ABSTRACT
Objective: In the present study, we aimed to examine the effects of repeated D-amphetamine (AMPH) exposure, a well-accepted animal model of acute mania in bipolar disorder (BD), and histone deacetylase (HDAC) inhibitors on locomotor behavior and HDAC activity in the prefrontal cortex (PFC) and peripheral blood mononuclear cells (PBMCs) of rats. Moreover, we aimed to assess brain-derived neurotrophic factor (BDNF) protein and mRNA levels in these samples. Methods: We treated adult male Wistar rats with 2 mg/kg AMPH or saline intraperitoneally for 14 days. Between the 8th and 14th days, rats also received 47.5 mg/kg lithium (Li), 200 mg/kg sodium valproate (VPT), 2 mg/kg sodium butyrate (SB), or saline. We evaluated locomotor activity in the open-field task and assessed HDAC activity in the PFC and PBMCs, and BDNF levels in the PFC and plasma. Results: AMPH significantly increased locomotor activity, which was reversed by all drugs. This hyperactivity was associated with increased HDAC activity in the PFC, which was partially reversed by Li, VPT, and SB. No differences were found in BDNF levels. Conclusion: Repeated AMPH administration increases HDAC activity in the PFC without altering BDNF levels. The partial reversal of HDAC increase by Li, VPT, and SB may account for their ability to reverse AMPH-induced hyperactivity. .
Subject(s)
Animals , Male , Brain-Derived Neurotrophic Factor/analysis , Dextroamphetamine/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Histone Deacetylases/analysis , Motor Activity/drug effects , Prefrontal Cortex/drug effects , Analysis of Variance , Antimanic Agents/pharmacology , Bipolar Disorder/drug therapy , Bipolar Disorder/metabolism , Brain-Derived Neurotrophic Factor/drug effects , Butyric Acid/pharmacology , Disease Models, Animal , Histone Deacetylases/drug effects , Lithium/pharmacology , Prefrontal Cortex/metabolism , Rats, Wistar , Real-Time Polymerase Chain Reaction , Valproic Acid/pharmacologyABSTRACT
OBJECTIVE: The present study aims to investigate the effects of ouabain intracerebroventricular injection on BDNF levels in the amygdala and hippocampus of Wistar rats.METHODS: Animals received a single intracerebroventricular injection of ouabain (10-3 and 10-2 M) or artificial cerebrospinal fluid and immediately, 1h, 24h, or seven days after injection, BDNF levels were measured in the rat's amygdala and hippocampus by sandwich-ELISA (n = 8 animals per group).RESULTS: When evaluated immediately, 3h, or 24h after injection, ouabain in doses of 10-2 and 10-3 M does not alter BDNF levels in the amygdala and hippocampus. However, when evaluated seven days after injection, ouabain in 10-2 and 10-3 M, showed a significant reduction in BDNF levels in both brain regions evaluated.DISCUSSION: In conclusion, we propose that the ouabain decreased BDNF levels in the hippocampus and amygdala when assessed seven days after administration, supporting the Na/K ATPase hypothesis for bipolar illness.
OBJETIVO: O presente estudo tem como objetivo investigar os efeitos da injeção intracerebroventricular de ouabaína sobre os níveis de BDNF na amígdala e no hipocampo de ratos Wistar.MÉTODOS: Os animais receberam uma única injeção intracerebroventricular de ouabaína (10-3 and 10-2 M) ou fluido cerebroespinhal artificial e, imediatamente, 3h, 24h ou sete dias após a injeção, os níveis de BDNF foram mensurados na amígdala e hipocampo dos ratos por ELISA sandwich (n = 8 animais por grupo).RESULTADOS: Quando avaliados imediatamente após a injeção, 3h ou 24h, ouabaína nas doses 10-2 e 10-3 M não alterou os níveis de BDNF em ambas as estruturas avaliadas. Entretanto, quando avaliados sete dias após a injeção, ouabaína nas doses 10-2 e 10-3 M mostrou uma significante redução nos níveis de BDNF em amígdala e hipocampo.CONCLUSÃO: Em conclusão, propõe-se que a administração de ouabaína diminuiu os níveis de BDNF em amígdala e hipocampo quando avaliados sete dias após a injeção, suportando a hipótese da participação da Na/K ATPase no transtorno bipolar.
Subject(s)
Animals , Male , Rats , Brain-Derived Neurotrophic Factor/adverse effects , Hippocampus , Ouabain/administration & dosage , Rats, Wistar , Amygdala , Bipolar DisorderABSTRACT
O 3,4-metilenodioximetanfetamina (MDMA) popularmente conhecido por êxtase é uma droga sintéticaque chegou ao Brasil nos anos 90, portanto poucos estudos científicos estão disponíveis sobre a epidemiologia e os padrões de consumo desta droga. O perfil dos usuários de êxtase é na maioria das vezes composto por indivíduos jovens de até 25 anos, poliusuários de drogas, homens, heterossexuais, solteiros, de nível superior completo ou incompleto e pertencente às classes sócio-econômicasmais elevadas. Farmacologicamente o êxtase atua sobre o sistema serotonérgico, promovendo aumentoda liberação e inibição da recaptação de 5-HT pelos terminais nervosos, aumentando efetivamente a concentração de 5-HT na fenda sináptica. Além disso, o êxtase também promove ativação de vias noradrenérgicas e dopaminérgicas centrais. Todas estas alterações neuroquímicas podem desencadear uma série de manifestações clínicas, tais como euforia, bem-estar, desinibição,sudorese e alucinações. O uso do êxtase também pode provocar complicações como hipertemia fulminante, complicações cardiovasculares e psiquiátricas, que podem inclusive levar a morte o indivíduo. Adicionalmente,o abuso de êxtase pode causar dependência e tolerância em humanos. Em conclusão, torna útil enfatizar a importância de programas educacionais na prevenção ao consumo de drogas, dando particular ênfase ao êxtase.Outro fator que merece atenção é a capacitação dos profissionais da saúde para atuarem em intervenções deemergência em casos de intoxicações decorrentes do uso abusivo de êxtase.
3,4-methylenedioxymethamphetamine (MDMA) popularly named ecstasy is a synthetic drug that arrived in Brazil in the 90s. Due to this fact, few studies are still available about the pattern of ecstasys users in Brazil. However, many epidemiological studies indicate that the profile of ecstasys users is generally young people (up to 25 years old), drug polyusers, men, heterosexual, single, graduate or undergraduate students, and belonging to a privileged economic class. Pharmacologically, ecstasy acts on the serotonergic system, by increasing the release and inhibiting the re-uptake of serotonin in thenervous system. Together, these actions produce a robust increase of serotonin concentrations in the synaptic cleft. Despite serotonergic effects, ecstasy also acts on noradrenergic and dopaminergic pathways, thus promotinga very complex myriad of clinic symptoms, such as euphoria, disinhibition, sweat, hallucinations. Use of ecstasy also can promote hyperthermia, cardiovascular andpsychiatric alterations, which could lead the user to death, besides dependence and tolerance when chronically used. In conclusion, educational programs back toward the prevention of ecstasy consumption and training of heath professional workers is absolutely required for reducing the abuse of this drug and for improving the treatment of users.