Selective estrogen receptor modulator effects in the rat brain.
The effects in the brain of selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene have not yet been fully elucidated. Based upon the hypothesis that serotonin (5-HT)-steroid hormone interactions are important in mood regulation, we have compared six SERMs (tamoxifen, raloxifene, levormeloxifene, NNC 45-0781, NNC 45-0320, NNC 45-1506) with 17beta-estradiol (E(2)) in terms of their ability to regulate mRNA levels of estrogen receptor (ER)alpha, ER beta, 5-HT(1A) receptor, and 5-HT reuptake transporter (SERT) in the midbrain, amygdala, and hypothalamus of ovariectomized (OVX) rats. Female rats (n = 6/group, 8 groups total) were OVX and allowed to recover for 2 weeks. During the third post-OVX week, rats were injected subcutaneously with E(2) (0.1 mg/kg) or one of the SERMs (5 mg/kg) once per day for 7 days. Twenty-four hours after the last injection, tissue was collected for the determination of mRNA levels by ribonuclease protection assay (RPA). E(2) treatment significantly decreased mRNA levels for ER alpha, ER beta, and SERT in midbrain and ER alpha in hypothalamus. Tamoxifen increased ER beta mRNA levels in hypothalamus, while raloxifene increased ER beta mRNA levels in amygdala. NNC 45-0320 decreased ER alpha mRNA in hypothalamus and decreased ER beta mRNA in amygdala. These results suggest that while SERMs are not full estrogen receptor agonists in the brain, the agonist/antagonist profiles for individual SERMs may differ among brain areas. This raises the possibility of developing new SERMs for selective functions in specific brain areas.
Zhou
Wenxia
W
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031, USA.
Koldzic-Zivanovic
Nina
N
Clarke
Charlotte H
CH
de Beun
René
R
Wassermann
Karsten
K
Bury
Paul S
PS
Cunningham
Kathryn A
KA
Thomas
Mary L
ML
D000679:Amygdala / Q000502:physiology; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D007031:Hypothalamus / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics; D026901:Membrane Transport Proteins; D008636:Mesencephalon / Q000502:physiology; D009419:Nerve Tissue Proteins; D010052:Ovariectomy; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D020849:Raloxifene Hydrochloride / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000235:genetics*; D011985:Receptors, Serotonin / Q000235:genetics; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins; D013629:Tamoxifen / Q000737:chemistry / Q000494:pharmacology
D002352:Carrier Proteins; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011759:Pyrrolidines; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D013629:Tamoxifen; D012701:Serotonin; D020849:Raloxifene Hydrochloride; D004958:Estradiol; C108255:levormeloxifene