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Introduction: Binge eating disorder (BED) is a widespread eating disorder that primarily affects women worldwide, and it is characterized by the presence of binge eating episodes and the absence of any compensatory behavior to prevent weight gain. BED presents elevated comorbidity with other psychiatric disorders, such as anxiety, and it has been suggested that stress sensibility could be a vulnerability factor for the development of BED and the associated anxiety comorbidity. In this study, we aim to investigate whether the Wistar-Kyoto rat strain (WKY), which has a stress hyper-reactive phenotype, could develop both binge-type eating and anxiety-like behaviors simultaneously. We also aim to compare its vulnerability to developing both behaviors with the Sprague Dawley rat strain (SD), a rat strain commonly used in binge-eating models. Methods: WKY and SD rats were subjected to the model of intermittent access to palatable food (sucrose solution 30% or shortening) without calorie restriction or stress exposure. We evaluated and compared the development of binge-type eating behavior, anxiety-like behavior, and serum corticosterone variation as an index of the stress response in both rat strains. Results: WKY rats presented a higher percentage of binge-type eaters and required less time to develop binge-type eating behavior than SD rats. The WKY eating pattern emulated a binge-eating episode regardless of the palatable food. Although the development of sucrose binge-type eating was similar between strains, WKY developed more easily the shortening binge-type eating than SD and was more susceptible to developing anxiety-like behavior. Additionally, sucrose binge eating seems to differentially affect both strains' hypothalamic-pituitary-adrenal (HPA) axis response to stress since it facilitated its response in SD and blunted it in WKY. Discussion: Our results show that high-stress sensitive phenotype is a common vulnerability factor for the development of binge-type eating and anxiety-like behavior. Regardless of the macronutrient composition of the palatable food, WKY is susceptible to developing a binge-type eating behavior and is more susceptible than SD to developing anxiety-like behavior simultaneously. In conclusion, results showed that a hyper-reactive stress phenotype predisposes the development of binge-type eating behavior and anxiety-like behavior in the absence of calorie restriction and stress exposure.
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BACKGROUND AND PURPOSE: Transient hypofunction of the NMDA receptor represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant pathway synapses, have barely been explored in this pathological condition. EXPERIMENTAL APPROACH: We identified a series of synaptic alterations of the lateral and medial perforant paths in animals postnatally treated with the NMDA antagonist MK-801. This dysregulation suggests decreased cognitive performance, for which the dentate gyrus is critical. KEY RESULTS: We identified alterations in the synaptic properties of the lateral and medial perforant paths to the dentate gyrus synapses in slices from MK-801-treated animals. Altered glutamate release and decreased synaptic strength precede an impairment in the induction and expression of long-term potentiation (LTP) and CB1 receptor-mediated long-term depression (LTD). Remarkably, by inhibiting the degradation of 2-arachidonoylglycerol (2-AG), an endogenous ligand of the CB1 receptor, we restored the LTD in animals treated with MK-801. Additionally, we showed for the first time, that spatial discrimination, a cognitive task that requires dentate gyrus integrity, is impaired in animals exposed to transient hypofunction of NMDA receptors. CONCLUSION AND IMPLICATIONS: Dysregulation of glutamatergic transmission and synaptic plasticity from the entorhinal cortex to the dentate gyrus has been demonstrated, which may explain the cellular dysregulations underlying the altered cognitive processing in the dentate gyrus associated with schizophrenia.
Assuntos
Giro Denteado , Maleato de Dizocilpina , Plasticidade Neuronal , Via Perfurante , Receptores de N-Metil-D-Aspartato , Animais , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Maleato de Dizocilpina/farmacologia , Via Perfurante/efeitos dos fármacos , Via Perfurante/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Masculino , Ratos , Endocanabinoides/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Ratos Wistar , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciação de Longa Duração/efeitos dos fármacosRESUMO
The menopause transition is a vulnerable period for developing both psychiatric and metabolic disorders, and both can be enhanced by stressful events worsening their effects. The present study aimed to evaluate whether a cafeteria diet (CAF) combined with chronic variable stress (CVS) exacerbates anxious- or depressive-like behavior and neuronal activation, cell proliferation and survival, and microglia activation in middle-aged ovariectomized (OVX) rats. In addition, body weight, lipid profile, insulin resistance, and corticosterone as an index of metabolic changes or hypothalamus-pituitary-adrenal (HPA) axis activation, and the serum pro-inflammatory cytokines IL-6, IL-ß, and TNFα were measured. A CAF diet increased body weight, lipid profile, and insulin resistance. CVS increased corticosterone and reduced HDL. A CAF produced anxiety-like behaviors, whereas CVS induced depressive-like behaviors. CVS increased serum TNFα independently of diet. A CAF and CVS separately enhanced the percentage of Iba-positive cells in the hippocampus; the combination of factors further increased Iba-positive cells in the ventral hippocampus. A CAF and CVS increased the c-fos-positive cells in the hippocampus; the combination of factors increased the number of positive cells expressing c-fos in the ventral hippocampus even more. The combination of a CAF and CVS generates a slight neuroinflammation process and neuronal activation in a hippocampal region-specific manner and differentially affects the behavior.
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Corticosterona , Resistência à Insulina , Menopausa , Microglia , Proteínas Proto-Oncogênicas c-fos , Animais , Feminino , Ratos , Ansiedade/etiologia , Ansiedade/psicologia , Peso Corporal , Depressão/etiologia , Dieta/efeitos adversos , Lipídeos , Menopausa/metabolismo , Microglia/metabolismo , Estresse Psicológico/metabolismo , Fator de Necrose Tumoral alfa , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Experimental manipulations that interfere with the functional expression of N-methyl-D-aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK-801 during early postnatal development alters glutamate release and impairs the induction of NMDAR-dependent long-term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated short- and long-term potentiation, are compromised in response to neonatal treatment with MK-801. Consistent with this tenet, short- and long-term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole-cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre- and postsynaptic modifications at the MF-CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired-pulse ratio, and reduced AMPAR-mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK-801-treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR-independent forms of synaptic plasticity of the hippocampus.
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Potenciação de Longa Duração , Receptores de N-Metil-D-Aspartato , Animais , Potenciação de Longa Duração/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Fibras Musgosas Hipocampais/fisiologia , Maleato de Dizocilpina/farmacologia , Células Piramidais/fisiologia , Hipocampo/metabolismo , Sinapses/fisiologia , Glutamatos , Transmissão Sináptica/fisiologiaRESUMO
Stress susceptibility could play a role in developing premenstrual anxiety due to abnormalities in the hypothalamus-pituitary-adrenal (HPA) axis and impairments in the GABAA receptors' benzodiazepine (BDZ) site. Hence, we studied the stress-vulnerable Wistar Kyoto rat strain (WKY) to evaluate progesterone withdrawal (PW) effects on anxiety, HPA axis response, and to explore indicators of GABAA functionality in the BDZ site. For five days, ovariectomized WKY rats were administered 2.0 mg/kg of progesterone. Twenty-four hours after the last administration, rats were tested in the anxiety-like burying behavior test (BBT) or elevated plus maze test (EPM), and corticosterone was determined. [3H]Flunitrazepam binding autoradiography served as the BDZ binding site index of the GABAA receptor in amygdala nuclei and hippocampus's dentate gyrus (DG). Finally, different doses of diazepam in PW-WKY rats were tested in the BBT. PW induced anxiety-like behaviors in both BBT and EPM compared with No-PW rats. PW increased corticosterone, but was blunted when combined with PW and BBT. PW increased [3H]Flunitrazepam binding in the DG and central amygdala compared with No-PW rats. Diazepam at a low dose induced an anxiogenic-like response in PW rats, suggesting a paradoxical response to benzodiazepines. Overall, PW induced anxiety-like behavior, a blunted HPA axis response, and higher GABAAR/BZD binding site sensitivity in a stress-vulnerable rat strain. These findings demonstrate the role of stress-susceptibility in GABAAR functionality in a preclinical approximation of PMDD.
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Ansiedade , Comportamento Animal , Progesterona , Receptores de GABA-A , Síndrome de Abstinência a Substâncias , Animais , Ansiedade/metabolismo , Comportamento Animal/fisiologia , Sítios de Ligação , Corticosterona/metabolismo , Diazepam/farmacologia , Feminino , Flunitrazepam/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Progesterona/administração & dosagem , Ratos , Ratos Endogâmicos WKY , Receptores de GABA-A/metabolismo , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
BACKGROUND AND PURPOSE: Dysregulation of dopaminergic transmission combined with transient hypofunction of N-methyl-d-aspartate receptors (NMDARs) is a key mechanism that may underlie cognitive symptoms of schizophrenia. EXPERIMENTAL APPROACH: Therefore, we aimed to identify electrophysiologic alterations in animals neonatally treated with the NMDA receptor antagonist, MK-801, or with saline solution. KEY RESULTS: Patch-clamp whole-cell recordings from MK-801-treated animals revealed altered passive and active electrophysiologic properties compared with CA1 pyramidal cells from saline-treated animals, including up-regulation of the K+ inward-rectifier conductance and fast-inactivating and slow/non-inactivating K+ currents. Up-regulation of these membrane ionic currents reduced the overall excitability and altered the firing properties of CA1 pyramidal cells. We also explored the capability of cells treated with MK-801 to express intrinsic excitability potentiation, a non-synaptic form of hippocampal plasticity associated with cognition and memory formation. CA1 pyramidal cells from animals treated with MK-801 were unable to convey intrinsic excitability potentiation and had blunted synaptic potentiation. Furthermore, MK-801-treated animals also exhibited reduced cognitive performance in the Barnes maze task. Notably, activation of D1/D5 receptors with SKF-38,393 partially restored electrophysiologic alterations caused by neonatal treatment with MK-801. CONCLUSION AND IMPLICATIONS: Our results offer a molecular and mechanistic explanation based on dysregulation of glutamatergic transmission, in addition to dopaminergic transmission, that may contribute to the understanding of the cognitive deterioration associated with schizophrenia.
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Maleato de Dizocilpina , Receptores de Dopamina D1 , Receptores de Dopamina D5 , Receptores de N-Metil-D-Aspartato , Animais , Maleato de Dizocilpina/farmacologia , Dopamina/farmacologia , Hipocampo/metabolismo , Neurônios/metabolismo , Células Piramidais/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão SinápticaRESUMO
Chronic stress exposure during adolescence is a significant risk factor for the development of depression. Chronic social defeat (CSD) in rodents is an animal model of depression with excellent ethological, predictive, discriminative, and face validity. Because the CSD model has not been thoroughly examined as a model of stress-induced depression within the adolescence stage, the present study analyzed the short- and long-term behavioral and neuroendocrine effects of CSD during early adolescence. Therefore, adolescent male Swiss-Webster (SW) mice were exposed to the CSD model from postnatal day (PND) 28 to PND37. Twenty-four hours (mid-adolescence) or 4 weeks (early adulthood) later, mice were tested in two models of depression; the social interaction test (SIT) and forced swimming test (FST); cognitive deficits were evaluated in the Barnes maze (BM). Finally, corticosterone and testosterone content was measured before, during, and after CSD exposure, and serotonin transporter (SERT) autoradiography was studied after CSD in adolescent and adult mice. CSD during early adolescence induced enduring depression-like behaviors as inferred from increased social avoidance and immobility behavior in the SIT and FST, respectively, which correlated in an age-dependent manner with SERT binding in the hippocampus; CSD during early adolescence also induced long-lasting learning and memory impairments in the Barnes maze (BM). Finally, CSD during early adolescence increased serum corticosterone levels in mid-adolescence and early adulthood and delayed the expected increase in serum testosterone levels observed at this age. In conclusion: (1) CSD during early adolescence induced long-lasting depression-like behaviors, (2) sensitivity of SERT density during normal brain development was revealed, (3) CSD during early adolescence induced enduring cognitive deficits, and (4) results highlight the vulnerability of the adolescent brain to social stressors on the adrenal and gonadal axes, which emphasizes the importance of an adequate interaction between both axes during adolescence for normal development of brain and behavior.
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Toluene is a widely misused solvent that causes a variety of behavioral effects in both humans and animals. Preclinical and clinical research has provided evidence that toluene inhalation produces psychoactive effects similar to those caused by other Central Nervous System depressant drugs, but little is known about the consequences of inhaling solvents other than toluene that are also present in commercial products. As part of this research project, we studied the effects of hydrocarbon solvents chemically related to toluene on anxiety-like behavior, passive-avoidance learning, nociception, motor coordination and social interaction. We tested independent groups of adolescent male Wistar rats in the burying behavior task, step through avoidance learning task, hot plate test, shock threshold test, social interaction or rotarod tests after a 30â¯min exposure to either cyclohexane, benzene, toluene or m-xylene (2000 to 8000â¯ppm). Control animals breathed only air. Benzene, toluene and m-xylene produced anxiolytic-like actions, impaired learning, caused antinociception and decreased social interaction in a concentration-dependent manner. Locomotor coordination was impaired only with 8000â¯ppm m-xylene and 8000â¯ppm toluene. Cyclohexane had no effect on any of the behavioral tasks. Our data suggest that the aromatic ring is critical for solvents to produce a wide variety of behavioral effects.
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Comportamento Animal/efeitos dos fármacos , Benzeno/toxicidade , Cicloexanos/toxicidade , Solventes/toxicidade , Tolueno/toxicidade , Xilenos/toxicidade , Animais , Ansiedade/induzido quimicamente , Aprendizagem da Esquiva/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Ratos , Ratos Wistar , Comportamento SocialRESUMO
The dopaminergic and histaminergic systems are the first to appear during the development of the nervous system. Through the activation of H1 receptors (H1Rs), histamine increases neurogenesis of the cortical deep layers, while reducing the dopaminergic phenotype (cells immunoreactive to tyrosine hydroxylase, TH+) in embryo ventral mesencephalon. Although the function of histamine in neuronal differentiation has been studied, the role of H1Rs in neurogenesis has not been addressed. For this purpose, the H1R antagonist/inverse agonist chlorpheniramine was systemically administered (5 mg/kg, i.p.) to pregnant Wistar rats (gestational days 12-14, E12-14), and control and experimental embryos (E14 and E16) and pups (21-day-old) were evaluated for changes in nigro-striatal development. Western blot and immunohistochemistry determinations showed a significant increase in the dopaminergic markers' TH and PITX3 in embryos from chlorpheniramine-treated rats at E16. Unexpectedly, 21-day-old pups from the chlorpheniramine-treated group, showed a significant reduction in TH immunoreactivity in the substantia nigra pars compacta and dorsal striatum. Furthermore, striatal dopamine content, evoked [3H]-dopamine release and methamphetamine-stimulated motor activity were significantly lower compared to the control group. These results indicate that H1R blockade at E14-E16 favors the differentiation of dopaminergic neurons, but hampers their migration, leading to a decrease in dopaminergic innervation of the striatum in post-natal life.
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Transient hypofunction of NMDA receptors during brain maturation has been linked to cellular and behavioral alterations that mirror symptoms of schizophrenia. In line with this notion, neonatal administration of the non-competitive NMDA receptor antagonist, MK-801, mimics the negative and cognitive symptoms of schizophrenia. By combining behavioral evaluations with extracellular recordings in acute hippocampal slices, we uncovered a progressive alteration of synaptic transmission of animals neonatally treated with MK-801. During the periadolescent stage (up to postnatal day 30), before any behavioral alterations were observed, the synaptic transmission of hippocampal area CA1 exhibited progressive signs of alteration, such as the reduction in synaptic strength and impairment of short- and long-term forms of synaptic plasticity. As expected, behavioral impairments were consistently observed during the young adult stage (postnatal day 90), a period in which a steady deterioration of long-term depression and long-term potentiation was observed. Taken together, these results suggest that synaptic dysregulation precedes behavioral deterioration in a model that mimics the negative and cognitive symptoms of schizophrenia.