RESUMO
Alterations of brain iron levels have been observed in a number of neurodegenerative disorders. We have previously demonstrated that iron overload in the neonatal period results in severe and persistent memory deficits in the adulthood. Protein degradation mediated by the ubiquitin-proteasome system (UPS) plays a central regulatory role in several cellular processes. Impairment of the UPS has been implicated in the pathogenesis of neurodegenerative disorders. Here, we examined the effects of iron exposure in the neonatal period (12th-14th day of postnatal life) on the expression of proteasome ß-1, ß-2, and ß-5 subunits, and ubiquitinated proteins in brains of 15-day-old rats, to evaluate the immediate effect of the treatment, and in adulthood to assess long-lasting effects. Two different memory types, emotionally motivated conditioning and object recognition were assessed in adult animals. We found that iron administered in the neonatal period impairs both emotionally motivated and recognition memory. Polyubiquitinated protein levels were increased in the hippocampus, but not in the cortex, of adult animals treated with iron. Gene expression of subunits ß1 and ß5 was affected by age, being higher in the early stages of development in the hippocampus, accompanied by an age-related increase in polyubiquitinated protein levels in adults. In the cortex, gene expression of the three proteasome subunits was significantly higher in adulthood than in the neonatal period. These findings suggest that expression of proteasome subunits and activity are age-dependently regulated. Iron exposure in the neonatal period produces long-lasting harmful effects on the UPS functioning, which may be related with iron-induced memory impairment.
Assuntos
Hipocampo/metabolismo , Ferro/farmacologia , Memória , Proteínas Ubiquitinadas/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Poliubiquitina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Ratos WistarRESUMO
Animals exposed to an early adverse event may be more susceptible to a second source of stress later in life, and these stressors may have additive deleterious effects. Sleep deprivation is known to be a stressor, affecting multiple body functions such as the cognition. Modafinil enhances working memory and attention in healthy non-sleep deprived subjects and in animal models of sleep deprivation. The first aim of the present study was to investigate the effects of maternal separation (MS) combined with paradoxical sleep deprivation (PSD) in adulthood on recognition memory in rats. Second, we aimed to evaluate whether the administration of modafinil would be able to ameliorate memory deficits induced by MS and PSD. Wistar rat pups were initially distributed into MS and handling (H) groups, with their litters standardized in 4 females and 4 males. In adulthood, the male rats were submitted to PSD or control condition, being redistributed afterwards in modafinil- or vehicle-treatment immediately after the training session of object recognition task. PSD did not potentiate the cognitive deficit due to MS. However, modafinil was able to recover memory impairments associated to PSD and also to MS in the neonatal period. This study demonstrates for the first time that modafinil ameliorates cognitive deficits associated to MS and to PSD in adulthood, independent from MS in the neonatal period.
Assuntos
Ansiedade de Separação/tratamento farmacológico , Ansiedade de Separação/psicologia , Compostos Benzidrílicos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Privação do Sono/tratamento farmacológico , Privação do Sono/psicologia , Análise de Variância , Animais , Transtornos Cognitivos/psicologia , Feminino , Manobra Psicológica , Modafinila , Gravidez , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/psicologiaRESUMO
Modafinil is a wake-promoting drug and has been approved for the treatment of excessive daytime sleepiness in narcolepsy and obstructive sleep apnea. Modafinil was shown to improve learning and memory in rodents, and to reverse memory deficits induced by sleep deprivation or stress. However, depending on the memory paradigm used, modafinil might also impair memory. We aimed to investigate the effects of modafinil on memory consolidation and retrieval for object recognition and inhibitory avoidance in naïve adult rats. We also investigated whether acute or chronic administration of modafinil would reverse memory deficits induced by iron overload, a model of memory impairment related to neurodegenerative disorders. Adult naïve rats received modafinil (0.0, 0.75, 7.5 or 75 mg/kg) either immediately after training or 1 h prior to testing in object recognition or inhibitory avoidance. Iron-treated rats received modafinil immediately after training in object recognition. In order to investigate the effects of chronic modafinil, iron-treated rats received daily injections of modafinil for 17 days, and 24 h later they were trained in object recognition or inhibitory avoidance. Acute modafinil does not affect memory consolidation or retrieval in naive rats. A single injection of modafinil at the highest dose was able to recover recognition memory in iron-treated rats. Chronic modafinil completely recovered iron-induced recognition memory and emotional memory deficits. Additional preclinical and clinical studies are necessary in order to support the applicability of modafinil in recovering memory impairment associated with neurodegenerative disorders.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Promotores da Vigília/uso terapêutico , Análise de Variância , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Comportamento Exploratório/efeitos dos fármacos , Inibição Psicológica , Compostos de Ferro/administração & dosagem , Masculino , Transtornos da Memória/etiologia , Modafinila , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Privação do Sono/complicações , Sorbitol/uso terapêuticoRESUMO
It has been demonstrated that experiences taking place early in life have a profound influence on brain development, interacting with the genetic background and determining differences in the vulnerability to the onset of bipolar disorder when the individual is exposed to a second adverse event later in life. Here, we investigated the effects of exposure to an early adverse life event (maternal deprivation) and to a later adverse life event [D-amphetamine (AMPH)] on cognition in an animal model of mania. We have previously demonstrated that that repeated AMPH exposure produces severe and persistent cognitive impairment, which was more pronounced when the animals were maternal deprived, suggesting that the early adverse life event could be potentiating the effects of the exposure to the second adverse life event later in life. Here, we show that valproic acid ameliorated the cognitive deficits induced by AMPH, but it was not effective when the animals were exposed to both stressors: maternal deprivation and AMPH treatment.
Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/psicologia , Estimulantes do Sistema Nervoso Central , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Dextroanfetamina , Estresse Psicológico/psicologia , Ácido Valproico/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Peso Corporal/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Feminino , Privação Materna , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Gravidez , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
We have previously shown that pharmacological blockade of the gastrin-releasing peptide receptor (GRPR) during the neonatal period in rats produces behavioral features of developmental neuropsychiatric disorders. Here, we show that social interaction deficits in this model are reversed by the atypical antipsychotic clozapine given in the adulthood. In addition, we analyzed the mRNA expression of three neuronal receptors potentially involved in the etiology of disorders of the autism spectrum. Rats were injected with the GRPR antagonist RC-3095 or saline (SAL) from postnatal days 1-10, and tested for social behavior and recognition memory in the adulthood. One hour prior to the behavioral testing, rats were given a systemic injection of clozapine or saline. The mRNA expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor, the epidermal growth factor receptor (EGFR), and GRPR was measured in the hippocampus and cortex of a separate set of rats given RC-3095 or SAL neonatally. Rats given neonatal RC-3095 showed decreased social interaction and impaired object recognition memory. Clozapine rescued the social interaction impairment. Neonatal treatment with RC-3095 also resulted in dose-dependent decreases in the expression of GRPR, NR1, and EGFR in the cortex, whereas all three receptor mRNAs were increased in the hippocampus in rats treated with the lower dose of RC-3095. The results contribute to further validate the novel rat model of neurodevelopmental disorders induced by GRPR blockade, and shows alterations in the expression of neuronal receptors in this model.
Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Clozapina/farmacologia , Receptores da Bombesina/antagonistas & inibidores , Comportamento Social , Animais , Bombesina/análogos & derivados , Bombesina/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , Receptores da Bombesina/metabolismo , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
The role of dopamine receptors in regulating the formation of recognition memory remains poorly understood. Here we show the effects of systemic administration of dopamine receptor agonists and antagonists on the formation of memory for novel object recognition in rats. In Experiment I, rats received an intraperitoneal (i.p.) injection of vehicle, the selective D1 receptor agonist SKF38393 (1.0 and 5.0mg/kg), or the D2 receptor agonist quinpirole (1.0 and 5.0mg/kg) immediately after training. In Experiment II, rats received an injection of vehicle, the dopamine receptor antagonist SCH23390 (0.1 and 0.05 mg/kg), or the D2 receptor antagonist raclopride (0.5 and 0.1mg/kg) before training, followed by an injection of vehicle or the nonselective dopamine receptor agonist apomorphine (0.05 mg/kg) immediately after training. SKF38393 at 5mg/kg produced an enhancement of novel object recognition memory measured at both 24 and 72 h after training, whereas the dose of 10mg/kg impaired 24-h retention. Posttraining administration of quinpirole did not affect 24-h retention. Apomorphine enhanced memory in rats given pretraining raclopride, suggesting that the effect was mediated by selective activation of D1 receptors. The results indicate that activation of D1 receptors can enhance recognition memory consolidation. Importantly, pharmacological activation of D1 receptors enhanced novel object recognition memory even under conditions in which control rats showed significant retention.
Assuntos
Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Reconhecimento Psicológico/fisiologia , Retenção Psicológica/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Análise de Variância , Animais , Apomorfina/farmacologia , Benzazepinas/farmacologia , Dopaminérgicos/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Quimpirol/farmacologia , Racloprida/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/agonistas , Reconhecimento Psicológico/efeitos dos fármacos , Retenção Psicológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estatísticas não Paramétricas , Fatores de TempoRESUMO
Increased levels of iron in brain regions have been reported in neurodegenerative disorders as well as in normal brain aging. We have previously demonstrated that neonatal iron loading induces cognitive impairment in adult rats. Here, we evaluate the effects of neonatal iron treatment on cognition in aged rats. We also investigated the effects of a late subchronic rosuvastatin treatment on iron- and age-induced cognitive deficits. Rats received vehicle or 10.0mg/kg Fe(2+) orally at postnatal days 12-14. When animals reached the age of 23 months, they received daily intraperitoneal injections of saline or rosuvastatin (0.2 or 2.0mg/kg) for 21 days. Twenty-four hours after the last injection, they were submitted to novel object recognition training. Retention test sessions were performed 1.5 and 24h after training, in order to assess short-term and long-term memory, respectively. Results indicated that aged animals that received iron in the neonatal period showed more severe memory deficits than vehicle-treated ones, suggesting that iron potentiates age-associated memory impairments. Rosuvastatin improved recognition memory deficits associated with iron loading and aging, providing evidence that statins may be considered for the treatment of age-associated cognitive decline.
Assuntos
Envelhecimento/psicologia , Fluorbenzenos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Ferro/toxicidade , Atividade Motora , Ratos , Ratos Wistar , Rosuvastatina CálcicaRESUMO
It is now generally accepted that iron accumulates in the brain during the ageing process. Increasing evidence demonstrate that iron accumulation in selective regions of the brain may generate free radicals, thereby possessing implications for the etiology of neurodegenerative disorders. In a previous study we have reported that aged rats present recognition memory deficits. The aim of the present study was to evaluate the effect of desferoxamine (DFO), an iron chelator agent, on age-induced memory impairment. Aged Wistar rats received intraperitoneal injections of saline or DFO (300mg/kg) for 2 weeks. The animals were submitted to a novel object recognition task 24h after the last injection. DFO-treated rats showed normal recognition memory while the saline group showed long-term recognition memory deficits. The results show that DFO is able to reverse age-induced recognition memory deficits. We also demonstrated that DFO reduced the oxidative damage to proteins in cortex and hippocampus. Thus, the present findings provide the first evidence that iron chelators might prevent age-related memory dysfunction.
Assuntos
Envelhecimento/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Desferroxamina/administração & dosagem , Ferro/metabolismo , Transtornos da Memória/fisiopatologia , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Ratos , Ratos Wistar , Sideróforos/administração & dosagemRESUMO
Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects. However, previous studies have not examined the effects of EPI on consolidation of recognition memory. Here we report that systemic administration of EPI enhances consolidation of memory for a novel object recognition (NOR) task under different training conditions. Control male rats given a systemic injection of saline (0.9% NaCl) immediately after NOR training showed significant memory retention when tested at 1.5 or 24, but not 96h after training. In contrast, rats given a post-training injection of EPI showed significant retention of NOR at all delays. In a second experiment using a different training condition, rats treated with EPI, but not SAL-treated animals, showed significant NOR retention at both 1.5 and 24-h delays. We next showed that the EPI-induced enhancement of retention tested at 96h after training was prevented by pretraining systemic administration of the beta-adrenoceptor antagonist propranolol. The findings suggest that, as previously observed in experiments using aversively motivated tasks, epinephrine modulates consolidation of recognition memory and that the effects require activation of beta-adrenoceptors.
Assuntos
Epinefrina/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Receptores Adrenérgicos beta/fisiologia , Reconhecimento Psicológico/fisiologia , Retenção Psicológica/fisiologia , Análise de Variância , Animais , Nível de Alerta/fisiologia , Masculino , Ratos , Ratos Wistar , Estatísticas não ParamétricasRESUMO
Esta revisão procura descrever os aspectos peculiares à memória e sua função tanto na formação do medo adquirido quanto no seu tratamento. busca-se explicar quais mecanismos bioquímicos e funcionais sobre a memória, o esquecimento, a extinção e sobre a repressão da sua formação. foi utilizada bibliografia atual de periódicos indexados a respeito de estudos tanto em animais experimentais quanto em seres humanos, assim como clássicos históricos da literatura científica mundial.
Assuntos
Humanos , Animais , Masculino , Feminino , Extinção Psicológica , Memória , Transtornos da Memória , Rememoração Mental , Medo/psicologiaRESUMO
Excess of iron in the brain has been implicated in the pathogenesis of several human neurodegenerative diseases, for example Alzheimer's disease and Parkinson's disease. It has been shown that the neonatal period is critical for the establishment of normal iron content in the adult brain. Moreover, it is known that aging alters the cerebral distribution of this metal. We have recently described that neonatal administration of iron severely impaired novel object recognition memory in rats. The aim of the present study was to determine whether selegiline, a monoamine oxidase (MAO) inhibitor known for its neuroprotective properties, could protect rats against cognitive impairment induced by neonatal administration of iron. In the first experiment, male Wistar rats received vehicle (5% sorbitol in water) or iron (10.0 mg/kg) orally from postnatal days 12 to 14 and saline (0.9% NaCl) or selegiline (1.0 or 10.0 mg/kg) intraperitoneally for 21 days, starting 24 h before the first iron dosing. In the second experiment, rats were given either vehicle or iron (10.0 mg/kg) orally from postnatal days 12 to 14 followed by saline or selegiline (1.0 or 10.0 mg/kg) intraperitoneally for 21 days, starting when rats reached adulthood (50th day after birth). Iron-treated rats given selegiline in both doses showed no deficits in recognition memory. Rats receiving iron but no selegiline presented memory deficits. This is the first study reporting the reversion of iron-induced memory impairment, supporting the view that our model can be considered as a useful tool in the search for new drugs with neuroprotective and/or memory enhancing properties.