, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Privratsky
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas 78229, USA.
authors.forename: Opeyemi S
authors.initials: OS
authors.lastname: Adeniji
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas 78229, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Frazer
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D010052:Ovariectomy; D010636:Phenols; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D011422:Propionates
chemical_list: D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D016666:Fluvoxamine; D009570:Nitriles; D010636:Phenols; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D017526:Receptor, IGF Type 1; D020813:Receptor, trkB; D018094:Receptors, Metabotropic Glutamate; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C493232:Slc6a4 protein, rat; C104077:metabotropic glutamate receptor type 1; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol