RESUMEN
S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties. Here, the drug was assessed in the perinatal stress (PRS) rat model, known to have a high predictive validity with monoaminergic antidepressants. The effects of a chronic treatment (i.p.) with S 47445 were investigated on risk-taking, motivational and cognitive behavior. S 47445 (1 and 10â¯mg/kg) increased the exploration of the elevated-plus maze and light/dark box as well as the time spent grooming in the splash test, and improved social memory in PRS rats. Also, the effects of S 47445 were examined on the synaptic neurotransmission. The reduced depolarization-evoked glutamate release induced by PRS was corrected with S 47445 (10â¯mg/kg). Remarkably, the reduction in glutamate release induced by PRS and corrected by S 47445 chronic treatment was correlated with all the behavioral changes. S 47445â¯at 10â¯mg/kg also normalized the lower levels of synaptic vesicle-associated proteins in ventral hippocampus in PRS rats. Finally, S 47445 reversed the decrease of mGlu5 receptors, GR and OXTR induced by PRS. Collectively, in an animal model of stress-related disorders, S 47445 corrected the imbalance between excitatory and inhibitory neurotransmission by regulating glutamate-evoked release that is predictive of PRS behavioral alterations, and also normalized the reduction of trafficking of synaptic vesicles induced by PRS. These results support the interest of glutamatergic-based therapeutic strategies to alleviate stress-related disorders.
Asunto(s)
Benzoxazinas/farmacología , Cognición/efectos de los fármacos , Emociones/efectos de los fármacos , Ácido Glutámico/metabolismo , Efectos Tardíos de la Exposición Prenatal/prevención & control , Estrés Psicológico/metabolismo , Triazinas/farmacología , Animales , Femenino , Hipocampo/metabolismo , Masculino , Proteínas del Tejido Nervioso/metabolismo , Embarazo , Ratas , Receptor del Glutamato Metabotropico 5/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Oxitocina/metabolismoRESUMEN
During the perinatal period, the brain is particularly sensitive to remodelling by environmental factors. Adverse early-life experiences, such as stress exposure or suboptimal maternal care, can have long-lasting detrimental consequences for an individual. This phenomenon is often referred to as 'early-life programming' and is associated with an increased risk of disease. Typically, rodents exposed to prenatal stress or postnatal maternal deprivation display enhanced neuroendocrine responses to stress, increased levels of anxiety and depressive-like behaviours, and cognitive impairments. Some of the phenotypes observed in these models of early-life adversity are likely to share common neurobiological mechanisms. For example, there is evidence for impaired glucocorticoid negative-feedback control of the hypothalamic-pituitary-adrenal axis, altered glutamate neurotransmission and reduced hippocampal neurogenesis in both prenatally stressed rats and rats that experienced deficient maternal care. The possible mechanisms through which maternal stress during pregnancy may be transmitted to the offspring are reviewed, with special consideration given to altered maternal behaviour postpartum. We also discuss what is known about the neurobiological and epigenetic mechanisms that underpin early-life programming of the neonatal brain in the first generation and subsequent generations, with a view to abrogating programming effects and potentially identifying new therapeutic targets for the treatment of stress-related disorders and cognitive impairment.
Asunto(s)
Conducta Animal , Epigénesis Genética , Animales , Encéfalo/embriología , Encéfalo/fisiología , Femenino , Ácido Glutámico/metabolismo , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Placenta/fisiología , Embarazo , Estrés FisiológicoRESUMEN
Rats exposed to early life stress are considered as a valuable model for the study of epigenetic programming leading to mood disorders and anxiety in the adult life. Rats submitted to prenatal restraint stress (PRS) are characterized by an anxious/depressive phenotype associated with neuroadaptive changes in the hippocampus. We used the model of PRS to identify proteins that are specifically affected by early life stress. We therefore performed a proteomic analysis in the hippocampus of adult male PRS rats. We found that PRS induced changes in the expression profile of a number of proteins, involved in the regulation of signal transduction, synaptic vesicles, protein synthesis, cytoskeleton dynamics, and energetic metabolism. Immunoblot analysis showed significant changes in the expression of proteins, such as LASP-1, fascin, and prohibitin, which may lie at the core of the developmental programming triggered by early life stress.
Asunto(s)
Hipocampo/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Ansiedad/metabolismo , Depresión/metabolismo , Femenino , Masculino , Proteínas de Microfilamentos/metabolismo , Trastornos del Humor/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Embarazo , Prohibitinas , Proteómica , Ratas , Ratas Sprague-Dawley , Proteínas Represoras/metabolismo , Restricción Física , Estrés Psicológico/metabolismo , Transferrina/metabolismoRESUMEN
We examined the interaction between early life stress and vulnerability to alcohol in female rats exposed to prenatal restraint stress (PRS rats). First we studied the impact of PRS on ethanol preference during adolescence. PRS slightly increased ethanol preference per se, but abolished the effect of social isolation on ethanol preference. We then studied the impact of PRS on short- and long-term responses to ethanol focusing on behavioral and neurochemical parameters related to depression/anxiety. PRS or unstressed adolescent female rats received 10% ethanol in the drinking water for 4 weeks from PND30 to PND60. At PND60, the immobility time in the forced-swim test did not differ between PRS and unstressed rats receiving water alone. Ethanol consumption had no effect in unstressed rats, but significantly reduced the immobility time in PRS rats. In contrast, a marked increase in the immobility time was seen after 5 weeks of ethanol withdrawal only in unstressed rats. Hippocampal levels of neuropeptide Y (NPY) and mGlu1a metabotropic glutamate receptors were increased at the end of ethanol treatment only in unstressed rats. Ethanol treatment had no effect on levels of corticotropin-releasing hormone (CRH) in the hippocampus, striatum, and prefrontal cortex of both groups of rats. After ethanol withdrawal, hippocampal levels of mGlu1 receptors were higher in unstressed rats, but lower in PRS rats, whereas NPY and CRH levels were similar in the two groups of rats. These data indicate that early life stress has a strong impact on the vulnerability and responsiveness to ethanol consumption during adolescence.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Etanol/farmacología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/fisiología , Animales , Conducta de Elección/fisiología , Cuerpo Estriado/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Femenino , Hipocampo/metabolismo , Pérdida de Tono Postural/efectos de los fármacos , Pérdida de Tono Postural/fisiología , Masculino , Neuropéptido Y/metabolismo , Corteza Prefrontal/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Aislamiento Social/psicologíaRESUMEN
Environmental changes that occur in daily life or, in particular, in situations like actual or simulated microgravity require neuronal adaptation of sensory and motor functions. Such conditions can exert long-lasting disturbances on an individual's adaptive ability. Additionally, prenatal stress also leads to behavioral and physiological abnormalities in adulthood. Therefore, the aims of the present study were (a) to evaluate in adult rats the behavioral motor adaptation that follows 14 days of exposure to simulated microgravity (hindlimb unloading) and (b) to determine whether restraint prenatal stress influences this motor adaptation. For this purpose, the authors assessed rats' motor reactivity to novelty, their skilled walking on a ladder, and their swimming performance. Results showed that unloading severely impaired motor activity and skilled walking. By contrast, it had no effect on swimming performance. Moreover, results demonstrated for the first time that restraint prenatal stress exacerbates the effects of unloading. These results are consistent with the role of a steady prenatal environment in allowing an adequate development and maturation of sensorimotor systems to generate adapted responses to environmental challenges during adulthood.
Asunto(s)
Suspensión Trasera , Actividad Motora/fisiología , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Estrés Fisiológico , Animales , Conducta Animal , Conducta Exploratoria/fisiología , Femenino , Miembro Posterior/fisiopatología , Masculino , Embarazo , Ratas , NataciónRESUMEN
We examined the influence of prenatal stress on alcohol preference in adult female rats exposed to an intense stress. To take into account interindividual variability, the study was conducted in animals categorized as low or high alcohol preferring. After footshock, control high-preferring rats strongly reduced their alcohol consumption; in contrast, alcohol consumption was not changed in high-preferring rats that were prenatally stressed.
Asunto(s)
Trastornos del Sistema Nervioso Inducidos por Alcohol/fisiopatología , Alcoholismo/fisiopatología , Trastornos de Ansiedad/fisiopatología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Estrés Fisiológico/complicaciones , Estrés Fisiológico/fisiopatología , Adaptación Psicológica/efectos de los fármacos , Adaptación Psicológica/fisiología , Trastornos del Sistema Nervioso Inducidos por Alcohol/etiología , Alcoholismo/etiología , Alcoholismo/psicología , Animales , Trastornos de Ansiedad/etiología , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Depresores del Sistema Nervioso Central/efectos adversos , Modelos Animales de Enfermedad , Estimulación Eléctrica/efectos adversos , Etanol/efectos adversos , Femenino , Embarazo , RatasRESUMEN
Antenatal glucocorticoids are highly effective in preventing respiratory distress of premature babies but can induce physiological and behavioral disturbances in young infants as well as in animals. Therefore, the hypothalamic-pituitary-adrenal (HPA) axis of rat neonates, and the consequences on behavioral development of offspring have been studied after five antenatal injections of dexamethasone (DEX) or vehicle. DEX decreased offspring body weight at birth, and significantly delayed the normal growth for the first 3 weeks of life. This paralleled diminished behavioral performances measured on postnatal day 3 (righting reflex) and postnatal day 10 (grasping test). Circulating levels of adrenocorticotrophin (ACTH) and corticosterone were significantly decreased on postnatal day 1 and this was related to a diminution of HPA axis activity shown by the decrease of central expression of corticotropin releasing hormone (CRH) mRNA, immunoreactive content in paraventricular neurons (PVN) and in the median eminence endings were significantly decreased. On the other hand, expression of another secretagogue of ACTH, arginine vasopressin (AVP), was differently affected in the PVN parvocellular neurons of offspring of the DEX group since AVP mRNA increased whereas immunoreactive content of the PVN parvocellular neurons was lowered. Simultaneously, the co-production of AVP and CRH in PVN neurons was stimulated. This can support the view that antenatal DEX reached the fetus and produced some damage which did not parallel that induced by prenatal stress of the pregnant females, especially the low body weight of offspring. The harmful consequence of antenatal DEX treatment was not restrictively due to the blunting of the HPA axis but also to the low body weight, which disturbed behavioral performances for the first weeks of life and could participate in other disorders in adult life.
Asunto(s)
Animales Recién Nacidos/fisiología , Conducta Animal/efectos de los fármacos , Glucocorticoides/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Hormona Adrenocorticotrópica/sangre , Animales , Arginina Vasopresina/biosíntesis , Arginina Vasopresina/metabolismo , Corticosterona/sangre , Hormona Liberadora de Corticotropina/biosíntesis , Hormona Liberadora de Corticotropina/metabolismo , Femenino , Fuerza de la Mano , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Hibridación in Situ , Tamaño de los Órganos/efectos de los fármacos , Equilibrio Postural/efectos de los fármacos , Embarazo , Desempeño Psicomotor/efectos de los fármacos , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Natación/psicologíaRESUMEN
Prenatal stress in the rat induces enhanced reactivity of the hypothalamus-pituitary-adrenal (HPA) axis, disturbances in a variety of circadian rhythms and increased anxiety-like behaviour. Such abnormalities parallel those found in human depressed patients. Prenatally stressed (PS) rats could represent, therefore, an interesting animal model for the evaluation of the efficacy of pharmacotherapeutic intervention in psychiatric disorders that has often been addressed using control animals. In the present study, PS and non-stressed rats were chronically treated with the tricyclic antidepressant imipramine (10 mg/kg i.p. for 21 days) and assessed in the forced swim test. Glucocorticoid receptor binding sites in the hippocampus were measured and 5-HT(1A) receptor mRNA levels in the frontal cortex were also assessed. PS rats were characterised by increased immobility in the forced swim test, reduced hippocampal corticosteroid receptor binding and increased levels of cortical 5-HT(1A) mRNA. All these parameters were significantly reversed by chronic imipramine treatment. Conversely, no significant effects were observed for non-stressed rats. All these effects are consistent with the expected pharmacotherapy of depression-like abnormalities in PS rats. These results further indicate that PS rats are a relevant animal model of depression.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Corteza Cerebral/metabolismo , Hipocampo/metabolismo , Imipramina/farmacología , Actividad Motora/efectos de los fármacos , ARN Mensajero/biosíntesis , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Glucocorticoides/efectos de los fármacos , Estrés Psicológico/psicología , Animales , Química Encefálica/fisiología , Corteza Cerebral/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Natación/psicologíaRESUMEN
There is growing evidence that prenatal adversities could be implicated in foetal programming of adult chronic diseases. Since maternal stress is known to disturb the foetal glucocorticoid environment, we examined the consequences of prenatal stress on foetal growth, on glucose-insulin metabolism and on feeding behaviour in the aged male rat. In foetuses at term, maternal stress reduced body, adrenal and pancreas weight as well as plasma corticosterone and glucose levels. In aged male rats (24 months of age), prenatal stress induced hyperglycaemia and glucose intolerance and decreased basal leptin levels. Moreover, after a fasting period, they showed an increased food intake. These data suggest that maternal stress induces a long-lasting disturbance in feeding behaviour and dysfunctions related to type 2 diabetes mellitus. This programming could be linked to the early restricted foetal growth and to the adverse glucocorticoid environment in utero.
Asunto(s)
Envejecimiento/fisiología , Conducta Alimentaria , Retardo del Crecimiento Fetal/etiología , Intolerancia a la Glucosa/etiología , Efectos Tardíos de la Exposición Prenatal , Estrés Psicológico/complicaciones , Glándulas Suprarrenales/anatomía & histología , Animales , Peso al Nacer , Glucemia/análisis , Corticosterona/sangre , Femenino , Leptina/sangre , Masculino , Tamaño de los Órganos , Páncreas/anatomía & histología , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Following the hypothesis of the "signal-to-noise" ratio we examined whether changes in the activity of group-I metabotropic glutamate (mGlu) receptors in the hippocampus are associated with a condition that specifically enhances the learning capacity in rats. As a model, we used rats that had been nursed by mothers drinking a solution of corticosterone (13.5 mg of daily intake of corticosterone hemisuccinate) during the lactation period. These rats were prone to learn, as indicated by a better performance in a passive avoidance test. Stimulation of polyphosphoinositide (PI) hydrolysis by the mGlu receptor agonist, 1S,3R-1-amino-cyclopentan-1,3-dicarboxylic acid (1S,3R-ACPD), was attenuated in hippocampal slices prepared from corticosterone-nursed male and female rats at 30 or 60 days of postnatal life, an age at which an increased learning capacity could be demonstrated. This effect was specific because the PI response to carbamylcholine was unchanged. A reduced PI hydrolysis in corticosterone-nursed rats was also observed when group-I mGlu receptors (i.e. mGlu1 and -5 receptors) were selectively activated using 3,5-dihydroxyphenylglycine or 1S,3R-APCD combined with the selective group-II mGlu receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propionate. Western blot analysis showed a selective reduction in the expression of mGlu1a receptor protein in the hippocampus of corticosterone-nursed rats, whereas expression of mGlu5 and mGlu2/3 receptors was unchanged. The reduction in mGlu-receptor mediated PI hydrolysis in the hippocampus may contribute to the greater learning capacity of corticosterone-nursed rats by reducing the background noise over which a specific signal must be superimposed during learning. This hypothesis was supported by the evidence that mGlu-receptor stimulated PI hydrolysis was amplified in hippocampal slices from rats subjected to a passive avoidance learning paradigm, and that this amplification was greater in slices from corticosterone-nursed rats of both sexes.
Asunto(s)
Aprendizaje por Asociación/fisiología , Reacción de Prevención/fisiología , Hipocampo/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Animales , Western Blotting , Corticosterona/administración & dosificación , Corticosterona/fisiología , Cicloleucina/análogos & derivados , Cicloleucina/farmacología , Femenino , Hipocampo/metabolismo , Hidrólisis , Lactancia , Masculino , Fosfatos de Fosfatidilinositol/metabolismo , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismoRESUMEN
Prenatally-stressed (PS) rats are characterized by a general impairment of the hypothalamo-pituitary-adrenal (HPA) axis and sleep disturbances indicating that this model has face validity with some clinical features observed in a subpopulation of depressed patients. The prolonged corticosterone secretion shown by PS rats in response to stress was positively correlated with an increased immobility behavior in the forced swim test. To investigate the predictive validity of this model, a separate group of animals was chronically treated with the antidepressant tianeptine (10 mg/kg i.p. for 21 days). Such chronic treatment reduced in PS rats immobility time in the forced swim test. These findings suggest that the PS rat is an interesting animal model for the evaluation of antidepressant treatment.
Asunto(s)
Antidepresivos Tricíclicos/uso terapéutico , Inmovilización , Efectos Tardíos de la Exposición Prenatal , Estrés Fisiológico/tratamiento farmacológico , Tiazepinas/uso terapéutico , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Corticosterona/sangre , Modelos Animales de Enfermedad , Femenino , Masculino , Embarazo , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Estrés Fisiológico/metabolismo , Natación , Factores de TiempoRESUMEN
We have shown that prenatal restraint stress (PNRS) induces higher levels of anxiety, greater vulnerability to drugs, a phase advance in the circadian rhythm of locomotor activity and an increase in the paradoxical sleep in adult rats. These behavioral effects result from permanent modifications to the functioning of the brain, particularly in the feedback mechanisms of the hypothalamic-pituitary-adrenal (HPA) axis: the secretion of corticosterone is prolonged after stress and the number of the central glucocorticoid receptors is reduced. These abnormalities are associated with modifications in the synthesis and/or release of certain neurotransmitters. Dysfunction of the HPA axis is due, in part, to stress-induced maternal increase of glucocorticoids, which influences fetal brain development. Some biological abnormalities in depression can be related to those found in PNRS rats reinforcing the idea of the usefulness of PNRS rats as an appropriate animal model to study new pharmacological approaches.
Asunto(s)
Glucocorticoides/sangre , Estrés Fisiológico/embriología , Animales , Trastornos de Ansiedad/fisiopatología , Conducta Animal/fisiología , Depresión , Femenino , Predicción , Glucocorticoides/fisiología , Humanos , Conducta Materna/fisiología , Modelos Animales , Periodicidad , Embarazo , Estrés Fisiológico/fisiopatologíaRESUMEN
At least two major physiological systems are involved in the adaptation of the organism to environmental challenges: the circadian system and the stress reaction. This study addressed the possibility that interindividual differences in stress sensitivity and in the functioning of the circadian system are related. At 2 months of age, corticosterone secretion in response to a 20-min restraint stress was assessed in 9 Sprague-Dawley rats for which running wheel activity was recorded as a rhythmic behavioral marker of the circadian clock. Two weeks later, the adaptive response of the circadian system to an abrupt shift in the light:dark (LD) cycle was assessed in those rats using a jet-lag paradigm. Finally, after resynchronization to the new LD cycle, rats were transferred to constant darkness to assess the free-running period of their circadian rhythm of running-wheel activity. Results indicate that stress-induced corticosterone secretion was (1) positively correlated with the number of days to resynchronize the circadian activity rhythm to the new LD cycle, and with the value of its free-running period, and (2) negatively correlated with the intensity of daily locomotor activity. Those data, emphasizing the interactions between the stress response of an organism and the functioning of its circadian system, could explain interindividual differences in humans' susceptibility to shift work or other circadian-related disorders.
Asunto(s)
Ritmo Circadiano/fisiología , Estrés Fisiológico/fisiopatología , Enfermedad Aguda , Adaptación Fisiológica/fisiología , Animales , Corticosterona/sangre , Corticosterona/metabolismo , Femenino , Síndrome Jet Lag/fisiopatología , Actividad Motora/fisiología , Ratas , Ratas Sprague-Dawley , Restricción FísicaRESUMEN
The effects of a melatonin agonist, S-20098, included in the diet were tested on a specific effect of aging in hamsters: the marked decline in the phase shifting effects of a 6-h pulse of darkness on a background of constant light. In contrast to young hamsters, old hamsters fed with the control diet showed little or no phase shifts in response to a dark pulse presented in the middle of their inactive or active period. Old hamsters fed with S-20098 showed phase shifts that were ~70% of the ones in young animals and significantly greater than those in old controls. The phase advancing response to a dark pulse presented during the inactive period was dose dependent and reversed after S-20098 discontinuation. Melatonin included in the diet showed comparable restorative effects on the phase shifting response to a dark pulse in old hamsters. Replacement therapy with melatonin or melatonin-related compounds could prove useful in treating, preventing, or delaying disturbances of circadian rhythmicity and/or sleep in older people.
Asunto(s)
Acetamidas/farmacología , Envejecimiento/fisiología , Ritmo Circadiano/fisiología , Melatonina/farmacología , Actividad Motora/efectos de los fármacos , Acetamidas/sangre , Animales , Ritmo Circadiano/efectos de los fármacos , Cricetinae , Oscuridad , Luz , Masculino , Melatonina/agonistas , Mesocricetus , Actividad Motora/fisiología , FotoperiodoRESUMEN
Prenatal stress in rats can exert profound influence on the off spring's development, inducing abnormalities such as increased "anxiety", "emotionality" or "depression-like" behaviours.Prenatal stress has long-term effects on the development of the hypothalamo-pituitary-adrenal(HPA) axis and forebrain cholinergic systems. These long-term neuroendocrinological effects are mediated, at least in part, by stress-induced maternal corticosterone increase during pregnancy and stress-induced maternal anxiety during the postnatal period. We have shown a significant phase advance in the circadian rhythms of corticosterone secretion and locomotor activity in prenatally-stressed (PNS) rats. When subjected to an abrupt shift in the light-dark(LD) cycle, PNS rats resynchronized their activity rhythm more slowly than control rats. In view of the data suggesting abnormalities in the circadian timing system in these animals, we have investigated the effects of prenatal stress on the sleep-wake cycle in adult male rats. PNS rats exhibited various changes in sleep-wake parameters, including a dramatic increase in the amount of paradoxical sleep. Taken together, our results indicate that prenatal stress can induce increased responses to stress and abnormal circadian rhythms and sleep in adult rats.Various clinical observations in humans suggest a possible pathophysiological link between depression and disturbances in circadian rhythmicity. Circadian abnormalities in depression can be related to those found in PNS rats. Interestingly, we have recently shown that the increased immobility in the forced swimming test observed in PNS rats can be corrected by chronic treatment with the antidepressant tianeptine, or with melatonin or S23478, a melatonin agonist. Those results reinforce the idea of the usefulness of PNS rats as an appropriate animal model to study human depression and support a new antidepressant-like effect of melatonin and the melatonin agonist S23478.
Asunto(s)
Conducta Animal , Corticosterona/sangre , Depresión/etiología , Conducta Materna , Complicaciones del Embarazo/etiología , Efectos Tardíos de la Exposición Prenatal , Estrés Psicológico/complicaciones , Animales , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Ritmo Circadiano , Depresión/sangre , Depresión/tratamiento farmacológico , Depresión/fisiopatología , Depresión/psicología , Modelos Animales de Enfermedad , Femenino , Edad Gestacional , Conducta Materna/efectos de los fármacos , Actividad Motora , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/fisiopatología , Complicaciones del Embarazo/psicología , Ratas , Ratas Sprague-Dawley , Sueño , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/psicología , Factores de TiempoRESUMEN
Modern neurosciences are now able to open new avenues concerning an experimental approach to clinical neurosciences and psychiatry. Detection and prediction of potential vulnerabilities such as behavioral disturbances and neurodegenerative diseases, are urgent tasks leading to prevention that must be encouraged in parallel to the enormous efforts displayed for treatments. Besides possible genetic origins of diseases, environmental factors are now coming under scrutiny, and especially deleterious and challenging life events and stress occurring during prenatal and postnatal critical periods may orient brain functions towards deleterious developments. The hypothesis that will be examined is that early events might be at the origin of pathological transformations and symptoms after long periods of apparent normal abilities and behavioral homeostasis. We used models of prenatal stress and postnatal manipulations such as cross-fostering. It will be demonstrated that such events induce long-term changes, cognitive and emotional modifications appearing first, when offspring are adults, followed by cognitive defects later in life. Increased sensitivity of the hypothalamic pituitary-adrenal axis (HPA), the endocrine system controlling the secretion of stress hormones (corticoids), appears to be a major element of pathogenesis. HPA axis dysfunction appears very early after birth (3 days) and lasts for months. Cumulative exposure to high levels of hormones seems to be detrimental for some brain regions, especially the hippocampus and major neurotransmitter systems such as dopamine neurons. We evidenced that neuronal modifications in hippocampal region are correlated with behavioral and cognitive defects, relating environment, stress in early life, hormonal changes, long-term neuropathological processes and impaired cognition in aging. Moreover appears in offspring, when adults, a proneness to engage in drug dependence. These data emphasize the need to consider early environmental life events as etiological factors for delayed neuropsychiatric disturbances, neurodegenerative defects included. Moreover, they strengthen the interest for a longitudinal approach to promote experimental psychopathology.
RESUMEN
We describe a case of homozygosity due to the substitution of aspartic acid with histidine at position 63 of the protein encoded by the gene (known as HFE) associated with hereditary hemochromatosis. Liver biopsy did not disclose stainable iron accumulation; serum ferritin was elevated (639 ng/mL), while the transferrin saturation index was within the normal range (38.1%). As the patient was affected by chronic hepatitis C virus, the high serum ferritin could be attributed to this disease, a frequent occurrence. We also describe a case of heterozygosity for both the substitution of tyrosine with cysteine at position 282 and the substitution of histidine to aspartic acid at position 63 (so-called "compound heterozygosity"). The patient had the typical biochemical abnormalities of iron overload: transferrin saturation index of 53.1% and elevated serum ferritin (658 ng/mL). The removal of > 5 g of iron by phlebotomies did not precipitate iron deficiency. Although the patient refused to undergo liver biopsy, clinical evidence alone enabled a diagnosis of hemochromatosis. These two cases concord with the present scientific orientation, i.e.: 1) homozygosity for the major mutation is associated with the phenotypical (clinical) picture of hemochromatosis, but compound heterozygosity also determines significant iron metabolism abnormalities; 2) homozygosity for the minor mutation does not appear to determine important phenotypical abnormalities.
Asunto(s)
Hemocromatosis/genética , Mutación , Adulto , Biopsia , Ferritinas/sangre , Hemocromatosis/complicaciones , Hemocromatosis/patología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico , Heterocigoto , Homocigoto , Humanos , Hígado/patología , Masculino , Fenotipo , FlebotomíaRESUMEN
The anatomical and functional links between the hormone stress axis and the cortico-limbic brain regions which integrate emotion and motivation are well documented. It is important, considering the consequences of stress on the brain, to take into account the regulatory buffer capacities of the personality-cognitive processes. Another point of interest is evaluation of the long term effects of repeated life events on chronic environmental pressures which induce brain negative feedback defects and, subsequently, insidious cellular changes in regions such as the hippocampus that lead to memory or adaptive impairments. An example is provided by perinatal stress that induces, later in life, both hormonal and cognitive deleterious changes.
Asunto(s)
Corticoesteroides/fisiología , Encéfalo/fisiología , Glucocorticoides/fisiología , Animales , Humanos , Sistema Límbico/fisiología , Estrés Fisiológico/fisiopatologíaRESUMEN
Prenatal stress predisposes rats to long-lasting disturbances that persist throughout adulthood (e.g., high anxiety, dysfunction of the hypothalamo-pituitary-adrenal axis, and abnormal circadian timing). These disturbances parallel to a large extent those found in depressed patients, in which hypercortisolemia and sleep alterations may be related to stress-inducing events. We studied sleep-wake parameters in control and prenatally stressed adult rats (3-4 months old) and examined possible relationships with their corticosterone levels (determined at 2 months of age). Under baseline conditions, prenatally stressed rats showed increased amounts of paradoxical sleep, positively correlated to plasma corticosterone levels. Other changes include increased sleep fragmentation, total light slow-wave sleep time, and a slight decrease in the percentage of deep slow-wave sleep relative to total sleep time. During recovery sleep from acute restraint stress, all sleep changes persisted and were correlated with stress-induced corticosterone secretion. High corticosterone levels under baseline conditions as well as an acute stress challenge may thus predict long-term sleep-wake alterations in rats. Taken together with other behavioral and hormonal abnormalities in prenatally stressed animals, the pronounced changes in sleep-wake parameters that are similar to those found in depressed patients suggest that prenatal stress may be a useful animal model of depression.