Estrogen receptor binding in regions of the rat hypothalamus and preoptic area after inhibition of dopamine-β-hydroxylase (original) (raw)
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In vivo occupancy of female rat brain estrogen receptors by 17β-estradiol and tamoxifen
NeuroImage, 2004
Estrogens or antiestrogens are currently used by millions of women, but the interaction of these hormonal agents with brain estrogen receptors (ER) in vivo has not been characterized to date. Our goal was to assess, in vivo, the extent and regional distribution of brain ER occupancy in rats chronically exposed to 17B-estradiol (E 2) or tamoxifen (TAM). For that purpose, female ovariectomized Sprague-Dawley rats were implanted with subcutaneous pellets containing either placebo (OVX), E 2 , or TAM for 3 weeks. ER occupancy in grossly dissected regions was quantified with 16A-[ 18 F]fluoroestradiol ([ 18 F]FES). Both E 2 and TAM produced significant decreases in radioligand uptake in the brain although the effect of E 2 was larger and more widespread than the effect of TAM. Detailed regional analysis of the interaction was then undertaken using a radioiodinated ligand, 11B-methoxy-16A-[ 125 I]iodo-estradiol ([ 125 I]MIE 2), and quantitative ex vivo autoradiography. E 2 treatment resulted in near-complete (86.6 F 17.5%) inhibition of radioligand accumulation throughout the brain, while ER occupancy in the TAM group showed a marked regional distribution such that percentage inhibition ranged from 40.5 F 15.6 in the ventrolateral part of the ventromedial hypothalamic nucleus to 84.6 F 4.5 in the cortical amygdala. These results show that exposure to pharmacologically relevant levels of TAM produces a variable, region-specific pattern of brain ER occupancy, which may be influenced by the regional proportion of ER receptor subtypes. These findings may partially explain the highly variable and region-specific effects observed in neurochemical, metabolic, and functional studies of the effects of TAM in the brain of experimental animals as well as human subjects.
Brain Research, 1977
The antiestrogens MER-25, C1-628, and nafoxidine inhibit the uptake of [3H]estradiol in whole homogenates and isolated cell nuclei of brain tissues and the pituitary, and inhibit estradiol-induced female sexual behavior. The antiestrogens were injected intraperitoneally 2 h prior to an intravenous injection of [3H]estradiol, and the animals were killed 2 h after the estradiol. C1-628 reduces radioactivity in whole homogenates and isolated cell nuclei of cerebral cortex, hypothalamus, preoptic areaseptum and pituitary. Nafoxidine reduces uptake in cell nuclei of the hypothalamus, preoptic area-septum and pituitary. In this paradigm, MER-25 inhibited uptake only in the pituitary. In the analogous behavioral experiments, with antiestrogens injected 2 h prior to an intravenous injection of unesterified estradiol, CI-628 and nafoxidine totally inhibited lordosis responding. MER-25 shows no inhibition of behavior in this paradigm. However, when MER-25 is injected 12 h prior to the estradiol, it inhibits retention of [3H]estradiol at 2 h in brain and pituitary cell nuclei, and loTdosis responding is also inhibited. Additionally, the antiestrogens can apparently displace previously bound [3H]estradiol. When the antiestrogens are injected 2 h prior to an injection of [aH]estradiol, MER-25, CI-628 and nafoxidine all show greater inhibition of nuclear estradiol retention at 12 h after the [3H]estradiol injection than at 2 h. Analogously, when C1-628 is injected 2 h after an intravenous injection of [~H]estradiol, it displaces most of the radioactivity present in hypothalamic-preoptic area nuclei at 12 h after the estradiol injection. These results indicate that antiestrogens can prevent or reverse the nuclear concentration ofestradiol in brain cells and are consistent with a role of the cell nucleus in the induction of estrous behavior by estradiol.
Brain Research Bulletin, 1984
Cellular mechanisms qfacute estrogen negative,feedback on LH secretion: Norepinephrine, dopumine und S-hydroxytryptamine metabolism in discrete regions sfthe rat brain. BRAIN RES BULL 13(3) 363-369, 1984.-Rats on diestrous day 1 were ovariectomized (OVX) and killed 10 days later. LH was measured by RIA and the metabolism of NE, DA and S-HT were assayed concurrently in the suprachiasmatic (SCN), medial preoptic (MPO), dorsomedial (DMN), rostra1 (AN,) and caudal (AN,) arcuate nuclei as weil as the median eminence (ME) utilizing HPLC with electrochemical detection. Serum LH increased 10-12 fold 10 days following OVX compared to diestrous controls. The i*ction of estradiol benzoate (Eb, 20 pg in corn oil/rat, SC) did not affect LH concentrations at 30 minutes but decreased serum LH both 60 and 180 min following its administration. OVX caused an increased NE metabolism (estimated by the concentration of the NE metabolite, 3-mefhoxy4hydroxyphenylethylene glycol) in the SCN, MPO, ME, and DMN and a decreased NE metabolism in the AN, compared to diestrous control values. All of these changes were reversed or attenuated 180 minutes following Eb treatment. Observed changes in the DA and S-I-IT neuronal systems were more restricted and less dramatic with the largest effects on DA metabolism occurring in the DMN and ME and the clearest changes in 5-HT metabolism occurring in the MPO, AN,, and AN,. The results demonstrate that the inhibition of LH secretion following the injection of Eb to OVX rats is accompanied by changes in metabolism in NE neurons in preoptic (SCN and IWO) and medial (ME, DMN, and AN,) hypothalamic areas, as well as in DA neurons in the DMN and ME, and in 5-HT neurons in the MPO, AN,, and AN,. Monoamine metabolism Luteinizing hormone Acute estrogen negative feedback
In vivo occupancy of female rat brain estrogen receptors by 17beta-estradiol and tamoxifen
NeuroImage, 2004
Estrogens or antiestrogens are currently used by millions of women, but the interaction of these hormonal agents with brain estrogen receptors (ER) in vivo has not been characterized to date. Our goal was to assess, in vivo, the extent and regional distribution of brain ER occupancy in rats chronically exposed to 17beta-estradiol (E(2)) or tamoxifen (TAM). For that purpose, female ovariectomized Sprague-Dawley rats were implanted with subcutaneous pellets containing either placebo (OVX), E(2), or TAM for 3 weeks. ER occupancy in grossly dissected regions was quantified with 16alpha-[(18)F]fluoroestradiol ([(18)F]FES). Both E(2) and TAM produced significant decreases in radioligand uptake in the brain although the effect of E(2) was larger and more widespread than the effect of TAM. Detailed regional analysis of the interaction was then undertaken using a radioiodinated ligand, 11beta-methoxy-16alpha-[(125)I]iodo-estradiol ([(125)I]MIE(2)), and quantitative ex vivo autoradiography. E...
Developing hypothalamic dopaminergic neurones as potential targets for environmental estrogens
Journal of Endocrinology, 1999
Environmental chemicals which mimic the actions of estrogen have the potential to affect any estrogen responsive tissue. The aim of the present study was to investigate their potential to mimic the effects of 17β-estradiol (E 2 ) on developing primary rat hypothalamic dopaminergic (DA) neurones maintained in a chemically defined medium. We now show that both E 2 and octylphenol (OP), but not the non-aromatizable androgen, dihydrotestosterone, enhanced the uptake of [ 3 H]DA by the cultured cells, whereas they had no effect on the uptake of [ 14 C]GABA. Although the sensitivity of responses may change with the age of the developing cultures, the dose response curves for E2 and OP were typically 'bell-shaped', with a rise in response followed by a decline to control levels with increasing concentrations. Effects were seen as low as 10 -14 M for E2 and 10 -11 M for OP. Responses to E2 (10 -12 M) and OP (10 -9 M) were reversed in the presence of the antiestrogen, ZM 182780 (10 -5 M). This study thus provides direct evidence, using a mechanistic rather than toxicological end-point, in support of the hypothesis that inappropriate exposure to environmental estrogens at critically sensitive stages of development, could potentially perturb the organisational activities of estrogen on selected neuronal populations in the CNS.
Brain Research, 2004
The effect of different dose, mode and duration of estradiol administration was examined in the different brain catecholaminergic areas in ovariectomized (OVX) female rats. We determined changes in mRNA levels of tyrosine hydroxylase (TH), rate-limiting enzyme in catecholamine (CA) biosynthesis, and of GTP cyclohydrolase I (GTPCH), rate-limiting enzyme in biosynthesis of tetrahydrobiopterin (BH4), as well as concentration of BH4, which is an essential cofactor for TH, tryptophan hydroxylase and nitric oxide synthase. Short-term administration of estradiol benzoate (EB) by five injections of 15 or 40 Ag/kg 12 h apart led to increase in TH and GTPCH mRNA levels in dopaminergic and noradrenergic cell bodies of the ventral tegmental area (VTA), substantia nigra (SN), locus coeruleus (LC) and the nucleus of solitary tract (NTS) depending on dose of administration. Estrogen-elicited alterations in BH4 concentrations were mostly correlated with changes in GTPCH mRNA levels, except in SN. Long-term administration of estradiol by injections (EB: 25 Ag/kg, 16 injections 24 h apart; 50 Ag/kg, 16 injections 48 h apart) or pellets (0.1 mg 17 h-estradiol, 14 days) were not very effective in modulating mRNA levels for both genes in most locations except the NTS. Long-term injections of EB elevated GTPCH mRNA levels throughout the NTS and in microvessels. Administration of estradiol by pellets led to decline of TH mRNA in rostral-medial and elevation in caudal parts of the NTS. Thus, estradiol has a complex and differential effect on TH and GTPCH gene expression in a tissue specific manner and depends on the mode of administration. D
The cellular effects of estrogens on neuroendocrine tissues
Journal of steroid biochemistry, 1988
Estrogen action on sensitive neurons in the rat diencephalon has been studied by morphologic techniques; evidence of estrogen action at every level is presented, including tracts, cells, circuitry and subcellular organelles. The demonstration in the arcuate nucleus of estrogen-induced synaptic remodelling, estrogen-induced postsynaptic membrane phenotypes, changes in intracellular membranes and rapid estrogen actions on neuronal endo-exocytosis indicates that cellular estrogen actions may underlie the neuronal control of reproduction.
Estrogen effects on the tuberoinfundibular dopaminergic system in the female rat brain
Brain Research, 1990
Estrogen effects on tyrosine hydroxylase (TH), monoamine oxidase types A and B (MAO), and dopamine (DA) in microdissected regions of the hypothalamus, preoptic area and substantia nigra (SNR) of the female rat brain were investigated. Ovariectomized (OVX) young adult female rats were implanted with single silastic capsules containing 100% estradiol valerate (EV). Control rats received empty silastic capsules. Two weeks following capsule insertion, EV decreased TH activity and DA concentration in the arcuate nucleus (AN) while no significant changes in TH activity or DA concentration were observed in the SNR, ventromedial nucleus (VMN), suprachiasmatic nucleus, paraventricular nucleus, medial preoptic nucleus, or the periventricular preoptic nucleus. Although estrogen suppressed TH and DA in the AN, 2 weeks following removal of the estrogen containing capsules, TH activity and DA concentration were restored to control (OVX) levels. Suppression of MAO activity occurred in both the AN and the VMN of rats implanted with EV capsules and returned to OVX levels following the removal of the estradiol load. These results revealed that estrogen effects on TH and MAO activities and DA concentration in the midbrain are region specific and reversible; and that among the dopaminergic systems studied, estrogen effects on TH and DA are confined to the tuberoinfundibular dopaminergic system (TIDAS). Furthermore, these results support our hypothesis that estrogen is a key regulator of DA function in the TIDAS via effects on TH. The importance of these findings to the control of gonadotropin secretion and reproductive cyclicity is discussed.
Toxicological Sciences, 2008
In female rodents, hypothalamic norepinephrine (NE) has a role in stimulating the secretion of gonadotropin-releasing hormone (GnRH) that triggers the ovulatory surge of luteinizing hormone (LH). NE synthesis from dopamine (DA) is catalyzed by dopamine-b-hydroxylase (DbH) which contains a copper cofactor. Sodium dimethyldithiocarbamate (DMDC) is a pesticide with metal chelating properties that has been found to reduce DbH activity. The resultant decrease in NE causes a suppression of both the LH surge and ovulation. The present study examined the dose-related impact of DMDC on hypothalamic GnRH neuronal activation indicated by the nuclear presence of the early gene product c-fos. It represents an essential link between effects on NE and suppression of the surge. Ovariectomized (OVX), estradiol-, and progesterone-primed Sprague-Dawley rats were given a single ip injection of 0, 3.6, 7.1, 14.2, or 28.4 mg/kg DMDC in separate groups of females to assess tissue GnRH/c-fos immunostaining, hypothalamic catecholamines, and serial blood samplings for LH. A dose-related decline in hypothalamic NE and increase in DA at 2 h after DMDC administration were consistent with a decrease in c-fos-positive GnRH neurons, with an almost complete absence of c-fos at the two highest doses. The effects correlated well with a suppression of the surge, although the percentage decrease in c-fos neurons at 7.1 mg/kg only attenuated the surge peak, not the overall amount of circulating LH. The present data offer further evidence that the impact of DMDC on the LH surge is central in origin and in doing so defines the toxic pathway for this effect on ovulation.