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Binge drinking : the impact on neurogenesis and current therapeutic approaches
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Binge drinking, um padrão caracterizado pelo consumo elevado de álcool numa única ocasião, pode ocorrer ao longo da vida, iniciando-se na adolescência e continuando na idade adulta. Adicionalmente aos efeitos de dependência, estudos anteriores demonstraram que a patologia induzida pelo álcool inclui alterações na neurogénese e ativação das células gliais. Além disso, foi apontado que o padrão binge produziu modificações nos mecanismos de memória e propriedades eletrofisiológicas no hipocampo. Esta desordem e os seus efeitos crónicos têm sido estudados extensivamente no hipocampo adolescente através de um modelo de consumo de 4 dias, mas os efeitos agudos permanecem desconhecidos. A par disso, a pesquisa de farmacoterapia focada no uso de álcool tem sido insignificante e as opções atuais têm várias desvantagens. Assim, compostos antioxidantes, tais como a N-acetilcisteína (NAC) podem ser úteis para controlar os efeitos danosos e dependência provocados pelo consumo de álcool. Portanto, com este estudo procurou-se determinar um limiar de danos cerebrais utilizando vários marcadores de remodelação neuronal. Além disso, utilizou-se o modelo de extinção-reincidência para testar a eficácia e tolerabilidade da NAC para atenuar o restabelecimento da busca de álcool. Dezasseis ratos Sprague-Dawley machos adolescentes foram expostos a álcool (3,0 g / kg, i.p) duas vezes consecutivas com um intervalo de 9 h. Os níveis de vimentina co-marcada com proteína ácida fibrilar glial (GFAP) (astrogliose reativa), doublecortin (neurónios recém-nascidos) e HMGB1 (neuroinflamação) foram avaliados no hipocampo 48h após a administração final de etanol. As técnicas de imunohistoquímica e imunohistofluorescência revelaram um aumento de pelo menos 20% tanto para a marcação vimentina + GFAP como para HMGB1, mas sem modificações significativas para a doublecortin. Com o objetivo de investigar as supostas propriedades anti-craving da NAC, dezassete ratos machos Long Evans foram expostos a várias sessões de acesso de curta duração (15 min) a álcool (20% v/v, per os) (Caixas de Skinner) após o tratamento NAC (100 mg / kg, i.p). Além disso, o teste de auto-administração de Skinner exige uma avaliação das capacidades locomotoras usando a técnica de campo aberto. Verificou-se uma redução de 35% do consumo de álcool e 80% de busca de álcool em relação ao grupo controlo, sem efeitos sedativos. Coletivamente, estes dados indicam que a exposição tipo binge de 1 dia é suficiente para obter sinais efetivos de inflamação no hipocampo que poderá estar envolvida em desregulações subsequentes. Além disso, a N-acetilcisteína evitou as alterações comportamentais e bioquímicas provocadas pelo álcool e revelou-se uma substância segura e bem tolerada com propriedades promissoras.
Binge-drinking, characterized by a consumption of high volumes of alcohol on a single occasion, can occur across the life span beginning in adolescence and continuing through adulthood. Besides addiction effects, previous studies showed that EtOH-induced pathology includes changes in neurogenesis and glial cell activation. Also, it was demonstrated that binge-like pattern of alcohol consumption produced modifications on mechanisms of memory and electrophysiological properties in hippocampus. This disorder and its chronic effects have been studied extensively in adolescent hippocampus through a 4-day binge alcohol model, but acute effects remain unknown. Additionally, pharmacotherapy research focused on alcohol use has been insignificant and current options have several disadvantages. Thus antioxidant compounds, such as N-acetylcysteine (NAC) could be useful to control the damage and craving effects done by alcohol consumption. Therefore, these experiments sought to determine a threshold for hippocampus damage using various markers of neuronal remodelling. Furthermore it was used the extinction-reinstatement model of relapse to test the ability and tolerability of NAC to attenuate the reinstatement of alcohol-seeking. Sixteen adolescent male Sprague-Dawley rats were exposed to ethanol (3.0 g/kg, i.p) for two consecutive times at 9-h intervals. Levels of vimentin co-labeled with glial fibrillary acidic protein (GFAP) (reactive astrogliosis), doublecortin (newborn neurons) and HMGB1 (neuroinflammation) were assessed in the hippocampus 48 h after the final ethanol administration. Immunohistochemistry and immunohistofluorescence revealed at least an increase by 20% for both vimentin+GFAP and HMGB1, but no significate modifications for doublecortin. In order to investigate the supposed anti-craving properties of NAC, seventeen adolescent male Long Evans rats were exposed to several sessions of short-time access (15 min) to alcohol (20% v/v, per os) in an operant auto-administration paradigm (Skinner boxes) after treatment (100 mg/kg, i.p). Also, the Skinner‘s auto-administration of ethanol test required an assessment of locomotor abilities using the open field technique. We found a reduction by 35% of alcohol consumption and 80% of alcohol seeking compared to saline group, without sedative compromising effects. Collectively, these data indicate that 1-day exposure of binge-like ethanol is enough to obtain effective signs of alcohol-induced hippocampal inflammation which might be involved in subsequent deregulations. Additionally, N-acetylcysteine prevented the behavioural and biochemical changes brought by alcohol and it reveals itself a safe and well-tolerated drug with promising properties.
Binge-drinking, characterized by a consumption of high volumes of alcohol on a single occasion, can occur across the life span beginning in adolescence and continuing through adulthood. Besides addiction effects, previous studies showed that EtOH-induced pathology includes changes in neurogenesis and glial cell activation. Also, it was demonstrated that binge-like pattern of alcohol consumption produced modifications on mechanisms of memory and electrophysiological properties in hippocampus. This disorder and its chronic effects have been studied extensively in adolescent hippocampus through a 4-day binge alcohol model, but acute effects remain unknown. Additionally, pharmacotherapy research focused on alcohol use has been insignificant and current options have several disadvantages. Thus antioxidant compounds, such as N-acetylcysteine (NAC) could be useful to control the damage and craving effects done by alcohol consumption. Therefore, these experiments sought to determine a threshold for hippocampus damage using various markers of neuronal remodelling. Furthermore it was used the extinction-reinstatement model of relapse to test the ability and tolerability of NAC to attenuate the reinstatement of alcohol-seeking. Sixteen adolescent male Sprague-Dawley rats were exposed to ethanol (3.0 g/kg, i.p) for two consecutive times at 9-h intervals. Levels of vimentin co-labeled with glial fibrillary acidic protein (GFAP) (reactive astrogliosis), doublecortin (newborn neurons) and HMGB1 (neuroinflammation) were assessed in the hippocampus 48 h after the final ethanol administration. Immunohistochemistry and immunohistofluorescence revealed at least an increase by 20% for both vimentin+GFAP and HMGB1, but no significate modifications for doublecortin. In order to investigate the supposed anti-craving properties of NAC, seventeen adolescent male Long Evans rats were exposed to several sessions of short-time access (15 min) to alcohol (20% v/v, per os) in an operant auto-administration paradigm (Skinner boxes) after treatment (100 mg/kg, i.p). Also, the Skinner‘s auto-administration of ethanol test required an assessment of locomotor abilities using the open field technique. We found a reduction by 35% of alcohol consumption and 80% of alcohol seeking compared to saline group, without sedative compromising effects. Collectively, these data indicate that 1-day exposure of binge-like ethanol is enough to obtain effective signs of alcohol-induced hippocampal inflammation which might be involved in subsequent deregulations. Additionally, N-acetylcysteine prevented the behavioural and biochemical changes brought by alcohol and it reveals itself a safe and well-tolerated drug with promising properties.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2016
Palavras-chave
Adolescência Binge-drinking Neurogénese Campo aberto Comportamento Mestrado Integrado - 2016