RESUMEN
In the last decades, the consumption of energy drinks has risen dramatically, especially among young people, adolescents and athletes, driven by the constant search for ergogenic effects, such as the increase in physical and cognitive performance. In parallel, mixed consumption of energy drinks and ethanol, under a binge drinking modality, under a binge drinking modality, has similarly grown among adolescents. However, little is known whether the combined consumption of these drinks, during adolescence, may have long-term effects on central function, raising the question of the risks of this habit on brain maturation. Our study was designed to evaluate, by behavioral, electrophysiological and molecular approaches, the long-term effects on hippocampal plasticity of ethanol (EtOH), energy drinks (EDs), or alcohol mixed with energy drinks (AMED) in a rat model of binge-like drinking adolescent administration. The results show that AMED binge-like administration produces adaptive hippocampal changes at the molecular level, associated with electrophysiological and behavioral alterations, which develop during the adolescence and are still detectable in adult animals. Overall, the study indicates that binge-like drinking AMED adolescent exposure represents a habit that may affect permanently hippocampal plasticity.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas , Bebidas Energéticas , Etanol , Hipocampo , Plasticidad Neuronal , Animales , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Etanol/farmacología , Etanol/administración & dosificación , Masculino , Bebidas Energéticas/efectos adversos , Plasticidad Neuronal/efectos de los fármacos , Ratas , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Ratas Wistar , Depresores del Sistema Nervioso Central/farmacología , Depresores del Sistema Nervioso Central/toxicidadRESUMEN
Previous work from our laboratory demonstrated that parental stress, induced by social isolation starting at puberty, leads to behavioral, endocrine, and biochemical changes in the male, but not female, offspring (ISO-O) of Sprague-Dawley rats. Here, we report alterations in the gut microbiota composition of ISO-O vs. grouped-housed offspring (GH-O), although all animals received the same diet and were housed in the same conditions. Analysis of bacterial communities by next-generation sequencing (NGS) of 16S rRNA gene revealed alterations at family and order levels within the main phyla of Bacteroides, Proteobacteria, and Firmicutes, including an almost total deficit in Limosilactobacillus reuteri (formerly Lactobacillus reuteri) and a significant increase in Ligilactobacillus murinus (formerly Lactobacillus murinus). In addition, we found an increase in the relative abundance of Rhodospirillales and Clostridiales in the families of Lachnospiraceae and Ruminococcaceae, and Bacteroidales in the family of Prevotellaceae. Furthermore, we examined plasma levels of the proinflammatory cytokines interleukin-1-beta and tumor necrosis factor-alpha, which did not differ between the two groups, while corticosterone concentrations were significantly increased in ISO-O rats. Our findings suggest that adverse environmental conditions experienced by parents may have an impact on the likelihood of disease development in the subsequent generations.
Asunto(s)
Microbioma Gastrointestinal , Lactobacillus , Ratas , Animales , Masculino , Ratas Sprague-Dawley , Microbioma Gastrointestinal/genética , ARN Ribosómico 16S/genética , Aislamiento SocialRESUMEN
Hormonal contraceptives are among the most widely used drugs by young healthy women to block ovulation and avoid pregnancy. They reduce the ovarian secretion of estradiol and progesterone, hormones that also modulate neuronal plasticity, cognitive functions, emotions and mood. Cannabis is the most commonly used illicit drug worldwide and its use is increasing among young women, many of which regularly take the "pill". Despite evidence of a bidirectional interaction between the endocannabinoid system and gonadal hormones, only very few studies have examined the consequences of cannabis consumption in young females under hormonal contraceptives treatment. To fill this gap, this study evaluated the behavioral effects of co-exposure to chronic 1) hormonal contraceptives, i.e., ethinyl estradiol (EE) plus levonorgestrel (LNG), one of the synthetic estrogen-progestin combinations of hormonal contraceptives, and 2) cannabinoid receptor agonist, i.e., WIN 55,212-2 (WIN), on motor activity, emotional state and cognitive functions in young adult female rats (8-11/experimental group). Hormonal and cannabinoid treatment started at post-natal day (PND) 52 and 56, respectively, while behavioral testing occurred between PND 84-95. The results show that chronic EE-LNG treatment, at doses (0.020 and 0.060 mg/rat, respectively) known to drastically reduce plasma progesterone levels, and the contextual exposure to WIN, at a dose (12.5 µg/kg/infusion) known to be rewarding in the rat, alters the hormonal milieu but does not cause further changes in locomotor activity compared to EE-LNG or WIN alone, and does not modify anxiety-like state (as measured by the elevated plus maze and the marble burying tests) and cognitive abilities (as measured by the novel object recognition and the prepulse inhibition tests) in young adult female rats. Although exposure to EE-LNG and WIN tends to increase the duration of immobility and to reduce the time spent swimming in the forced swimming test, there was not a significant additive effect suggestive of a depressive-like state. These findings allow deepening the current knowledge on the interaction between cannabinoid agonists and hormonal contraceptives and suggest that low, rewarding doses of cannabinoids do not significantly alter the motor and cognitive skills and do not induce anxiety or depressive-like states in females that use hormonal contraceptives.
Asunto(s)
Cannabinoides , Progesterona , Adulto Joven , Femenino , Ratas , Humanos , Animales , Progesterona/farmacología , Anticonceptivos Orales Combinados/farmacología , Cannabinoides/farmacología , Estradiol , EstrógenosRESUMEN
The neuroactive steroid allopregnanolone ((3α,5α)-3-hydroxypregnan-20-one or 3α,5α-THP) plays a key role in the response to stress, by normalizing hypothalamic-pituitary-adrenal (HPA) axis function to restore homeostasis. Most studies have been conducted on male rats, and little is known about the allopregnanolone response to stress in females, despite that women are more susceptible than men to develop emotional and stress-related disorders. Here, we provide an overview of animal and human studies examining the allopregnanolone responses to acute stress in females in the context of stress-related neuropsychiatric diseases and under the different conditions that characterize the female lifespan associated with the reproductive function. The blunted allopregnanolone response to acute stress, often observed in female rats and women, may represent one of the mechanisms that contribute to the increased vulnerability to stress and affective disorders in women under the different hormonal fluctuations that occur throughout their lifespan. These studies highlight the importance of targeting neuroactive steroids as a therapeutic approach for stress-related disorders in women.
Asunto(s)
Neuroesteroides , Pregnanolona , Animales , Femenino , Humanos , Sistema Hipotálamo-Hipofisario , Masculino , Sistema Hipófiso-Suprarrenal , RatasRESUMEN
Steroid hormones influence different aspects of brain function, including development, neurogenesis, neuronal excitability, and plasticity, thus affecting emotional states, cognition, sociality, and reward. In women, their levels fluctuate across the lifespan and through the reproductive stages but are also altered by exogenous administration of hormonal contraceptives (HC). HC are widely used by women throughout their fertile life both for contraceptive and therapeutic benefits. However, awareness of their effects on brain function and behavior is still poorly appreciated, despite the emerging evidence of their action at the level of the central nervous system. Here, we summarize results obtained in preclinical studies, mostly conducted in intact female rodents, aimed at investigating the neurobiological effects of HC. HC can alter neuroactive hormones, neurotransmitters, neuropeptides, as well as emotional states, cognition, social and sexual behaviors. Animal studies provide insights into the neurobiological effects of HC with the aim to improve women's health and well-being.
Asunto(s)
Encéfalo , Anticonceptivos , Animales , Anticonceptivos/farmacología , Emociones , Femenino , Hormonas , Humanos , Conducta SexualRESUMEN
Hormonal contraceptives prevent ovulation with subsequent reduction in endogenous levels of estradiol, progesterone and its neuroactive metabolite allopregnanolone. These neurosteroids modulate several brain functions, including neuronal plasticity, cognition and memory. We hypothesized that hormonal contraceptives might affect synaptic plasticity, learning and memory, as a consequence of suppressed endogenous hormones levels. Female rats were orally treated with a combination of ethinyl estradiol (EE, 0.020 mg) and levonorgestrel (LNG, 0.060 mg) once daily for four weeks. Decreased hippocampal brain-derived neurotrophic factor (BDNF) levels and altered histone H3 post-translational modifications (PTMs) were observed 14 days after discontinuation from chronic EE-LNG treatment. These effects were not accompanied by alterations in long-term plasticity at glutamatergic synapses, recognition memory in the novel object and novel place location tests, or spatial learning, memory, and behavioral flexibility in the Morris water maze test. Thus, decreased BDNF content does not affect synaptic plasticity and cognitive performance; rather it might be relevant for the occurrence of certain psychiatric symptoms, reported by some women using hormonal contraceptives. These results provide the first evidence of hippocampal epigenetic changes induced by hormonal contraceptives and complement previous studies on the neurobiological actions of hormonal contraceptives; the finding that effects of chronic EE-LNG treatment on BDNF content and histone PTMs are observed 14 days after drug discontinuation warrants further investigation to better understand the implications of such long-term consequences for women's health.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Histonas , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Anticonceptivos/metabolismo , Anticonceptivos/farmacología , Femenino , Hipocampo , Histonas/metabolismo , Humanos , Plasticidad Neuronal , Procesamiento Proteico-Postraduccional , RatasRESUMEN
Gamma-aminobutyric acid type B receptor (GABABR) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABABR using the 2-bottle choice paradigm. We found that GABAB(1), knockout (KO), and heterozygous (HZ) mice drank higher amounts of an alcoholic solution, preferred alcohol to water, and reached higher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates. The GABABR agonist GHB significantly reduced alcohol consumption in the GABAB(1) HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABABR and δ-containing GABAA receptor (δ-GABA A R), we profiled δ subunit mRNA expression levels in brain regions in which the crosstalk was characterized. We found a loss of the alcohol-sensitive GABAAR δ subunit in the hippocampus of the GABAB(1) KO alcohol-naïve mice that was associated with increased É£2 subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABAAR responsiveness to alcohol that has been previously described in an animal model of excessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revert the dramatic loss of hippocampal δ-GABAAR occurring in the GABAB(1) KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABAB(1) KO and WT mice because of previous involvement of GABABR in the regulation of cerebral levels of these compounds. We found that systemic administration of alcohol (1.5 g/kg) did not produce alcohol-induced neurosteroid response in the GABAB(1) KO mice but elicited an expected increase in the hippocampal level of progesterone and 3α,5α-THP in the WT controls. In conclusion, we show that genetic ablation of the GABAB(1) subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABAAR, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABAB(1) KO mice. In addition, we documented that GABAB(1) deficiency results in lack of alcohol-induced neurosteroids, and we discussed the potential implications of this finding in the context of alcohol drinking and dependence.
RESUMEN
Spinocerebellar ataxia 38 (SCA 38) is an autosomal dominant disorder caused by conventional mutations in the ELOVL5 gene which encodes an enzyme involved in the synthesis of very long fatty acids, with a specific expression in cerebellar Purkinje cells. Three Italian families carrying the mutation, one of which is of Sardinian descent, have been identified and characterized. One session of cerebellar intermittent theta burst stimulation (iTBS) was applied to 6 affected members of the Sardinian family to probe motor cortex excitability measured by motor-evoked potentials (MEPs). Afterwards, patients were exposed to ten sessions of cerebellar real and sham iTBS in a cross-over study and clinical symptoms were evaluated before and after treatment by Modified International Cooperative Ataxia Rating Scale (MICARS). Moreover, serum BDNF levels were evaluated before and after real and sham cerebellar iTBS and the role of BDNF Val66Met polymorphism in influencing iTBS effect was explored. Present data show that one session of cerebellar iTBS was able to increase MEPs in all tested patients, suggesting an enhancement of the cerebello-thalamo-cortical pathway in SCA 38. MICARS scores were reduced after ten sessions of real cerebellar iTBS showing an improvement in clinical symptoms. Finally, although serum BDNF levels were not affected by cerebellar iTBS when considering all samples, segregating for genotype a difference was found between Val66Val and Val66Met carriers. These preliminary data suggest a potential therapeutic use of cerebellar iTBS in improving motor symptoms of SCA38.
Asunto(s)
Ataxia Cerebelosa , Ataxias Espinocerebelosas , Ataxia , Factor Neurotrófico Derivado del Encéfalo/genética , Estudios Cruzados , Potenciales Evocados Motores/fisiología , Humanos , Plasticidad Neuronal/fisiología , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/terapia , Estimulación Magnética TranscranealRESUMEN
Patients with Parkinson's Disease (PD) experience bothersome motor fluctuations and Levodopa-induced Dyskinesias (LIDs). Cerebellar continuous theta burst stimulation (cTBS) was used as an inhibitory protocol of repetitive transcranial magnetic stimulation (rTMS) to reduce LIDs in PD patients. The influence of Val66Met polymorphism of Brain Derived Neurotrophic Factor (BDNF) gene on the therapeutic response to cTBS was investigated and the serum levels of BDNF were measured before and after treatment. Eleven patients were exposed to a session of cTBS and sham stimulation (one week apart) after the administration of 125 % of their usual morning dose of Levodopa and LIDs were video-recorded and evaluated at different time points (0, 15, 30, 45, 60, 90â¯min after Levodopa). Cerebellar cTBS significantly reduced LIDs with respect to sham stimulation and decreased serum BDNF levels. These effects were evident in the Val66Val group (7 subjects) but not in the Val66Met group (4 subjects). These data confirm the efficacy of cerebellar cTBS in reducing LIDs in PD patients and show that the clinical effect is accompanied by a decrease in serum BDNF levels. Moreover, they suggest that BDNF Val66Met polymorphism may influence the clinical and biological response to cTBS.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/sangre , Cerebelo/fisiopatología , Discinesia Inducida por Medicamentos/terapia , Enfermedad de Parkinson/terapia , Estimulación Magnética Transcraneal/métodos , Anciano , Antiparkinsonianos/efectos adversos , Factor Neurotrófico Derivado del Encéfalo/genética , Femenino , Humanos , Levodopa/efectos adversos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Ritmo TetaRESUMEN
Hormonal contraceptives are frequently prescribed drugs among women, mainly for their reversible contraceptive purposes but also for beneficial effects in some gynecological pathologies. Despite extensive studies aimed at elucidating the physical effects of hormonal contraceptives and ameliorating some unwanted outcomes, little is known yet about the effects of these drugs on brain function and related behavior, which are known to be modulated by endogenous steroid hormones. We describe the current literature on preclinical studies in animals undertaken to investigate effects of hormonal contraceptives on brain function and behavior. These studies suggest that hormonal contraceptives influence neurohormones, neurotransmitters, neuropeptides, and emotional, cognitive, social and sexual behaviors. Animals allow examination of the basic biological mechanisms of these drugs, devoid of the psychological aspect often associated to hormonal contraceptives' use in women. Understanding the neurobiological effects of these drugs may improve women's health and may help women making informed choices on hormonal contraception.
Asunto(s)
Ansiedad , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Agentes Anticonceptivos Hormonales/farmacología , Depresión , Aprendizaje/efectos de los fármacos , Neuropéptidos/efectos de los fármacos , Neuroesteroides , Pregnanolona/farmacología , Conducta Sexual/efectos de los fármacos , Conducta Social , Estrés Psicológico , Transmisión Sináptica/efectos de los fármacos , Animales , Ansiedad/inducido químicamente , Ansiedad/metabolismo , Ansiedad/fisiopatología , Depresión/inducido químicamente , Depresión/metabolismo , Depresión/fisiopatología , Femenino , Humanos , Estrés Psicológico/inducido químicamente , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismoRESUMEN
Aging increases the risk of cancer partly through alterations in the tissue microenvironment. Time-restricted feeding (TRF) is being proposed as an effective strategy to delay biological aging. In the present studies, we assessed the effect of long-term exposure to TRF on the emergence of the age-associated, neoplastic-prone tissue landscape. Animals were exposed to either ad libitum feeding (ALF) or TRF for 18 months and then transplanted with hepatocytes isolated from pre-neoplastic nodules. Both groups were continued ALF and the growth of transplanted cells was evaluated 3 months later. A significant decrease in frequency of larger size clusters of pre-neoplastic hepatocytes was seen in TRF-exposed group compared to controls. Furthermore, TRF modified several parameters related to both liver and systemic aging towards the persistence of a younger phenotype, including a decrease in liver cell senescence, diminished fat accumulation and up-regulation of SIRT1 in the liver, down-regulation of plasma IGF-1, decreased levels of plasma lipoproteins and up-regulation of hippocampal brain-derived growth factor (BDNF).These results indicate that TRF was able to delay the onset of the neoplastic-prone tissue landscape typical of aging. To our knowledge, this is the first investigation to describe a direct beneficial effect of TRF on early phases of carcinogenesis.
Asunto(s)
Envejecimiento/patología , Ingestión de Alimentos/fisiología , Hepatocitos/patología , Hígado/patología , Neoplasias/patología , Animales , Senescencia Celular/fisiología , Modelos Animales de Enfermedad , Ayuno , Masculino , Ratas , Microambiente Tumoral/fisiologíaRESUMEN
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by changes in social interactions, impaired language and communication, fear responses and presence of repetitive behaviours. Although the genetic bases of ASD are well documented, the recent increase in clinical cases of idiopathic ASD indicates that several environmental risk factors could play a role in ASD aetiology. Among these, maternal exposure to psychosocial stressors during pregnancy has been hypothesized to affect the risk for ASD in offspring. Here, we tested the hypothesis that preconceptional stressful experiences might also represent crucial elements in the aetiology of ASD. We previously showed that social isolation stress during adolescence results in a marked decrease in the brain and plasma concentrations of progesterone and in the quality of maternal care that these female rats later provide to their young. Here we report that male offspring of socially isolated parents showed decreased agonistic behaviour and social transmission of flavour preference, impairment in reversal learning, increased seizure susceptibility, reduced plasma oxytocin levels, and increased plasma and brain levels of BDNF, all features resembling an ASD-like phenotype. These alterations came with no change in spatial learning, aggression, anxiety and testosterone plasma levels, and were sex-dependent. Altogether, the results suggest that preconceptional stressful experiences should be considered as crucial elements for the aetiology of ASD, and indicate that male offspring of socially isolated parents may be a useful animal model to further study the neurobiological bases of ASD, avoiding the adaptations that may occur in other genetic or pharmacologic experimental models of these disorders.
Asunto(s)
Trastorno del Espectro Autista/etiología , Exposición Materna/efectos adversos , Exposición Paterna/efectos adversos , Aislamiento Social/psicología , Estrés Psicológico/psicología , Animales , Trastorno del Espectro Autista/sangre , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/fisiopatología , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Isoniazida/efectos adversos , Masculino , Oxitocina/sangre , Fenotipo , Corteza Prefrontal/metabolismo , Embarazo , Ratas , Convulsiones/inducido químicamente , Convulsiones/fisiopatología , Conducta Social , Testosterona/sangreRESUMEN
We previously demonstrated that socially isolated rats at weaning showed a significant decrease in corticosterone and adrenocorticotropic hormone (ACTH) levels, associated with an enhanced response to acute stressful stimuli. Here we shown that social isolation decreased levels of total corticosterone and of its carrier corticosteroid-binding globulin, but did not influence the availability of the free active fraction of corticosterone, both under basal conditions and after acute stress exposure. Under basal conditions, social isolation increased the abundance of glucocorticoid receptors, while it decreased that of mineralocorticoid receptors. After acute stress exposure, socially isolated rats showed long-lasting corticosterone, ACTH and corticotrophin releasing hormone responses. Moreover, while in the hippocampus and hypothalamus of group-housed rats glucocorticoid receptors expression increased with time and reached a peak when corticosterone levels returned to basal values, in socially isolated rats expression of glucocorticoid receptors did not change. Finally, social isolation also affected the hypothalamic endocannabinoid system: compared to group-housed rats, basal levels of anandamide and cannabinoid receptor type 1 were increased, while basal levels of 2-arachidonoylglycerol were decreased in socially isolated rats and did not change after acute stress exposure. The present results show that social isolation in male rats alters basal HPA axis activity and impairs glucocorticoid-mediated negative feedback after acute stress. Given that social isolation is considered an animal model of several neuropsychiatric disorders, such as generalized anxiety disorder, depression, post-traumatic stress disorder and schizophrenia, these data could contribute to better understand the alterations in HPA axis activity observed in these disorders.
Asunto(s)
Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Aislamiento Social , Hormona Adrenocorticotrópica/metabolismo , Análisis de Varianza , Animales , Animales Recién Nacidos , Corticosterona/metabolismo , Electrochoque/efectos adversos , Endocannabinoides/metabolismo , Pie/inervación , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Antagonistas de Hormonas/administración & dosificación , Masculino , Mifepristona/administración & dosificación , Piperidinas/administración & dosificación , Pirazoles/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismo , Estrés Psicológico/patología , Factores de TiempoRESUMEN
Variations in maternal care in the rat influence the development of individual differences in behavioral and endocrine responses to stress. This study aimed to examine the interaction between intragastric intubation during late gestation and postpartum stress, induced by pup separation, on maternal behavior and on dams' emotional state and HPA axis function. Rats received intragastric intubation of water on days 12-20 of gestation or remained untreated in their home cage (naïve dams). Pup separation was used as a model of postpartum stress. The procedure consisted of a daily separation of the dam from its litter for 3h from PND 3 until PND 15. Pup separation was carried out in both naïve and intubated dams. The behavioral results indicate that the association of these two stressors significantly decreased arched-back nursing (ABN) and licking and grooming (LG), behaviors considered important parameters to discriminate the high quality of maternal care. Moreover, dams that received both stressors displayed less nest building and blanket nursing behaviors; no effect on the frequency of passive and total nursing was recorded. The analysis of single effects on ABN and LG, revealed that dams that underwent gestational stress induced by intragastric intubation displayed less LG, but ABN was overall unchanged. On the contrary, pup separation stress significantly increased ABN and LG upon reunion of naïve dams with their pups. Treatments per se or the association of both induced modest changes in plasma levels of allopregnanolone and corticosterone that likely did not influence maternal care. These data show that the association of a mild stress during gestation with an unfavorable experience after parturition had a significant impact on maternal care. This effect seems independent from HPA axis activation or from changes in emotional state; further studies would be necessary to ascertain the neural changes that could contribute to altered maternal behavior in stressed mothers. Moreover, these results suggest that the use of intragastric intubation during gestation would interfere with measures of drug-induced changes in maternal behavior and likely their consequences on the offspring.
Asunto(s)
Conducta Materna/fisiología , Privación Materna , Periodo Posparto/psicología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Estrés Psicológico/fisiopatología , Factores de Edad , Animales , Animales Recién Nacidos , Corticosterona/sangre , Femenino , Aseo Animal , Postura , Embarazo , Pregnanolona/sangre , Ratas , Ratas Sprague-DawleyRESUMEN
RATIONALE: Social isolation of rats immediately after weaning is thought to represent an animal model of anxiety-like disorders. Socially isolated virgin females showed a significant decrease in allopregnanolone levels, associated with increased anxiety-related behavior compared with group-housed rats. OBJECTIVES: The present study investigates whether post-weaning social isolation affects maternal behavior and assesses neuroactive steroid levels in adult female rats during pregnancy and postpartum. RESULTS: Socially isolated dams displayed a reduction in the frequency of arched back nursing (ABN) behavior compared to group-housed dams. In addition, both total and active nursing were lower in socially isolated dams compared to group-housed dams. Compared to virgin females, pregnancy increases allopregnanolone levels in group-housed as well as isolated dams and such increase was greater in the latter group. Compared to pregnancy levels, allopregnanolone levels decreased after delivery and this decrease was more pronounced in isolated than group-housed dams. Moreover, the fluctuations in plasma corticosterone levels that occur in late pregnancy and during lactation follow a different pattern in socially isolated vs. group-housed rats. CONCLUSIONS: The present results show that social isolation in female rats decreases maternal behavior; this effect is associated with lower allopregnanolone concentrations at postpartum, which may account, at least in part, for the poor maternal care observed in socially isolated dams. In support of this conclusion is the finding that finasteride-treated dams, which display a decrease in plasma allopregnanolone levels, also showed a marked reduction in maternal care, suggesting that allopregnanolone may contribute to the quality of maternal care.
Asunto(s)
Ansiedad/sangre , Conducta Materna/fisiología , Pregnanolona/sangre , Aislamiento Social , Animales , Corticosterona/sangre , Modelos Animales de Enfermedad , Femenino , Embarazo , Ratas , Ratas Sprague-Dawley , DesteteRESUMEN
BACKGROUND: Allopregnanolone plays a role in the stress response and homeostasis. Alterations in the estrogen milieu during the perinatal period influence brain development in a manner that persists into adulthood. Accordingly, we showed that a single administration of estradiol benzoate (EB) on the day of birth decreases brain allopregnanolone concentrations in adult female rats. OBJECTIVE: We examined whether the persistent decrease in allopregnanolone concentrations, induced by neonatal EB treatment, might affect sensitivity to stress during adulthood. METHODS: Female rats were treated with 10 µg of EB or vehicle on the day of birth. During adulthood, the response to acute foot shock stress was assessed by measuring changes in brain allopregnanolone and corticosterone levels, as well as extracellular dopamine output in the medial prefrontal cortex (mPFC). RESULTS: Neonatal EB treatment enhanced stress-stimulated allopregnanolone levels in the hypothalamus, as well as extracellular dopamine output in the mPFC; this latest effect is reverted by subchronic progesterone treatment. By contrast, neonatal EB treatment did not alter stress-induced corticosterone levels, sensitivity to hypothalamic-pituitary-adrenal (HPA) axis negative feedback, or abundance of glucocorticoid and mineralocorticoid receptors. CONCLUSIONS: The persistent decrease in brain allopregnanolone concentrations, induced by neonatal EB treatment, enhances stress-stimulated allopregnanolone levels and extracellular dopamine output during adulthood. These effects are not associated to an impairment in HPA axis activity. Heightened sensitivity to stress is a risk factor for several neuropsychiatric disorders; these results suggest that exposure to estrogen during development may predispose individuals to such disorders.
Asunto(s)
Encéfalo/efectos de los fármacos , Corticosterona/metabolismo , Dopamina/metabolismo , Estradiol/análogos & derivados , Estrógenos/farmacología , Pregnanolona/metabolismo , Estrés Psicológico/metabolismo , Animales , Animales Recién Nacidos , Encéfalo/metabolismo , Estimulación Eléctrica , Estradiol/farmacología , Femenino , Sistema Hipotálamo-Hipofisario , Hipotálamo/efectos de los fármacos , Sistema Hipófiso-Suprarrenal , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Progesterona/farmacología , Progestinas/farmacología , Ratas , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/metabolismoRESUMEN
OBJECTIVE: We report synthesis of two carbon-11 labeled imidazopyridines TSPO ligands, [(11)C]CB184 and [(11)C]CB190, for PET imaging of inflammatory process along with neurodegeneration, ischemia or brain tumor. Biodistribution of these compounds was compared with that of [(11)C]CB148 and [(11)C](R)-PK11195. METHODS: Both [(11)C]CB184 and [(11)C]CB190 having (11)C-methoxyl group on an aromatic ring were readily prepared using [(11)C]methyl triflate. Biodistribution and metabolism of the compounds were examined with normal mice. An animal PET study using 6-hydroxydopamine treated rats as a model of neurodegeneration was pursued for proper estimation of feasibility of the radioligands to determine neuroinflammation process. RESULTS: [(11)C]CB184 and [(11)C]CB190 were obtained via O-methylation of corresponding desmethyl precursor using [(11)C]methyl triflate in radiochemical yield of 73 % (decay-corrected). In vivo validation as a TSPO radioligand was carried out using normal mice and lesioned rats. In mice, [(11)C]CB184 showed more uptake and specific binding than [(11)C]CB190. Metabolism studies showed that 36 % and 25 % of radioactivity in plasma remained unchanged 30 min after intravenous injection of [(11)C]CB184 and [(11)C]CB190, respectively. In the PET study using rats, lesioned side of the brain showed significantly higher uptake than contralateral side after i.v. injection of either [(11)C]CB184 or [(11)C](R)-PK11195. Indirect Logan plot analysis revealed distribution volume ratio (DVR) between the two sides which might indicate lesion-related elevation of TSPO binding. The DVR was 1.15 ± 0.10 for [(11)C](R)-PK11195 and was 1.15 ± 0.09 for [(11)C]CB184. CONCLUSION: The sensitivity to detect neuroinflammation activity was similar for [(11)C]CB184 and [(11)C](R)-PK11195.
Asunto(s)
Compuestos de Bencilideno/síntesis química , Radioisótopos de Carbono , Imidazoles/síntesis química , Isoquinolinas/síntesis química , Morfinanos/síntesis química , Piridinas/síntesis química , Radiofármacos/síntesis química , Animales , Animales no Consanguíneos , Compuestos de Bencilideno/química , Compuestos de Bencilideno/farmacocinética , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radioisótopos de Carbono/química , Proteínas Portadoras/metabolismo , Imidazoles/química , Imidazoles/farmacocinética , Inyecciones Intravenosas , Isoquinolinas/química , Isoquinolinas/farmacocinética , Masculino , Mesilatos/química , Ratones , Estructura Molecular , Morfinanos/química , Morfinanos/farmacocinética , Octanoles/química , Tomografía de Emisión de Positrones , Piridinas/química , Piridinas/farmacocinética , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas Wistar , Receptores de GABA/metabolismo , Receptores de GABA-A/metabolismo , Agua/químicaRESUMEN
RATIONALE: GABAergic neuronal circuits regulate neuroendocrine stress response, and the most potent positive endogenous modulator of GABAA receptor function is allopregnanolone. This neurosteroid acts in a nongenomic manner to selectively increase the inhibitory signal meditated by GABAA receptors; in addition, it also induces long-lasting changes in the expression of specific GABAA receptor subunits in various brain regions, with consequent changes in receptor function. OBJECTIVE: The objective of this review is to summarize our findings on emotional state and stress responsiveness in three animal models in which basal brain concentrations of allopregnanolone differ. It is postulated that individual differences in allopregnanolone levels can influence general resilience. RESULTS: The results showed that there is an apparent correlation between endogenous levels of brain allopregnanolone and basal and stress-stimulated HPA axis activity. CONCLUSION: The relationship between endogenous brain levels of allopregnanolone and HPA axis activity and function sustains the therapeutic potential of this neurosteroid for the treatment of stress-associated disorders.
Asunto(s)
Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Pregnanolona/farmacología , Animales , Privación Materna , Pregnanolona/metabolismo , Ratas , Resiliencia Psicológica , Aislamiento SocialRESUMEN
Neuroactive steroids modulate anxiety in experimental animals and possibly in humans. The secretion of these compounds has been found to be altered in panic disorder (PD), with such alterations having been suggested to be a possible cause or effect of panic symptomatology. Panic-like attacks can be induced in healthy individuals by administration of panicogenic agents or by physical procedures, and we have now measured the plasma concentrations of neuroactive steroids in such individuals before, during, and after panicogenic inhalation of CO2 in order to investigate whether abnormalities of neuroactive steroid secretion might contribute to the pathogenesis of PD. Fifty-nine psychologically and physically healthy subjects, including 42 women (11 in the follicular phase of the menstrual cycle, 14 in the luteal phase, and 17 taking contraceptive pills) and 17 men, who experienced a panic-like attack on previous exposure to 7% CO2 were again administered 7% CO2 for 20min. Thirty-three of these individuals (responders) again experienced a panic-like attack, whereas the remaining 26 subjects did not (nonresponders). All subjects were examined with the VAS-A and PSL-III-R scales for anxiety and panic symptomatology before and after CO2 inhalation. The plasma concentrations of progesterone, 3α,5α-tetrahydroprogesterone (3α,5α-THPROG=allopregnanolone), 3α,5α-tetrahydrodesoxycorticosterone (3α,5α-THDOC), dehydroepiandrosterone (DHEA), and cortisol were measured 15min and immediately before the onset of CO2 administration as well as immediately, 10, 30, and 50min after the end of CO2 inhalation. Neuroactive steroids were measured in the laboratory of Prof. Biggio in Cagliari, Sardinia, Italy. Neurosteroid levels did not change significantly in both responders and nonresponders before, during, or after CO2 inhalation. These data suggest that neuroactive steroid concentrations before, during, or after CO2 inhalation do not seem to correlate with panic symptomatology during panic-like attacks in subjects not affected by PD, and they therefore do not support the notion that abnormalities in neuroactive steroid secretion are either a cause or an effect of such attacks.
Asunto(s)
Dióxido de Carbono/efectos adversos , Neurotransmisores/metabolismo , Trastorno de Pánico/etiología , Trastorno de Pánico/metabolismo , Adulto , Dióxido de Carbono/administración & dosificación , Femenino , Humanos , Exposición por Inhalación , Masculino , Ciclo Menstrual/fisiología , Persona de Mediana Edad , Neurotransmisores/sangre , Trastorno de Pánico/psicología , Esteroides/metabolismo , Adulto JovenRESUMEN
Social isolation in male rats at weaning results in reduced basal levels of the neuroactive steroid 3α,5α-tetrahydroprogesterone (3α,5α-TH PROG) in the brain and plasma as well as increased anxiety-like behavior. We now show that socially isolated female rats also manifest a reduced basal cerebrocortical concentration of 3α,5α-TH PROG as well as an anxiety-like profile in the elevated plus-maze and Vogel conflict tests compared with group-housed controls. In contrast, despite the fact that they were raised under normal conditions, adult male offspring of male and female rats subjected to social isolation before mating exhibited an increased basal cerebrocortical level of 3α,5α-TH PROG but no difference in emotional reactivity compared with the offspring of group-housed parents. These animals also showed an increased basal activity of the hypothalamic-pituitary-adrenal axis as well as reduced abundance of corticotropin-releasing factor in the hypothalamus and of corticotropin-releasing factor receptor type 1 in the pituitary. Moreover, negative feedback regulation of hypothalamic-pituitary-adrenal axis activity by glucocorticoid was enhanced in association with up-regulation of glucocorticoid receptor expression in the hippocampus. There was also attenuation of corticosterone release induced by foot-shock stress in the offspring of socially isolated parents. The increase in the brain concentration of 3α,5α-TH PROG induced by acute stress was also blunted in these animals. Our results thus show that a stressful experience before mating can influence neuroendocrine signaling in the next generation.