Long-term treatment with 3, 4-methylenedioxymethamphetamine caused retina damage in C57BL/6 mice / Tratamento a longo prazo com 3, 4-metilenedioximetanfetamina causando dano na retina em camundongos C57BL/6

ABSTRACT Purpose: As a class of psychostimulant drugs, amphetamines are widely abused for their stimulant, euphoric, and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Following the onset of these effects, 3,4 methylenedioxymethamphetamine produces persistent damage to dopamine and serotonin nerve terminals, resulting in long-lasting neurotoxicity. The purpose of this investigation was to assess the effects of treatment with low dose of methylenedioxymethamphetamine on retinal function of C57BL/6 mice and its underlying mechanisms. Methods: C57BL/6 mice were divided randomly into two groups (n=10): one group was treated with phosphate buffered saline by intraperitoneal injection daily; the other group was treated with 1 mg/kg methylenedioxymethamphetamine by intraperitoneal injection daily for three months. Electroretinography was used to test retinal function every month. H&E staining and terminal deoxynucleotidyl transferase assay were used to evaluate the retinal morphology and histology. Enzyme-linked immunosorbent assay assays were used to measure markers of oxidative stress and inflammatory factors. Gene and protein expression was detected by real-time PCR and western blot. Results: Three-month treatment with methylenedioxymethamphetamine induced significant retinal dysfunction via photoreceptor cell apoptosis by oxidative stress and inflammatory responses. Conclusions: These results suggest that long-term treatment with methylenedioxymethamphetamine increases inflammatory responses in photoreceptor cells resulting in retinal dysfunction in C57BL/6 mice. Thus, this investigation provides preclinical rationale for the retina damage caused by the methylenedioxymethamphetamine abuse.

RESUMO Objetivos: Como uma classe de drogas psicoesti mulantes, as anfetaminas são amplamente usadas por suas propriedades estimulantes, eufóricas e alucinógenas. Muitos desses efeitos resultam de aumentos agudos na neurotransmissão da dopamina e da serotonina. Após o início desses efeitos, a 3,4-metilenedioximetanfetamina produz danos persistentes nos terminais nervosos de dopamina e serotonina, resultando em neurotoxicidade duradoura. O objetivo desta investigação foi avaliar os efeitos do tratamento baixa dose de metilenedioximetanfetamina na função da retina em camundongos C57BL/6 e seus mecanismos subjacentes. Métodos: Camundongos C57BL/6 foram divididos aleatoriamente em dois grupos (n=10): um grupo foi tratado com solução salina tamponada de fosfato por injeção intraperitoneal diária; o outro grupo foi tratado com 1 mg/kg de metilenedioximetanfetamina por injeção intraperitoneal diária durante 3 meses. Eletroretinografia foi utilizada para testar a função da retina a cada mês. A coloração H&E e análise com deoxinucleotidil terminal transferase foram utilizados para avaliar a morfologia e histologia da retina. Testes de imunoabsorção enzimática foram utilizados para medir marcadores de estresse oxidativo e fatores inflamatórios. A expressão de genes e proteínas foi detectada por PCR em tempo real e western blot. Resultados: O tratamento de três meses com metilenedioximetanfetamina induziu disfunção de retina significativa por apoptose de células fotorreceptoras por estresse oxidativo e resposta inflamatória. Conclusões: Estes resultados sugerem que o tratamento a longo prazo com metilenedioximetanfetamina aumenta as respostas inflamatórias em células fotorreceptoras, resultando em disfunção de retina em camundongos C57BL/6. Assim, a investigação foence uma justificação pré-clínica para os danos na retina causados pelo abuso de metilenedioximetanfetamina.

Differentiation of MDMA or 5-MeO-DIPT induced cognitive deficits in rat following adolescent exposure

The so-called "club drug" Foxy or Methoxy Foxy (5-Methoxy-N,N-di(iso)propyltryptamine hydrochloride; 5-MeO-DIPT) is a newer drug of abuse that has recently gained in popularity among recreational users as an alternative to MDMA (Ecstasy). While considerable research into the consequences of MDMA use is available, much remains unknown about the neurobiological consequences of 5-MeO-DIPT use. In the present study, beginning at 35 days of age adolescent rats were given repeated injections of 10 mg/kg of 5-MeO-DIPT, MDMA, or a corresponding volume of isotonic saline. Adult animals (135 days old) were trained and tested on a number of tasks designed to assess the impact, if any, and severity of 5-MeO-DIPT and MDMA, on a series of spatial and nonspatial memory tasks. Both the 5-MeO-DIPT- and the MDMA-treated rats were able to master the spatial navigation tests where the task included a single goal location and all groups performed comparably on these phases of training and testing. Conversely, the performance of both groups of the drug-treated rats was markedly inferior to that of the control animals on a task where the goal was moved to a new location and on a response learning task, suggesting a lack of flexibility in adapting their responses to changing task demands. In addition, in a response learning version of a learning set task, 5-MeO-DIPT rats made significantly more working memory errors than MDMA or control rats. Results are discussed in terms of observed alterations in serotonin activity in the forebrain and the consequences of compromised serotoninergic systems on cognitive processes.

Êxtase (MDMA): efeitos farmacológicos e tóxicos, mecanismo de ação e abordagem clínica / Ecstasy (MDMA): pharmacological and toxic effects, mechanism of action and clinical management

CONTEXTO: O 3,4-metilenodioximetanfetamina (MDMA, êxtase) é um derivado da anfetamina, cujo consumo por jovens tem aumentado. OBJETIVOS: Conduzir uma revisão de literatura sobre os aspectos farmacológicos e fisiopatológicos do MDMA, incluindo o mecanismo de ação que possa explicar os efeitos neurotóxicos e a toxicidade aguda e a longo prazo. MÉTODOS: Revisão da literatura usando as palavras-chave: 3,4-methylenedioxymethamphetamine, ecstasy, neurotoxicity, intoxication, drug abuse, por intermédio do MEDLINE e LILACS. A busca incluiu todos os artigos publicados no período entre 1985 e 2007. RESULTADOS: Ainda existem muitas questões sem respostas sobre a farmacologia do êxtase e a fisiopatologia dos efeitos tóxicos dessa substância. A simples descrição do mecanismo de ação é insuficiente para explicar todos os efeitos induzidos pelo êxtase. O mecanismo exato responsável por mediar os efeitos tóxicos do MDMA sobre os neurônios da serotonina precisa ser elucidado. CONCLUSÕES: Existem poucas informações na literatura sobre a farmacologia e o mecanismo de ação do MDMA que possam explicar os efeitos neurotóxicos e outros efeitos fisiopatológicos. São necessários mais estudos para que o profissional de saúde possa obter informações e conhecimentos a fim de combater os efeitos terríveis do êxtase na população jovem vulnerável.

BACKGROUND: The consumption of the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) by young people increased in the past years. OBJECTIVES: To conduct a literature review on the pharmacology of MDMA and particularly with respect to the putative mechanism of action implicated in the acute and long-term toxicity and neurotoxic effects. METHODS: A literature review using the key words: 3,4-methylenedioxymethamphetamine, ecstasy, neurotoxicity, intoxication, abuse drugs was performed in the databases MEDLINE and LILACS. The search covered all articles published between 1985 and 2007. RESULTS: There were still many unanswered questions regarding the pharmacology of ecstasy and the pathophysiology of its toxic effects. The fundamental mechanism of action is insufficient to explain all effects induced by the drug. The exact mechanism responsible for mediating the toxic effects of MDMA on 5-HT neurons remain to be elucidated. DISCUSSION: There is limited information in published literature about the underlying pharmacology and mechanism of action that could account for the neurotoxic and other phathophysiological effect of MDMA.