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PubMed1995

The role of estrogen receptor in modulation of chromatin conformation in the 5' flanking region of the rat prolactin gene.

To determine whether the estrogen receptor (ER) has a role in the modification of chromatin structure, we developed cell lines to model discrete stages in the estrogen response. Each cell line carries a population of stably expressed papillomavirus-based minichromosomes containing the 5' flanking region of the rat prolactin gene. We examined ER effects at the distal enhancer domain of the rat prolactin promoter, using DNaseI to probe for alterations of the nucleoprotein complex. Within 1 h after the start of estrogen treatment, modifications in the chromatin state of the distal enhancer region were detected in a pituitary-derived, permissive cell line (GH3G1J). In rat-1 fibroblast cell lines that maintain the same stably expressed papillomavirus-based minichromosomes in the absence of ER or pituitary-specific transcription factors (Rat-1.2A2; non-permissive), no estrogen-induced modifications in the chromatin state were detected at 1 or 24 h. In rat-1 fibroblast cell lines that also contained ectopically expressed, functional ER (Rat-1 + ER.8A1), no estrogen-induced modifications in the chromatin state were detected at 1 h, but a 24 h a specific modification in the local structure was induced. These data support a model in which the ER interacts with chromatin to modify local structure in such a way as to induce a permissive state for interactions of transcription factors necessary for hormone-induced activation of gene transcription.

Animals↗
PubMed2003

Distribution of estrogen receptors alpha and beta mRNA in mouse urogenital tissues and their expression after oophorectomy and estrogen replacement.

Estrogen receptors are present in the urogenital tract. However, little is known about the quantitative distribution of the traditional estrogen receptor (ERalpha) mRNA and the recently identified ERbeta mRNA. By quantitative reverse transcription polymerase chain reaction analysis, the distributions of ERalpha and ERbeta mRNA in mouse urogenital tissues and their expression in selected urogenital tissues after oophorectomy, with or without estrogen replacement, were evaluated. ERalpha mRNA concentrations were higher in the ovary, oviduct, uterus and vagina than in the kidney, ureter or bladder ( P<0.05); ERbeta transcripts were highest in the ovary, oviduct and bladder ( P<0.05). After oophorectomy and estrogen replacement, significant changes were identified in ERalpha and ERbeta mRNA expression. ERalpha and ERbeta mRNA are differentially expressed in mouse urogenital tissues. Oophorectomy and estrogen replacement affect estrogen receptors differently in the bladder, vagina and uterus. These results may explain some tissue-specific responses to estrogen and selective estrogen receptor modulators. The mRNA distributions of estrogen receptors alpha and beta and their expression after oophorectomy, with or without estrogen replacement, differ in mouse urogenital tissues.

Animals↗
PubMed2002

[Rationale for the treatment of postmenopausal women by SERM].

Raloxifene has been developed as a selective estrogen receptor modulator (SERM) that binds to estrogen receptor (ER) and acts as an estrogen agonist in some tissues while acting as an estrogen antagonist in certain tissues. Raloxifene exerts anti-estrogenic actions in the uterus and the mammary gland, whereas it has estrogenic effects on bone and serum lipids. As a result, raloxifene increases bone volume and reduces vertebral fractures without increasing the incidence of uterine cancer. In addition, raloxifene reduces the incidence of breast cancer to nearly a third of those without raloxifene treatment by markedly reducing the development of ER-positive breast cancer. Raloxifene also reduces the risk of cardiovascular events among postmenopausal women with increased cardiovascular risk. From these observations, postmenopausal osteoporotic women without multiple or severe fractures who have risk factors for breast cancer or cardiovascular disorders can be excellent candidates for raloxifene treatment.

English Abstract↗
PubMed2006

Developments in the pharmacotherapeutic management of osteoporosis.

During the last two decades, several medications have been granted a marketing authorisation for the management of osteoporosis. Bisphosphonates are the most widely prescribed drugs in this area, worldwide. Alendronate and risedronate are given daily or weekly and have demonstrated their ability to reduce fracture rates at the spine and hip. Ibandronate has demonstrated spine antifracture efficacy with intervals between dosings greater than weekly. New developments in this class include intravenous administration of ibandronate or zoledronate, once every three months or once yearly. Raloxifene, a selective estrogen-receptor modulator, reduces spine fractures and, in post-hoc analyses, non-spine fractures in high-risk subjects. New selective estrogen-receptor modulators, including lasofoxifene, bazedoxifene and arzoxifene, are expected to demonstrate antifracture efficacy at the hip level, whilst retaining the extra-skeletal benefits (such as in the breast) that are obtained with raloxifene. The peptides from the parathyroid hormone family are potent stimulators of bone formation. Teriparatide (1 - 34 amino acid fragment of the parathyroid hormone) reduces spine and non-spine fractures, an effect that is sustained for up to 30 months after the withdrawal of treatment. The intact hormone (1 - 84 amino acids) showed similar results on spine fractures, and more data are requested to evaluate its effect on non-spine or hip fractures. Strontium ranelate is suggested to be the first medication to uncouple bone formation from bone resorption. It has shown antifracture efficacy at all sites in a large number of postmenopausal women. New developments include: denosumab, an antibody against receptor activator of NF-kappaB ligand (RANKL); a cytokine that is responsible for osteoclastogenesis; and inhibitors of cathepsin K, a cysteine protease that is involved in the cleavage of collagen.

Antibodies, Monoclonal↗
PubMed2000

AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor.

Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.

Animals↗
PubMed2005

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands.

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ERalpha and ERbeta. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17beta-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ERalpha-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ERbeta-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139-151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ERbeta agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ERalpha-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

Adoptive Transfer↗
PubMed2002

Role of antiestrogens and aromatase inhibitors in breast cancer treatment.

This review explores the recent experience with, and the basis for, the use of selective estrogen receptor modulators to treat and prevent breast cancer. As new agents are unveiled, they will continue to be tested against tamoxifen. A number of new selective estrogen receptor modulators are in clinical development in an attempt to decrease the unwanted effects of tamoxifen. Raloxifene holds the promise of treating osteoporosis with the beneficial side effect of breast cancer prevention. Additionally, two different classes of hormonal agents, the aromatase inhibitors and estrogen receptor down-regulators, which have no estrogen-like properties at any site, appear to be promising new treatments for advanced breast cancer.

Aromatase Inhibitors↗
PubMed2003

DT56a (Tofupill/Femarelle) selectively stimulates creatine kinase specific activity in skeletal tissues of rats but not in the uterus.

The novel natural product DT56a (Tofupill/Femarelle), derived from soybean, has been shown to relieve menopausal vasomotor symptoms and to increase bone mineral density with no effect on sex steroid hormone levels or endometrial thickness. In the present study, we compared the effects of DT56a and estradiol-17beta (E2) on bone and cartilage (Ep) of immature or ovariectomized female rats, by measuring the changes in the specific activity of the BB isozyme of creatine kinase (CK). Single short-term injection of high doses of DT56a induced estrogenic activity in bones and uterus similar to that of E2. When administered in multiple oral doses, DT56a stimulated skeletal tissues similarly to E2, but whereas E2 increased CK specific activity in the uterus, DT56a did not. The selective estrogen receptor modulator (SERM) raloxifene (Ral) blocked the stimulation of CK by either DT56a or by E2 in all tissues tested. Our findings suggest that DT56a acts as a selective estrogen receptor modulator stimulating skeletal tissues without affecting the uterus. The effect of DT56a on other systems, such as the vascular and the central nervous system, are currently under investigation.

Animals↗
PubMed1999

The Molecular Pharmacology of SERMs.

Estrogen-containing medicines have been used successfully for the past 50 years for the treatment of conditions associated with menopause. Although initially considered a reproductive hormone, millions of years of clinical exposure to estrogen(s) have indicated that its influence extends to a variety of target tissues not generally considered to be involved in reproduction. Specifically, estrogen has positive actions in the skeleton, the cardiovascular system and possibly the central nervous system, activities that combine to have a positive impact on mortality and morbidity. However, despite the medical benefits afforded by estrogen replacement therapy, the number of women who initiate or remain on therapy for longer than one year is relatively small. This is due in part to the fear that estrogens increase the risk for breast cancer. Consequently, it was realized several years ago that novel estrogen receptor modulators were needed, which would retain the beneficial effects of estrogens in most target organs but be inactive in the breast. Although the perfect tissue-selective estrogen remains to be identified, progress in this direction has been made. In the past year, for example, we have seen selective estrogen receptor modulators (SERMs) enter into the clinic for the prevention of osteoporosis. Compounds of this class, which function as estrogens in the skeletal system but oppose estrogen action in the breast, are the first step in developing the perfect hormone replacement therapy. This review summarizes the complex pharmacology of the SERMs and illustrates how they differ mechanistically from estradiol, the physiological ligand of the estrogen receptor.

Journal Article↗
PubMed2005

Chronic estrogenic drug treatment increases preproenkephalin mRNA levels in the rat striatum and nucleus accumbens.

Estrogens modulate the expression of preproenkephalin (PPE) in the hypothalamus but little is known for other brain regions. The present study investigated the effect of hormonal withdrawal and replacement therapy on PPE expression in the striatum, nucleus accumbens and cortex. Ovariectomized Sprague-Dawley rats were treated for 2 weeks with estradiol, a specific ligand for estrogen receptor alpha (ERalpha), 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and estrogen receptor beta (ERbeta) 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), or the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene. Brain PPE mRNA levels, measured by in situ hybridization, were high in the striatum and nucleus accumbens compared to the low expression in the cortex. Ovariectomy decreased uterine weights compared to intact uterus, which was corrected by estradiol and PPT. Tamoxifen and raloxifene partially stimulated uterine weights while DPN left it unchanged. In the anterior, median and posterior striatum and in the core and shell of the nucleus accumbens, ovariectomy decreased PPE mRNA levels compared to intact rats, this was corrected by estradiol treatment except for the posterior striatum. PPT, DPN, tamoxifen and raloxifene reproduced the estradiol effect. In the prefrontal and cingulate cortices, neither ovariectomy nor treatments changed PPE mRNA levels. These results show for the first time that estradiol increases PPE mRNA in the striatum and nucleus accumbens. This effect is observed also with estrogen receptor agonists for the ERalpha and ERbeta as well as with SERMs.

Analysis of Variance↗
PubMed2005

TAS-108, a novel oral steroidal antiestrogenic agent, is a pure antagonist on estrogen receptor alpha and a partial agonist on estrogen receptor beta with low uterotrophic effect.

PURPOSE: Investigators are currently conducting phase II trials on TAS-108, a novel oral steroidal antiestrogenic agent. The purpose of this study is to investigate the molecular and pharmacologic properties of TAS-108 compared with other antiestrogenic agents such as tamoxifen,raloxifene, and fulvestrant. EXPERIMENTAL DESIGN: The antagonistic or agonistic activities of these agents against both estrogen receptors (ER) alpha and beta were compared in the reporter assay systems. Their effects on the uterus were evaluated in ovariectomized rat models. The antitumor activity of TAS-108 given p.o. was evaluated in both dimethylbenzanthracene-induced mammary tumor model and human breast cancer MCF-7 cell line xenografts. RESULTS: TAS-108 inhibited the transactivation of ERalpha under the presence of 17beta-estradiol (E2) and did not induce the transactivation of ERalpha in the absence of E2, unlike the agonistic activity of tamoxifen. On the other hand, it exhibited the most agonistic activity on ERbeta among the antiestrogenic agents tested. When given p.o. in the ovariectomized rat, TAS-108 showed a much weaker estrogenic effect on utterine weight compared to tamoxifen, or with similar levels of raloxifene, a selective estrogen receptor modulator. Also, TAS-108 strongly inhibited tumor growth in dimethylbenzanthracene-induced mammary carcinomain the rat, the endogenous E2 model, at a dosage of 1 to 3 mg/kg/day. It also inhibited high exogenous E2, inducing tumor growth against MCF-7 xenografts at a dosage of 1 mg/kg/day without any toxic manifestation. CONCLUSIONS: Taken together, p.o. treatment with TAS-108 has a novel mode of action on ERs and inhibits E2-dependent tumor growth with little uterotrophic effect.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2002

Chemoprevention of breast cancer: implications for postmenopausal women.

Estrogen administration is associated with reduction in perimenopausal symptoms and the risk for several conditions affecting postmenopausal women. As estrogen administration also increases the risk for breast cancer, a common dilemma facing many women and their physicians is whether to use estrogen replacement therapy (ERT), a selective estrogen receptor modulator (SERM) that antagonises estrogenic effects in breast tissue but retains some estrogen agonist properties in other organs, or neither. For women with average to moderate risk of breast cancer and with perimenopausal symptoms, ERT may be the best short-term choice. For very high-risk women (>1% per year) with menopausal symptoms, alternatives to ERT might be offered and tried first. A diagnosis of ductal carcinoma in situ or invasive breast cancer within the last 2 to 5 years should be considered a relative contraindication for ERT unless the tumour was estrogen receptor negative. High-risk women without menopausal symptoms are the best candidates for the only currently approved drug for breast cancer risk reduction, tamoxifen. Although the drug is approved for women with a 5-year risk of breast cancer > or = 1.7% (0.34% per year), postmenopausal women most likely to experience a favourable benefit/risk ratio are those with a Gail estimated risk of >0.5% per year without a uterus or >1% per year if they retain their uterus. Tamoxifen should not be used in women with prior history of thromboembolic or precancerous uterine conditions. Tamoxifen is often used in Europe in conjunction with transdermal ERT in hysterectomised women without obvious loss of efficacy or increased risk of thromboembolism. Raloxifene is a second generation SERM with estrogen-like agonist effects on bone but with less uterine estrogen agonist activity than tamoxifen. Raloxifene may have less potent breast antiestrogenic effects than tamoxifen, particularly in a moderate- to high-estrogen environment. Raloxifene is approved for use in reducing risk of osteoporosis, but not breast cancer. Whether it is as effective as tamoxifen in reducing breast cancer risk in postmenopausal women is the subject of a current trial. All women regardless of breast cancer risk are advised to employ nonpharmacological risk reduction measures, including normalisation of bodyweight, exercise, adequate calcium and vitamin D intake, and avoidance of smoking and alcohol. The preventive options are best weighed during an individualised consultation where a woman's menopausal symptoms and risk for breast cancer and other diseases can be examined, and the options for improving postmenopausal health can be discussed.

Anticarcinogenic Agents↗
PubMed2003

The role of estrogen and estrogen-related drugs in cardiovascular diseases.

The cardiovascular effects of estrogen have recently become a focus of basic and clinical cardiovascular medicine because of the multiplicity of its beneficial effects. Various basic and clinical studies have revealed that estrogen has potent cardiovascular effects against ischemic or non-ischemic injury of the heart and vessels, leading to the concept that administration of estrogen may reduce cardiovascular disease in postmenopausal women. Indeed, among the groups of the postmenopausal women who have a higher risk of cardiovascular diseases, the hormone therapy has been associated with improved outcomes for cardiovascular events. Estrogen binds to the estrogen receptor, which is a member of the steroid hormone family of nuclear receptors and is the estrogen response element in target genes, leading to the transcriptional regulation of many genes. In addition to these genomic effects of estrogen, it has been recently reported that estrogen can have rapid "nongenomic" effects. In contrast to such data, recent clinical prevention trials in postmenopausal women treated with a combination of estrogen and progestins have not revealed any beneficial effects on cardiovascular morbidity or mortality, and estrogen itself increases the risk of endometrial and breast cancer. Under these circumstances, a selective estrogen receptor modulator (SERM), which exerts estrogenic agonistic or antagonistic actions on various tissues, has been recently introduced for new hormone therapy because it reduces the adverse effects of estrogen. Here, we summarize the effects of estrogen and SERM on the cardiovascular system and discuss cellular mechanisms that may be involved.

Animals↗
PubMed2001

Beyond tamoxifen new endpoints for breast cancer chemoprevention, new drugs for breast cancer prevention.

Although tamoxifen appears to markedly reduce breast cancer risk in women with a prior diagnosis of atypical hyperplasia or in situ carcinoma, it is not clear what other groups of women receive substantial benefit. Major breast chemoprevention priorities are to (1) develop new agents that (a) have fewer side effects, (b) are effective in ER--as well as tamoxifen-resistant precancerous tissue, and (c) are compatible with hormone therapy; and (2) develop efficient clinical strategies including prognostic and predictive morphologic and molecular biomarkers. Breast tissue may be repeatedly sampled for evidence of intraepithelial neoplasia by fine needle aspiration, ductal lavage, or needle biopsy to select candidates at highest short-term risk as well as to monitor response in small proof of principle studies prior to a large cancer incidence trial. Molecular marker expression may also be used to select a cohort most likely to respond to a particular agent. A large number of new agents are attractive as potential prevention agents and some are already in clinical prevention testing. Compounds which should be effective in ER + precancerous tissue but may have a better side-effect profile include new selective estrogen receptor modulators which lack uterine estrogen agonist activity, isoflavones, aromatase inactivators/inhibitors for postmenopausal women, and gonadotropin-releasing hormone regimens for premenopausal women. Retinoids, rexinoids, and deltanoids may be efficacious in ER+ tissue resistant to tamoxifen. Agents which should theoretically have activity in ER- or ER+ precancerous tissue include polyamine synthesis inhibitors, tyrosine kinase inhibitors, combined demethylating agents and histone deacetylase inhibitors, as well as metalloprotease and angiogenesis inhibitors. Sample Phase I and Phase II clinical trial designs are reviewed using modulation of molecular markers and breast intraepithelial neoplasia as the major endpoints.

Aneuploidy↗
PubMed2005

Viral-mediated temporally controlled dopamine production in a rat model of Parkinson disease.

Regulation of gene expression is necessary to avoid possible adverse effects of gene therapy due to excess synthesis of transgene products. To reduce transgene expression, we developed a viral vector-mediated somatic regulation system using inducible Cre recombinase. A recombinant adeno-associated virus (AAV) vector expressing Cre recombinase fused to a mutated ligand-binding domain of the estrogen receptor alpha (CreER(T2)) was delivered along with AAV vectors expressing dopamine-synthesizing enzymes to rats of a Parkinson disease model. Treatment with 4-hydroxytamoxifen, a synthetic estrogen receptor modulator, activated Cre recombinase within the transduced neurons and induced selective excision of the tyrosine hydroxylase (TH) coding sequence flanked by loxP sites, leading to a reduction in transgene-mediated dopamine synthesis. Using this strategy, aromatic L-amino acid decarboxylase (AADC) activity was retained so that l-3,4-dihydroxyphenylalanine (L-dopa), a substrate for AADC, could be converted to dopamine in the striatum and the therapeutic effects of L-dopa preserved, even after reduction of TH expression in the case of dopamine overproduction. Our data demonstrate that viral vector-mediated inducible Cre recombinase can serve as an in vivo molecular switch, allowing spatial and temporal control of transgene expression, thereby potentially increasing the safety of gene therapy.

Animals↗
PubMed2005

Update on drug-induced depression in the elderly.

BACKGROUND: Depression is a common disorder in the elderly. Use of certain medications may be a potentially preventable cause of new-onset depression or worsening of established depression. OBJECTIVE: This paper reviews recent publications evaluating medications commonly used in the elderly as potential causes of depressive symptoms. METHODS: Relevant articles examining the association between medication use and symptoms of depression were identified through searches of MEDLINE (1996-March 2005) and International Pharmaceutical Abstracts (1996-March 2005) using the MeSH heading depression and the subheading chemically induced. Included articles were limited to those that discussed medications commonly used in the elderly and that employed a rigorous study design. RESULTS: A wide variety of medications have been implicated as potential causes of depressive symptoms in numerous reports, although many of these reports relied on data obtained from observational rather than experimental studies. The most extensively studied agents include anti hypertensives, lipid-lowering drugs, and selective estrogen-receptor modulators. The data on antihypertensive agents were contradictory; however, most studies found no association between use of the newer lipid-lowering drugs (statins) or selective estrogen-receptor modulators and the emergence of depressive symptoms. Corticosteroids, although not studied recently, generally have been associated with depressive symptoms in the older literature. CONCLUSIONS: The recent data evaluating whether medications can induce or worsen symptoms of depression are largely contradictory. This reflects a relative lack of controlled studies of this association and the difficulties in determining whether depressive symptoms are caused by a particular medication or by other factors. Nonetheless, when new or worsening symptoms of depression occur, medications should be considered a potential cause and withdrawn as appropriate. Nonpharmacologic and/or pharmacologic treatment is indicated for those whose depressive symptoms do not resolve.

Adrenal Cortex Hormones↗
PubMed2004

Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor alpha modulators.

The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.

Animals↗
PubMed2005

ERbeta-selective SERMs produce mnemonic-enhancing effects in the inhibitory avoidance and water maze tasks.

Estradiol (17beta-E2) can have mnemonic-enhancing effects; however, its mechanisms for these effects are not well-understood. The present studies examined effects of 17beta-E2 and selective estrogen receptor modulators (SERMs) on emotional and spatial memory of female, Long-Evans rats. First, whether or not 17beta-E2 has dose-dependent effects on inhibitory avoidance memory was investigated. Only the highest concentration of 17beta-E2 examined (10 microg), which produces physiological concentrations of E2, was effective at enhancing inhibitory avoidance memory (Experiment 1). Further studies were designed to elucidate whether SERMs may produce mnemonic effects similar to those of 17beta-E2. Compounds utilized were, the ERalpha-selective SERMs, propyl pyrazole triol (PPT) or 17alpha-E2, the ERbeta-specific SERMs, diarylpropionitrile (DPN) or 7,12-dihydrocoumestan (coumestrol), or vehicle (oil). Post-training administration of 10 microg 17beta-E2 or coumestrol enhanced memory in the inhibitory avoidance task compared to vehicle (Experiment 2). Memory in the water maze was enhanced by post-training administration of 17beta-E2, coumestrol, or DPN, compared to vehicle (Experiment 3). Co-administration of 17alpha-E2&DPN enhanced inhibitory avoidance memory similar to that seen following 17beta-E2 or coumestrol (Experiment 4). Administration of E2 2 h post-training was not effective at enhancing memory in the inhibitory avoidance or water maze tasks (Experiment 5). Lordosis of rats was enhanced by 17beta-E2, 17alpha-E2, or PPT, compared to vehicle (Experiment 6). These data suggest that: E2's actions at ERbeta, rather than ERalpha, may enhance spatial memory, E2's actions at ERalpha can facilitate sexual behavior, and that E2's actions involving both ERalpha and ERbeta may be important for emotional memory.

Animals↗