Immediate and residual effects of tamoxifen and ethynylestradiol in the female rat hypothalamus.
Very little is known about the impact of selective estrogen receptor modulators (SERMs) on the brain. We examined the effects of tamoxifen (TAMOX) and the synthetic estrogen 17alpha-ethynylestradiol (EE) on estrogen-dependent gene expression and receptor binding in the female rat brain. Both immediate and residual effects were examined in both the presence and absence of 17beta-estradiol. Two groups of adult, ovariectomized, female rats (n=30 per group) were injected with TAMOX (5 mg/kg), EE (0.1 mg/kg), or sesame oil daily for 14 days. Animals from the first group were implanted with blank or 17beta-estradiol Silastic capsules concurrently with the last three SERM injections (immediate, group 1). Animals from the second group received either blank or 17beta-estradiol implants 2 weeks after the last injection (residual, group 2). All animals were sacrificed 72 h after implantation. TAMOX increased uterine weight in the absence of estrogen, but inhibited uterine weight gain in the presence of estrogen in both groups 1 and 2. TAMOX and EE increased oxytocin receptor binding in the ventromedial nucleus of the hypothalamus (VMN) in the absence of estrogen in both groups 1 and 2. The estrogen-dependent induction of PR mRNA expression in the VMN was significantly attenuated by TAMOX in group 1. Finally, TAMOX and EE had opposite effects on ERbeta mRNA expression in the paraventricular nucleus in the absence of 17beta-estradiol in group 1. Neither had any effect in group 2 when 17beta-estradiol was present. These results suggest that TAMOX has mixed agonist/antagonist effects in the female rat brain, many of which persist at least 2 weeks after the administration ceases.
Patisaul
Heather B
HB
NSF Center for Behavioral Neuroscience, Emory University, Atlanta, GA 30329, USA. hbeaupr@emory.edu
Aultman
Eleni A
EA
Bielsky
Isadora F
IF
Young
Larry J
LJ
Wilson
Mark E
ME
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D004334:Drug Administration Schedule / Q000662:veterinary; D045166:Estradiol Congeners / Q000009:adverse effects / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000009:adverse effects / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000009:adverse effects / Q000494:pharmacology*; D005187:Fallopian Tubes / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D017403:In Situ Hybridization; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018045:Receptors, Oxytocin / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013629:Tamoxifen / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors; D014668:Vasotocin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D045166:Estradiol Congeners; D004965:Estrogen Antagonists; D012333:RNA, Messenger; D018045:Receptors, Oxytocin; D011980:Receptors, Progesterone; D013629:Tamoxifen; C076093:vasotocin, (beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)-O-methyl-Tyr(2)-Thr(4)-Orn(8)-Tyr(9)-NH2; D004997:Ethinyl Estradiol; D014668:Vasotocin