Biomedical subjects

O F Almeida

Publications and source records attributed to O F Almeida.

At least 19 recordsLinked to original sources

PubMed2001

Exposure to a novel stimulus reduces anxiety level in adult and aging rats.

Male Wistar rats aged 3, 15 and 24 months were isolated and housed individually for 72 h prior to being subjected to inanimate objects (two objects per rat, each 1.5 cm in diameter and 4 cm in length, made of surgical gauze). Following the exposure to the objects, rats were subsequently tested in an elevated plus-maze. The inanimate objects induced locomotor activity, chewing and transportation of the object. This changed to social interaction and play-like behavioral activity in rats of all ages that were kept in small groups with a latency of 1 to 2 min. One hour after the start of exposure, the animals were tested in the elevated plus-maze to measure anxiety behavior. It was found that all age groups spent significantly more time in the open arm of the elevated plus-maze than the corresponding controls. Latencies to first entry into open arms were also significantly lowered. The number of entries to the open or to the dark arm, however, did not show statistical difference, indicating that the novel object-induced activity failed to exert influence on gross motor activity in the elevated plus-maze. In conclusion, the stimulation elicited by the exposure to novel stimulus (inanimate objects) resulted in a significant reduction of anxiety level both in adult and in aging rats.

Aging↗

PubMed2000

Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement.

We recently demonstrated that stress-induced cognitive deficits in rats do not correlate with hippocampal neuronal loss. Working on the premise that subtle structural changes may however be involved, we here evaluated the effects of chronic stress on hippocampal dendrite morphology, the volume of the mossy fiber system, and number and morphology of synapses between mossy fibers and CA3 dendritic excrescences. To better understand the mechanisms by which stress exerts its structural effects, we also studied these parameters in rats given exogenous corticosterone. Further, to search for signs of structural reorganization following the termination of the stress and corticosterone treatments, we analysed groups of rats returned to treatment-free conditions. All animals were assessed for spatial learning and memory performance in the Morris water maze. Consistent with previous findings, dendritic atrophy was observed in the CA3 hippocampal region of chronically stressed and corticosterone-treated rats; in addition, we observed atrophy in granule and CA1 pyramidal cells following these treatments. Additionally, profound changes in the morphology of the mossy fiber terminals and significant loss of synapses were detected in both conditions. These alterations were partially reversible following rehabilitation from stress or corticosterone treatments. The fine structural changes, which resulted from prolonged hypercortisolism, were accompanied by impairments in spatial learning and memory; the latter were undetectable following rehabilitation. We conclude that there is an intimate relationship between corticosteroid levels, hippocampal neuritic structure and hippocampal-dependent learning and memory.

Animals↗

PubMed2000

Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate.

Glucocorticoid receptor (GR) activation induces apoptosis of granule cells in the hippocampus. In contrast, neuroprotection is seen after mineralocorticoid receptor (MR) activation. To date there is no in vivo evidence for direct interactions between corticosteroids and any of the key regulatory molecules of programmed cell death. In this report, we show that the opposing actions of MR and GR on neuronal survival result from their ability to differentially influence the expression of members of the bcl-2 gene family; specifically, in the rat hippocampus, activation of GR induces cell death by increasing the ratio of the proapoptotic molecule Bax relative to the antiapoptotic molecules Bcl-2 or Bcl-x(L); the opposite effect is observed after stimulation of MR. The same results were obtained in both young and aged animals; however, older subjects (which were more susceptible to GR-mediated apoptosis) tended to express the antiapoptotic genes more robustly. Using a loss-of-function mouse model, we corroborated the observations made in the rat, demonstrating Bax to be essential in the GR-mediated cell death-signaling cascade. In addition, we show that GR activation increases and MR activation decreases levels of the tumor suppressor protein p53 (a direct transcriptional regulator of bax and bcl-2 genes), thus providing new information on the early genetic events linking corticosteroid receptors with apoptosis in the nervous system.

Aging↗

PubMed1999

Stress- and corticosteroid-induced modulation of the locomotor response to morphine in rats.

Stress alters the sensitivity to drugs of abuse and is, therefore, considered to be an important contributory factor to drug-seeking behaviour. There is only a limited amount of information available on stress-induced alterations in the behavioural response to opioids. We thus evaluated the influences of different stressors (restraint, handling, social defeat) on the locomotor effects induced by morphine. Further the importance of additional factors such as the number of stress events or the delay between stress and locomotor testing on stress-induced alterations were evaluated. Since these modulatory effects of stress on the locomotor effects of morphine might be mediated via the release of endogenous corticosteroids we also tested the influence of repeated intermittent and chronic administration of corticosterone (CORT) and the synthetic corticosteroid dexamethasone (DEX) on the locomotor response to morphine. Enhanced morphine-induced locomotor activity was observed in response to the repeated application (three times) of all stressors: restraint, handling and social defeat. An augmentation of the locomotor effects of a low (1 and 5 mg/kg) but not of a high dose (10 mg/kg) of morphine was seen after three, but not after one stress event. In addition, the repeated application of restraint stress (three times) resulted in an augmentation of morphine-induced locomotor stimulation 3 days, but not 1 or 10 days , after the last stress event. Similarly the repeated intermittent and chronic administration of corticosteroids, in particular of DEX, increased morphine's efficacy in stimulating locomotor activity. Our results show that stress is able to alter the locomotor stimulant effects of morphine in rats--a phenomenon called stress-induced behavioural sensitization. Moreover, these stress-induced alterations depend upon temporal factors such as number of stress events and the interval between stress and locomotor testing. Further, stress-induced CORT-release seems to be involved in stress-induced behavioural sensitization to morphine.

Adrenal Cortex Hormones↗

PubMed1999

Ligand and subfield specificity of corticoid-induced neuronal loss in the rat hippocampal formation.

Adult male rats were treated chronically with the selective type II corticosteroid receptor agonist dexamethasone, with dexamethasone plus aldosterone, a selective type I receptor agonist, and with a supraphysiological dose of corticosterone sufficient to occupy both type I and type II receptors; injection-free and oil (vehicle)-treated rats served as controls. Following one month of treatment, the animals were killed and their brains were processed for stereological assessment of volumes and total numbers of neurons in the hippocampal formation. Dexamethasone treatment resulted in significant reductions in the total number of dentate granule and the CA3 pyramidal cells and in the volumes of some layers of these subfields; however, this steroid did not influence any morphometric parameter in the CA1 subfield, and the number of hilar cells was also unaltered. In contrast to the results obtained with dexamethasone, the other two groups of corticoid injected animals did not reveal changes in total cell numbers in any of the subfields of the hippocampal formation, although in the corticosterone-treated group a reduction in the volumes of the hilus and of the stratum radiatum of the CA3 subfield was observed. The present data show that the exclusive activation of type II corticosteroid receptors results in subfield-specific neuronal loss in the hippocampal formation of rats. This type II receptor-mediated neuronal loss can, however, be abrogated by the simultaneous stimulation of type I corticosteroid receptors. Together, these findings extend and support previous studies which suggested that activation of type I corticosteroid receptors may promote neuronal survival and that neurodegeneration may be triggered by type II corticosteroid receptor stimulation. An important implication of this result is that elevated levels of the endogenous corticosteroid receptor ligands (e.g., during stress) is unlikely to cause severe structural damage to the hippocampal formation due to the contemporaneous occupation of type I receptors.

Aldosterone↗

PubMed1999

Plasticity of hippocampal corticosteroid receptors during aging in the rat.

Aging is commonly associated with dysregulation of the hypothalamo-pituitary-adrenal axis and cognitive impairment. On the basis of suggestions that these disruptions ensue from changes in the hippocampal complement of corticosteroid (mineralocorticoid and glucocorticoid) receptors (MR and GR), we examined the availability of hippocampal MR and GR by measuring the in vivo uptake of 3H-aldosterone and 3H-dexamethasone (selective MR and GR agonists, respectively); MR and GR mRNA levels were also measured. We observed age-related declines in both the synthesis of MR and GR and the uptake of their respective ligands. Whereas MR mRNA levels and ligand uptake declined in parallel, GR binding declined more steeply than GR mRNA. This latter result, together with our finding that aged rats show impaired corticosteroid receptor mRNA and protein up-regulation after corticosteroid withdrawal, indicates decreased transcription of MR and GR genes and posttranslational modification of GR mRNA during aging. Given that corticosteroids can influence MR and GR synthesis and binding, and based on the finding that aged subjects show reduced basal secretion of corticosterone, we propose that this relative hypocorticalism may be responsible for the changes observed in MR and GR activity, which then leads to disturbances in neuroendocrine regulation and cognitive function in aged subjects.

Aging↗

PubMed1999

European Neuroendocrine Association--ninth meeting. 3-7 September 1999, Odense, Denmark.

The Ninth Meeting and Workshops of the European Neuroendocrine Association (ENEA) were held in Odense, Denmark. Training workshops covering topics of interest to basic and clinical neuroendocrinologists occupied the first two days of the meeting; on the remaining 3 days, sessions were organized into meet-the professor sessions, plenary lectures, symposia, and free oral and poster communications. The symposia covered most of the principal areas of neuroendocrinology which have important clinical implications (regulation of growth and metabolism, neuroendocrine tumors, hypogonadism, and hormone resistance syndromes), but some symposia covered more basic research in the field (neuroendocrinology of behavior, mutant mouse models, neuronal plasticity and the molecular biology of pituitary tumors). Papers in the free communication sessions generally interphased well with the themes of the symposia.

Journal Article↗

PubMed1999

Steroid action in neural and neuroendrocine systems.

Five papers were presented at the symposium on new aspects of steroid action on neural and neuroendocrine systems which was held within the framework of the Fifth International Brain Research Organization's (IBRO) World Congress of Neuroscience, held from 11-15 July 1999. The symposium was organized and chaired by Gabor Makara (Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary). Results from behavioral, endocrinological, cellular, molecular and neuroanatomical aspects of steroid actions in the brain were used to illustrate that steroid hormones can influence neural function by both rapid (cell membrane-mediated) and slower (gene transcription-dependent) mechanisms. The data reported were discussed in the context of their significance to brain physiology and pathophysiology, and consideration was given to particular aspects which could be of relevance to the use of steroids for the prevention and treatment of brain disorders.

Journal Article↗

PubMed1998

Gender differences in ethanol preference and ingestion in rats. The role of the gonadal steroid environment.

An ethanol oral self administration paradigm showed the existence of gender differences in alcohol preference in rats: whereas males and females initiated alcohol drinking at similar rates, females maintained their preference for ethanol over a longer duration. Neonatal estrogenization of females, which effectively confers a male phenotype on a genetically female brain, resulted in patterns of drinking that were similar to those displayed by intact male rats, indicating that gender differences in alcohol drinking patterns may be, at least partially, accounted for by sexual differentiation of the brain. To test whether gonadal steroids also exert activational effects on ethanol-seeking behavior, we also examined the effects of gonadectomy alone, or in combination with gonadal steroid replacement therapy. Castration did not significantly alter ethanol consumption in males, although treatment of castrated rats with dihydrotestosterone resulted in a significant inhibition of this parameter. As compared with the situation in intact female rats, ethanol ingestion was significantly reduced in ovariectomized female rats receiving estradiol (E2) and in ovariectomized female rats receiving combined E2 and progesterone replacement therapy. However, neither ovariectomy nor progesterone replacement in ovariectomized rats resulted in ethanol drinking patterns that were different compared to those observed in intact female controls. Thus, dihydrotestosterone and E2, respectively, appear to exert modulatory influences on the male and female rats' preference for ethanol, but further investigations are necessary to determine to what extent these effects result from activational actions on the brain.

Alcohol Drinking↗

PubMed1998

Gender specificity in the neural regulation of the response to stress: new leads from classical paradigms.

Pronounced gender-related differences are observable in the regulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) activity under basal and stress-related conditions, and by circulating glucocorticoid levels. This article reviews recent studies that have unequivocally demonstrated that these differences emerge from the organizational effects of gonadal steroids during early brain development. Although largely masked by the dominating role of glucocorticoids in maintaining feedback thresholds, gonadal steroids continue to exert gender-specific activational effects on the LHPA axis through adulthood. The importance of these modulatory effects of gonadal steroids may be reflected in gender differences in the incidence of psychopathologies that are accompanied by symptoms of LHPA dysregulation. One goal of this review is to highlight the need for further investigations into the (still elusive) cellular and molecular mechanisms underlying the activational effects of sex steroids, which may provide leads for neuroprotective hormone replacement strategies.

Animals↗

PubMed1998

Inherent glucocorticoid response potential of isolated hypothalamic neuroendocrine neurons.

Within the broader framework of facilitating investigations into the inherent responses of restricted neuronal phenotypes devoid of their in vivo afferents, serum- and steroid-free cultures enriched in corticotropin-releasing hormone (CRH), arginine vasopressin (AVP), and beta-endorphin (beta-END) peptidergic neurons were prepared from the hypothalamic paraventricular (PVN: CRH and AVP) and/or arcuate (ARC: beta-END) nuclei of juvenile male rats. The functional viability of these ARC/PVN cultures was verified by their ability to synthesize and secrete CRH, AVP, and beta-END under basal and depolarizing (veratridine) conditions in vitro. Peptide secretion was shown to be Ca2+ and Na+ dependent in that it was blocked in the presence of verapamil and tetrodotoxin, respectively. Exposure of ARC/PVN cocultures to the glucocorticoid dexamethasone (DEX) resulted in a dose-dependent increase of CRH secretion and an inhibition of AVP and beta-END; the CRH responses deviated strikingly from predictions based on in vivo experiments. Steroid withdrawal or treatment with the glucocorticoid receptor antagonist RU38486 reversed these trends. Opposite effects of DEX on CRH secretion were observed in cultures consisting of PVN cells only. Supported by studies using an opioid receptor agonist (morphine) and antagonist (naloxone), these observations demonstrate that ARC-derived (beta-END) neurons modulate the responses of PVN neurons to DEX.

Animals↗

PubMed1998

Chronic melatonin treatment counteracts glucocorticoid-induced dysregulation of the hypothalamic-pituitary-adrenal axis in the rat.

Transient exposure of rats to high doses of dexamethasone (DEX; 500 microg/day for 5 days) produced a host of symptoms that are indicative of hypothalamic-pituitary-adrenal (HPA) axis dysregulation, such as increased adrenocortical secretion over 24 h, blunted and prolonged secretory response to emotional stress, refractoriness of adrenocorticotropin in vitro release to stimulation with the secretagogues corticotropin-releasing hormone (CRH) and vasopressin, decreased levels of mRNA encoding type II corticosteroid receptors in the hippocampus and increased numbers of transcripts encoding CRH in the paraventricular nucleus. Daily administration of melatonin (MEL; 80 microg/kg) concomitantly with, and for 5 days after discontinuation of, glucocorticoid treatment 'normalized' most of the symptoms of impaired HPA regulation caused by the exposure to DEX. While none of the treatments used caused major shifts in circadian patterns of corticosterone secretion, MEL administration was associated with diminished overall corticosterone secretion and increased sensitivity to glucocorticoid feedback. Taken together, these findings indicate that chronic MEL treatment may protect several regulatory components of the HPA axis from glucocorticoid-induced deterioration.

Adrenal Glands↗

PubMed1998

Maintenance of hippocampal cell numbers in young and aged rats submitted to chronic unpredictable stress. Comparison with the effects of corticosterone treatment.

Exposure of rats to sustained stress has been associated with behavioural impairments, the degree of impairment being greater with increasing age of the subject. Although the behavioural deficits have been frequently attributed to stress-induced neuronal loss in the hippocampus, the validity of that view may be disputed since it is based on data collected using conventional morphometric methods which are subject to bias. The question of whether stress per se does indeed induce hippocampal cell losses was therefore re-examined using unbiased stereological tools in the present work. Specifically, we used the optical fractionator and the Cavalieri principle, to respectively estimate the total number of neurons and volumes of the main divisions of the hippocampal formation of young and old rats which had been exposed for 1 month to an unpredictable stress paradigm. The efficacy of the treatment was confirmed by elevated serum corticosterone levels measured at various intervals during the experimental period. In order to evaluate whether any deleterious effects might have occurred merely due to the stress-induced elevations in corticosterone secretion, we conducted a parallel study on animals that were injected with corticosterone over a similar duration. Neither stress nor treatment with corticosterone was found to result in significant cell losses in any division of the hippocampal formation; likewise, neither treatment produced significant volumetric differences. Further, these results were not influenced by age of the experimental subjects. The present findings therefore call for a reappraisal of the hypothesis that hippocampal cell loss accounts for the behavioural impairments observed by others following prolonged stress and/or chronic elevation of serum corticosterone levels.

Aging↗

PubMed1997

Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events.

Stressful experience during early brain development has been shown to produce profound alterations in several mechanisms of adaptation, while several signs of behavioral and neuroendocrine impairment resulting from neonatal exposure to stress resemble symptoms of dysregulation associated with major depression. This study demonstrates that when applied concomitantly with the stressful challenge, the steroid GABA(A) receptor agonist 3,21-dihydropregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) can attenuate the behavioral and neuroendocrine consequences of repeated maternal separation during early life, e.g., increased anxiety, an exaggerated adrenocortical secretory response to stress, impaired responsiveness to glucocorticoid feedback, and altered transcription of the genes encoding corticotropin-releasing hormone (CRH) in the hypothalamus and glucocorticoid receptors in the hippocampus. These data indicate that neuroactive steroid derivatives with GABA-agonistic properties may exert persisting stress-protective effects in the developing brain, and may form the basis for therapeutic agents which have the potential to prevent mental disorders resulting from adverse experience during neonatal life.

Adrenal Cortex↗

PubMed1997

Chronic alcohol consumption and withdrawal do not induce cell death in the suprachiasmatic nucleus, but lead to irreversible depression of peptide immunoreactivity and mRNA levels.

There is evidence that chronic ethanol treatment (CET) disrupts the biological rhythms of various brain functions and behaviors. Because the suprachiasmatic nucleus (SCN) is widely recognized as the dominant pacemaker of the circadian system, we have examined the effects of CET and withdrawal on the main morphological features and chemoarchitecture of this hypothalamic nucleus. Groups of rats ethanol-treated for 6 and 12 months were compared with withdrawn rats (ethanol-treated for 6 months and then switched to a normal diet for an additional 6 months) and with groups of age-matched control and pair-fed control rats. The volume and the total number of neurons of the SCN were estimated from conventionally stained material, whereas the total number of astrocytes and of neurons containing vasopressin (AVP), vasoactive intestinal polypeptide (VIP), gastrin-releasing peptide (GRP), and somatostatin (SS) were estimated from immunostained sections. The estimates were obtained using unbiased stereological methods, based on Cavalieri's principle and the optical fractionator. The volume of the SCN and the total number of SCN neurons and astrocytes did not vary among groups. We found, however, that CET induced a significant reduction in the total number of AVP-, VIP-, GRP-, and SS-containing neurons. Withdrawal from alcohol did not reduce but rather augmented the loss of VIP- and GRP-immunoreactive neurons. The CET-induced neurochemical alterations seem to result from a decrease in neuropeptide synthesis, as revealed by the reduction in AVP and VIP mRNA levels demonstrated by in situ hybridization with radioactively labeled 48-mer AVP and 30-mer VIP probes. It is thus possible to conclude that the irreversible CET-induced changes in the neurochemistry of the SCN might underpin the disturbances in circadian rhythms observed after long-term alcohol consumption.

Alcohol Drinking↗

PubMed1997

Activational effects of gonadal steroids on hypothalamo-pituitary-adrenal regulation in the rat disclosed by response to dexamethasone suppression.

Previous studies demonstrated that gonadal steroids secreted during perinatal life permanently 'organize' the mechanisms governing hypothalamo-pituitary-adrenal (HPA) function, leading to sexually differentiated patterns of pituitary-adrenal activity under basal and stress conditions. In this paper, we show that gonadal steroids can also exert 'activational' effects upon the HPA system. Examination of the ability of different doses of dexamethasone to suppress the nocturnal increase in corticosterone secretion and to attenuate the gene expression of CRH in the hypothalamic paraventricular nucleus of intact and gonadectomized male and female rats revealed that ovarian steroids make an important contribution to the higher sensitivity of the pituitary-adrenal axis in females to glucocorticoid suppression, whereas testicular steroids may be causal to the male's moderate responsiveness to glucocorticoid feedback. These findings may be implicated in a number of psychiatric and neurological disease states commonly associated with impaired HPA regulation, but which may be primarily rooted in altered gonadal steroid secretion.

Adrenal Glands↗

PubMed1997

Chronic melatonin treatment and the hypothalamo-pituitary-adrenal axis in the rat: attenuation of the secretory response to stress and effects on hypothalamic neuropeptide content and release.

The pituitary-adrenal secretory response to acute and chronic stress, suppressibility of adrenocortical secretions by exogenous glucocorticoids, and hypothalamic content and in vitro release of the two major peptidergic activators of the hypothalamo-pituitary-adrenal (HPA) axis, corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP), were examined in rats receiving daily melatonin (MEL) injections coincident with the circadian increment of endogenous pineal and adrenocortical secretory activity. After 7 days of MEL administration, the rats displayed a significant attenuation of the adrenocortical secretory response to acute and chronic stress. Chronic MEL treatment also prevented the decline in adrenocorticotropic hormone (ACTH) release resulting from chronic stress exposure. Hypothalamic CRH content was significantly lower in rats receiving MEL treatment, while AVP remained largely unaltered; however, MEL administration counteracted the chronic stress-induced decrease in hypothalamic AVP content and in vitro release. When exposed to dexamethasone in vitro, hypothalamic explants from MEL-treated rats responded with a stronger suppression of CRH and AVP release than those originating from vehicle-injected animals. These observations indicate that MEL attenuates the adrenocortical response to stress and influences the biosynthesis, release and glucocorticoid responsiveness of hypothalamic ACTH secretagogues.

Adrenocorticotropic Hormone↗

PubMed1996

Gonadal steroids exert facilitating and "buffering" effects on glucocorticoid-mediated transcriptional regulation of corticotropin-releasing hormone and corticosteroid receptor genes in rat brain.

Gonadal steroids profoundly influence several brain functions and are apparently responsible for gender-specific differences in the regulation of hypothalamic-pituitary-adrenal (HPA) secretions. In this study, we examined the so-called "activational" effects of gonadal steroids on the glucocorticoid-mediated regulation of the gene transcription of corticotropin-releasing hormone (CRH) and corticosteroid receptors in brain areas of relevance for the control of pituitary-adrenal secretion. The efficacy of adrenalectomy (ADX) and chronic treatment with high doses of corticosterone (B) to regulate the gene transcription of CRH and corticosteroid receptors in the hypothalamic paraventricular nucleus (PVN) and hippocampus was studied in male and female rats under the conditions of deprivation of gonadectomy (GDX) and replacement with different gonadal steroids, such as estradiol (E2), progesterone (P), and dihydrotestosterone (DHT). In both sexes, ADX alone or in combination with GDX increased, and B treatment suppressed, the steady-state levels of CRH and corticosteroid receptor mRNAs, whereas GDX alone failed to affect any of the parameters studied. Administration of gonadal hormones to steroid-deprived (ADX/GDX) animals partially attenuated the upregulation of mRNAs encoding corticosteroid receptors in the hippocampus. Supplementation with gonadal steroids modified the effects of B on the gene transcription of CRH and corticosteroid receptors. Whereas P alone or in combination with E2 counteracted the B-induced downregulation of GR and CRH gene transcription in females, DHT and E2 administration further potentiated the effects of B on these parameters in a sex-specific manner. Taken together, the results indicate that gonadal steroids have minor influence on MR, GR, and CRH gene transcription under basal conditions, exert "glucocorticoid-like" effects on the transcription of corticosteroid receptors in the hippocampus of steroid-deprived animals, and interact with glucocorticoid-mediated mechanisms of regulation in the HPA axis through gender-specific "buffering" and "potentiating" effects.

Adrenal Glands↗