Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gender-specific differences in susceptibility to a number of disorders related to catecholaminergic systems, including depression and hypertension, have been postulated to be mediated, at least in part, by estrogens. In this study, we examined if estrogens may regulate gene expression of norepinephrine biosynthetic enzymes. Administration of five injections of 15 or 40 microg/kg estradiol benzoate to ovariectomized (OVX) female rats elicited a dose-dependent elevation in mRNA levels of tyrosine hydroxylase (TH) in locus coeruleus, to as great as 3-fold over control. Dopamine beta-hydroxylase (DBH) mRNA levels were also similarly increased. To examine the mechanism, PC12 cells were cotransfected with luciferase reporter constructs under control of DBH or TH promoters [pDBH/Luc(-2,236/+21) or pTH/Luc(-272/+27 or -773/+27)] with an expression vector for estradiol receptor alpha. The cells were treated with 17beta-estradiol (E(2)) for 12-36 h. E(2) triggered a several fold increase in luciferase activity under control of the DBH promoter in a dose-dependent fashion. Omission of estrogen receptor alpha or addition of the estrogen receptor antagonist ICI 182,780 prevented the DBH promoter-driven increase in luciferase. When E(2) was given with 0.2 mM CPT-cAMP, reporter activity with pDBH/Luc(-2,236/+21) was increased greater than with either treatment alone. In contrast, addition of E(2) to cells transfected with pTH/Luc(-272/+27) elicited no change in basal luciferase activity nor in the response to 0.2 mM CPT-cAMP. These findings are the first to reveal that estrogen can stimulate DBH gene expression. Differing mechanisms may underlie the regulation of TH and DBH gene expression by estrogens.
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PMID:Estradiol stimulates gene expression of norepinephrine biosynthetic enzymes in rat locus coeruleus. 1191 91

Estradiol influences Ca(2+) regulation and Ca(2+)-dependent synaptic plasticity, suggesting estrogenic effects on Ca(2+)-dependent enzymes that regulate synaptic plasticity may mediate hormonal influences on cognition. In ovariectomized female rats, injections of estradiol benzoate (EB, 10 microg) reduced hippocampal cytosolic activity of serine/threonine protein phosphatases, calcineurin and protein phosphatase 1 (PP1). The decreased activity was rapid and recovered substantially over a 24-h period. Decreased calcineurin activity was associated with a decreased level of calcineurin in the cytosol. In contrast, expression of PP1 was not altered suggesting that the level of calcineurin activity regulated PP1 activity. EB application to hippocampal slices rapidly decreased cytosolic phosphatase activity, which was not blocked by the estrogen receptor antagonist, ICI 182780. Decreased phosphatase activity was associated with an increase in CA3-CA1 synaptic transmission. In addition, EB application shifted synaptic plasticity, blocking the induction of long-term depression and facilitating the establishment of long-term potentiation. The reduction in calcineurin activity and shift in synaptic plasticity were mimicked to a lesser extent by 17-alpha-estradiol. From these results we suggest that EB can act to rapidly influence Ca(2+) signaling pathways including the activity of Ca(2+)-regulated phosphatases involved in synaptic plasticity.
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PMID:Calcineurin as a potential contributor in estradiol regulation of hippocampal synaptic function. 1212 87

Periods of intense hormonal fluctuations have been associated with heightened prevalence and exacerbation of underlying psychiatric illness, particularly the occurrence of premenstrual dysphoria, puerperal depression and depressive symptoms during perimenopause. It has been speculated that sex steroids such as estrogens, progestogens, testosterone and dehydroepiandrosterone (DHEA) exert a significant modulation of brain functioning, possibly through interactions with various neurotransmitter systems. It is therefore intuitive that abrupt alterations of these hormones would interfere with mood and behaviour. On the other hand, accumulating data suggest that hormonal interventions may also promote relief or even remission of depressive symptoms, as already demonstrated in studies with patients experiencing postpartum depression and perimenopausal depressive disorders. The extent to which perimenopause, alone, may increase the risk for depression is unclear. However, existing data strongly suggest that some women are particularly vulnerable to developing significant physical and psychological disturbances when entering perimenopause. This article reviews the effect of sex hormones and selective estrogen receptor modulators (SERMs) on mood among peri- and postmenopausal women. There are preliminary, though promising, data on the use of estradiol (particularly transdermal estradiol) to alleviate depression during perimenopause, use of a combination of estrogens and selective serotonin reuptake inhibitors for depression during the postmenopausal period, and the use of testosterone to improve psychological well-being and increase libido among women with induced menopause. Further studies would help to better delineate the usage of hormones as an antidepressant strategy (monotherapy or augmenting treatment) for peri- and postmenopausal women. A brief review of some nonhormonal interventions for the treatment of menopause-related symptoms that may significantly affect a woman's quality of life is also presented. There are some preliminary data suggesting the efficacy of antidepressants for the treatment of hot flushes; existing data on diet supplements and herbal products have shown more mixed results.
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PMID:Effect of reproductive hormones and selective estrogen receptor modulators on mood during menopause. 1253 10

Osteoporosis is a silent disease that affects 10 million Americans; 80% of those affected are women. Although the disease is more common in postmenopausal Caucasian women, all ages and races are at risk. Osteoporosis can be a debilitating disease that can cause pain, fractures, depression, and social withdrawal. Signs of osteoporosis include kyphosis, loss of height, and protrusion of the abdomen. Because symptoms generally do not occur until after the disease has progressed, clinicians should include osteoporosis screening and preventative education as part of the regular gynecologic care. Diagnosis is typically made by a dual energy x-ray absorptiometry (DEXA) scan. Treatment consists of dietary and lifestyle changes, along with pharmacologic intervention. Although hormone therapy has been shown to be effective in preventing osteoporosis, the risks of long-term treatment with HRT are discussed. The following effective treatment options for women who have been diagnosed with the disease are discussed: bisphosphonates, calcitonin, and selective estrogen receptor modulators (SERMs). Because midwives regularly care for women of all ages, they are ideal candidates to provide women with preventative education, screening, counseling, and treatment.
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PMID:Pharmacotherapeutics for osteoporosis prevention and treatment. 1258 4

Numerous reports demonstrate the potency of estrogens to modulate brain function and their implications in schizophrenia and depression. The 5-HT(1A) receptor has been suggested to be implicated in depression and anxiety. Selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene, have estrogenic and/or antiestrogenic activity depending on the target tissue. Hence, SERMs have beneficial effects in skeleton and cardiovascular systems but act as antagonists in breast and uterus. The aim of the present study was thus to investigate in ovariectomized rats the effects of 17beta-estradiol, tamoxifen and raloxifene treatments on 5-HT(1A) receptor binding sites (agonist and antagonist) and mRNA levels in the hippocampal formation, prefrontal and cingulate cortex, as well as dorsal raphea nucleus which are known to express estrogen receptors (ER). Two weeks ovariectomy of female rats led to a 60% decrease of uterine weight, which was prevented by a 2-week 17beta-estradiol treatment; tamoxifen and raloxifene increased uterine weights by 35% and 15%, respectively, but significantly less than estradiol treatment. Specific binding to 5-HT(1A) receptors was determined by autoradiography of brain sections using the selective ligands: [3H]8-OH-DPAT and [3H]MPPF. Ovariectomy and hormone replacement therapy did not significantly affect 5-HT(1A) receptor agonist and antagonist specific binding sites as well as mRNA levels in all subregions of the hippocampus, prefrontal and cingulate cortex as well as dorsal raphea nucleus. Although the present treatments had functional effects as assessed with uterine weights, ovariectomy and estrogen-receptor directed drugs had no effect on hippocampal 5-HT(1A) receptors as compared to 5-HT(2A) receptors previously reported.
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PMID:Effect of chronic estradiol, tamoxifen or raloxifene treatment on serotonin 5-HT1A receptor. 1267 Jul 5

Estrogen may have an important role in the brain beyond the development and regulation of reproductive function. Gender differences in the incidence of depression suggest that regulation of mood represents one such action. The locus coeruleus, a brain stem noradrenergic nucleus implicated in mood regulation, concentrates [(3)H]estradiol, but expression of the two estrogen receptor (ER) subtypes (ERalpha and ERbeta) varies across species. Further, the role of each subtype in estrogen action on noradrenergic neurons is unknown. We examined the expression of ERs in the Cath.a (central-adrenergic-tyrosine-hydroxylase-expressing) cell line derived from mouse brain stem and found that they express ERbeta protein but not ERalpha protein. Transient transfection assays using an estrogen-responsive reporter gene indicate that ERbeta is functional. The pure estrogen antagonist ICI 182,780 completely abolished estrogen's effects. Selective ER modulator results suggest that ER in Cath.a cells behaves in a manner consistent with ERbeta pharmacology. R,R-Tetrahydrochrysene, an ERalpha agonist, had no effect on luciferase-driven activity in Cath.a cells. This study provides the first report of a cell line that spontaneously expresses functional ERbeta protein. Cath.a cells may prove to be a useful tool in elucidating basic pharmacologic properties of ERbeta. It may also help reveal the molecular mechanisms involved in mood regulation by estrogen.
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PMID:Expression of functional estrogen receptor beta in locus coeruleus-derived Cath.a cells. 1281 May 37

The discovery of the second estrogen receptor (ER) in 1995 surprised many endocrinologists and resulted in some scepticism regarding its physiological importance. However, 8 years later, it is clear that the multiple actions of estrogen in the body are mediated by two receptors that, although similar, are distinct gene products with non-overlapping functions. This clear delineation of the functions of the two receptors in such a short time was made possible by the development of ER alpha and ER beta knockout mice. The distinct patterns of tissue distribution of these two receptors has heightened interest in novel estrogen targets in the body and has led to awareness of new sites for pharmacological intervention in diseases such as depression, prostate dysfunction, leukaemia, inflammatory bowel disease and colon cancer.
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PMID:What pharmacologists can learn from recent advances in estrogen signalling. 1296 73

Macaques (Macaca spp.) are useful models to evaluate effects of ovarian sex steroids and selective estrogen receptor modulators (SERMs) on mood and cognitive function due to similarities to women in their reproductive and central nervous systems. The results of nonhuman primate studies support the hypothesis that estrogen mediates specific aspects of attention and memory, yet much work is needed to understand which cognitive processes are affected, whether natural versus surgical menopause effects are different, and the interaction of age and ovarian senescence on cognitive function. This knowledge is necessary to determine whether to support the cognitive function of women in the menopausal phase of life and, if so, to determine efficacious therapeutic interventions. Mood disorders are prevalent in women and are associated with reproductive function in women and macaques. Exogenous steroid therapies, including oral contraceptives and postmenopausal hormone replacement therapies, have behavioral effects in women and appear to affect the behavior and underlying neural substrates of monkeys. Additional research is necessary to confirm and extend these observations. Ovarian steroids have multiple effects on serotonin synthesis, reuptake, and degradation, on neural activity that drives serotonin release, and on receptor activation in primates. This system modulates cognitive function and mood and is the target of a broad class of antidepressant therapies. Understanding the effects of ovarian steroids on the neural serotonergic system is necessary to understand depression in women. These studies are best carried out in primate models, which are more similar to humans in neural serotonergic function than other animal models.
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PMID:Cognition, mood disorders, and sex hormones. 1511 38

Estradiol (E2) may influence depressive symptomology of women and decrease depressive behavior among rodents. The mechanism(s) for E2's antidepressant effects are not well understood. To determine whether antidepressant effects of E2 may involve actions at intracellular estrogen receptor (ER) alpha or beta isoforms, selective ER modulators (SERMs) were administered (10 microg sc) to ovariectomized rats 48 h before testing in the forced swim test, an animal model of depression, and the horizontal crossing task. Rats received sesame oil vehicle, 17beta-E2, which has a high affinity for ERalpha and ERbeta, SERMs that vary in their activity at ERalpha and beta, or a tricyclic antidepressant (desipramine; 30 mg/kg ip), as a positive control. ERalpha-selective SERMs were propyl pyrazole triol (PPT) and 17alpha-E2. PPT has more selective effects at ERalpha than does 17alpha-E2, which also binds ERbeta. ERbeta-selective SERMs were diarylpropionitrile (DPN) and 7,12-dihydrocoumestan (coumestrol). DPN is more selective at ERbeta than coumestrol, which also binds ERalpha. 17beta-E2, ERbeta-selective SERMs (DPN, coumestrol), and desipramine administration produced antidepressive behavior (decreased immobility, increased struggling and swimming). ERalpha-selective SERMs (PPT, 17alpha-E2) were not different from vehicle. There were no differences among groups in the number of beam breaks made in the horizontal crossing task. These data suggest that E2's antidepressive effects may involve actions at ERbeta.
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PMID:Antidepressant effects of ERbeta-selective estrogen receptor modulators in the forced swim test. 1525 Dec 61

Tamoxifen is a selective estrogen receptor modulator used in estrogen receptor-positive breast cancer. Tamoxifen is metabolized to an extremely potent antiestrogen by cytochrome P450 (CYP) 2D6, 2C9, and 3A isoforms. The selective serotonin reuptake inhibitors (SSRIs) are potent inhibitors of these CYPs. Since the prevalence of depression in breast cancer patients is nearly triple that of the general population, it is likely that a subgroup of breast cancer patients will receive long-term treatment with both an SSRI and tamoxifen. A case control design was used to investigate the possibility that a resultant decrease in production of the 4-hydroxy metabolite from chronic inhibition results in the attenuation of the antitumor effect of tamoxifen. Twenty-eight patients without recurrences of breast cancer (controls) were matched to an equal number of cases (recurrences) by cancer stage and year of diagnosis. Data were analyzed on all chronic medication exposure (> 3 months) in both cases and controls classified as to their status as CYP 2D6, 2C9, and 3A inhibitors, substrates, or inducers. No significant difference was found for CYP inhibitor or substrate exposure between cases and controls. Indeed, controls showed a slightly greater exposure to inhibitors of the relevant CYP isoforms compared to cases. These results suggested a trend toward the null hypothesis. It is unlikely that the effect of chronic exposure to potent CYP isoform inhibitors affects the antitumor effect of tamoxifen and its 4-hydroxy metabolite, supporting the safety of the continued practice of concomitant SSRI administration to breast cancer patients with depression.
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PMID:Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition. 1528 89


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