title: Uncoupling of 5-HT1A receptors in the brain by estrogens: regional variations in antagonism by ICI 182,780.
abstract: Previously we have shown that 17beta-estradiol (in vivo and in vitro) rapidly decreases the function of serotonin(1A) (5-HT(1A)) receptors, allowing us to hypothesize that 17beta-estradiol accomplished this via activation of a membrane estrogen receptor. Hippocampus and frontal cortex obtained from ovariectomized rats were incubated with 17beta-estradiol or bovine serum albumin (BSA)-estradiol in the presence or absence of the estrogen receptor (ER) antagonist ICI 182,780. Membranes were prepared to measure R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding (a measure of 5-HT(1A) receptor coupling and function). In both hippocampus and frontal cortex, 17beta-estradiol and BSA-estradiol (50 nM) decreased R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. ICI 182,780 blocked the effect of both the estrogens in hippocampus, but only the effect of 17beta-estradiol in frontal cortex. Due to the inability of ICI 182,780 to block the effects of BSA-estradiol in frontal cortex, similar experiments were performed using the selective estrogen receptor modulator tamoxifen as the agonist. Tamoxifen (100 nM and 1 microM) decreased R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. ICI 182,780 (1 microM) blocked the ability of tamoxifen to decrease 5-HT(1A) receptor coupling in the hippocampus, but not in the frontal cortex. Taken together, these data support the existence of a pharmacologically distinct ER in hippocampus vs. frontal cortex that might be responsible for rapid uncoupling of 5-HT(1A) receptors.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas School of Medicine, Kansas City, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Mize
authors.forename: L J
authors.initials: LJ
authors.lastname: Young
authors.forename: R H
authors.initials: RH
authors.lastname: Alper
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D014475:Uncoupling Agents / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011960:Receptors, Estrogen; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D014475:Uncoupling Agents; D000077267:Fulvestrant; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004958:Estradiol