Función de la impulsividad en el trastorno por consumo de sustancias / Impulsivity`s role in substance use disorder

Resumen La proporción de usuarios de una sustancia de abuso que desarrolla problemas con su consumo (abuso o dependencia) representa solo una parte de esta población. En México, el 63.8 % de la población consume alcohol, y de ellos, el 15 % desarrolla algún trastorno por consumo de alcohol (TCA). Se ha observado una relación causal entre el trastorno por consumo de sustancias (TCS) y la falta de autocontrol. Es decir, satisfacer necesidades de manera impulsiva, v. gr., consumir una droga sin evaluar las consecuencias. La corteza prefrontal (CPF) es el principal sustrato neuroanatómico del autocontrol y característicamente la CPF alcanza la madurez alrededor de los 30 años, sugieriendo que el autocontrol se alcanza despues de esta edad. Se ha propuesto que todos los grupos etarios que no han consolidado el uso del autocontrol son vulnerables al TCS. Similarmente ocurre con aquellos sujetos que por algún trastorno psiquiátrico tienen como característica una limitada función prefrontal. La CPF coordina una red subcortical cuya interacción depende de distintos sistemas de neurotransmisión, entre ellos, endocanabinoides. En este trabajo se revisó la función de la CPF y del sistema de endocanabinoides (sECB) y su relación con la vulnerabilidad a la adicción y otros trastornos psiquiátricos.

Abstract The proportion of users of a substance of abuse who develop problems with its use (abuse or dependence) represents only a part of this population. In Mexico, 63.8% of the population consumes alcohol and only 15% of them develop an alcohol use disorder (AUD). A causal relation has been observed between substance use disorder (SUD) and the lack of self-control. Which means, satisfying needs in an impulsive way, v.gr. using a drug, without considering the consequences. The prefrontal cortex (PFC) is the main neuroanatomical substrate of self-control and characteristically reaches maturity around the age of 30, suggesting that self-control is reached after this age. We suggest that all age groups that have not consolidated the use of self-control are vulnerable to SUD. The same occurs with those who, due to a psychiatric disorder, have the characteristic of a limited prefrontal function. The PFC coordinates a subcortical network whose interaction depends on different neurotransmission systems among them, the endocannabinoids system (ECBs). In this work we will review the function of the PFC, the ECBs and its relationship with vulnerability to addiction and other psychiatric disorders.

Síndrome X frágil: presentación clínica, patología y tratamiento / Fragile X syndrome: clinical presentation, pathology and treatment

Resumen El síndrome X frágil es la condición monogenética que produce más casos de autismo y de discapacidad intelectual. La repetición de tripletes CGG (> 200) y su metilación conllevan el silenciamiento del gen FMR1. La proteína FMRP (producto del gen FMR1) interacciona con los ribosomas, controlando la traducción de mensajeros específicos y su pérdida produce alteraciones de la conectividad sináptica. El tamizaje de síndrome X frágil se realiza por reacción en cadena de la polimerasa. La recomendación actual de la Academia Americana de Pediatría es realizar pruebas a quienes presenten discapacidad intelectual, retraso global del desarrollo o antecedentes familiares de afección por la mutación o premutación. Países hispanos como Colombia, Chile y España reportan altas prevalencias de síndrome X frágil y han creado asociaciones o corporaciones nacionales de X frágil que buscan acercar a los pacientes a redes disponibles de diagnóstico y tratamiento.

Abstract Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.

História da neurotransmissão: um breve relato / History of neurotransmission: a brief report

Objetivos: Descrever, de forma resumida, as principais descobertas históricas referentes a aquisiçao dos conhecimentos acerca da neurotransmissão. Métodos: Foi realizada busca de artigos nas bases de dados LILACS, Pubmed, Medline, Up to date e Medscape, durante o período de janeiro a maio de 2018, com o critério de atualidade como publicado nos últimos cinco anos, bem como foi revisada literatura consagrada em Neurologia. Resultados: A história da neurotransmissão evoluiu gradualmente a partir do século XIX e ao longo dos anos através dos esforços meticulosos de um grande número personalidades históricas. Seu desenvolvimento foi de extrema relevância para a evolução médica nos campos da neurofisiologia, da neurologia, da neuropsiquiatria, da psicofarmacologia e da anestesia. Conclusões: Encontramos marcos fundamentais na evolução da história da neurotransmissão e das estruturas da arquitetura neuronal nela implicadas, desde a descoberta do neurônio, do impulso elétrico, dos neurotransmissores e de mecanismos de transdução celular, bem como os cientistas que realizaram essas descobertas, elementos importantes para a compreensão da neurobiologia do cérebro.

Objectives: To describe, in a summary form, the main historical findings regarding the acquisition of knowledge about neurotransmission. Methods: A search of articles in the LILACS, Pubmed, Medline, Up to date and Medscape databases was performed, with the current criterion as published in the last five years, as well as literature review consecrated in Neurology. Results: The history of neurotransmission evolved gradually from the nineteenth century and over the years through the meticulous efforts of a large number of historical personalities, Its development was extremely relevant to medical developments in the fields of neurophysiology, neurology, neuropsychiatry, psychopharmacology and anesthesia. Conclusions: We found key milestones in the evolution of the history of neurotransmission and the neuronal architecture structures involved, from the discovery of the neuron, the electrical impulse, neurotransmitters and cellular transduction mechanisms, as well as the scientists who made these discoveries, important elements to understand the neurobiology of the brain.

Thiamine deficiency contributes to synapse and neural circuit defects

BACKGROUND: The previous studies have demonstrated the reduction of thiamine diphosphate is specific to Alzheimer's disease (AD) and causal factor of brain glucose hypometabolism, which is considered as a neurodegenerative index of AD and closely correlates with the degree of cognitive impairment. The reduction of thiamine diphosphate may contribute to the dysfunction of synapses and neural circuits, finally leading to cognitive decline. RESULTS: To demonstrate this hypothesis, we established abnormalities in the glucose metabolism utilizing thiamine deficiency in vitro and in vivo, and we found dramatically reduced dendrite spine density. We further detected lowered excitatory neurotransmission and impaired hippocampal long-term potentiation, which are induced by TPK RNAi in vitro. Importantly, via treatment with benfotiamine, Aß induced spines density decrease was considerably ameliorated. CONCLUSIONS: These results revealed that thiamine deficiency contributed to synaptic dysfunction which strongly related to AD pathogenesis. Our results provide new insights into pathogenesis of synaptic and neuronal dysfunction in AD.

Psicobiología del suicidio y las ideas suicidas / Psychobiology of suicide and suicidal ideas

Se realiza una revisión de las principales basesgenéticas y neurobiológicas del suicidio y lasideas suicidas, analizando las contribuciones de la genética y la imagenología estructuraly funcional. Se comparan principalmente lasdiferencias entre pacientes depresivos con ysin ideas suicidas. Se comprueba el peso de losantecedentes familiares y genéticos como unaprimera contribución a la vulnerabilidad suicida. Los estudios estructurales muestran los cambios hipometabólicos más globales (corteza temporal, parietal, etc.) correspondientes a la depresión, con una diferencia distintiva en las áreas prefrontales, particularmente en las regiones mediales laterales y basales en los pacientes suicidas. Se comprueban las alteraciones bioquímicas centradas en el metabolito de la serotonina, elácido 5-hidroxiindolacético (5-HIAA) y en losreceptores postsinápticos y recaptadores deserotonina, también en las áreas prefrontales.Se analizan los estudios que atribuyen a estoscambios la disfunción cognitiva observada en pacientes suicidas.

A review of the main genetic and neurobiological bases of suicide and suicidal ideas is carried out, analyzing the contributions of genetics and structural and functional imaging. The differences between depressive patients with and without suicidal ideas are mainly compared. The weight of family and genetic background is checked as a first contribution to suicidal vulnerability. Structural studies show the most global hypometabolic changes (temporal cortex, parietal, etc.) corresponding to depression, with a distinctive difference in the prefrontal areas, particularly in the medial-lateral and basal regions in suicidal patients. Biochemical alterations are verified in the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and in post-synaptic receptors and deserotonin reuptakers, also in prefrontal areas. They attribute to these changes the cognitive dysfunction observed in suicidal patients.

Association between levobupivacaine and pancuronium. Interference in neuromuscular transmission and blockade in rats

ABSTRACT PURPOSE: To evaluate the effects of levobupivacaine on neuromuscular transmission and neuromuscular blockade produced by pancuronium in vitro. METHODS: Thirty rats were distributed into groups (n = 5) according to the drug used alone or in combination: Group I - levobupivacaine (5 µg.mL-1); Group II - pancuronium (2 µg.mL-1); Group III - pancuronium (2 µg.mL-1) + levobupivacaine (5µg.mL-1). The following parameters were evaluated: 1) amplitude of diaphragmatic response to indirect stimulation, before and 60 minutes after the addition of levobupivacaine and pancuronium alone, and after the addition of levobupivacaine combined with pancuronium; 2) membrane potentials (MP) and miniature endplate potentials (MEPP). RESULTS: Levobupivacaine alone did not alter the amplitude of muscle response and MP. In preparations previoulsy exposed to levobupivacaine, the block with pancuronium was significantly denser (90.2 ± 15.2%), showing a significant difference (p=0.031) in comparison to the block produced by pancuronium alone (48.9% ± 9.8%). There was a decrease in the frequency and amplitude of MEPPs. CONCLUSION: Levobupivacaine potentiated the neuromuscular blockade produced by pancuronium, confirming a presynaptic action by a decrease in miniature endplate potentials.

Time perception and age / Percepção do tempo e idade

ABSTRACT Our internal clock system is predominantly dopaminergic, but memory is predominantly cholinergic. Here, we examined the common sensibility encapsulated in the statement: “time goes faster as we get older”. Objective To measure a 2 min time interval, counted mentally in subjects of different age groups. Method 233 healthy subjects (129 women) were divided into three age groups: G1, 15-29 years; G2, 30-49 years; and G3, 50-89 years. Subjects were asked to close their eyes and mentally count the passing of 120 s. Results The elapsed times were: G1, mean = 114.9 ± 35 s; G2, mean = 96.0 ± 34.3 s; G3, mean = 86.6 ± 34.9 s. The ANOVA-Bonferroni multiple comparison test showed that G3 and G1 results were significantly different (P < 0.001). Conclusion Mental calculations of 120 s were shortened by an average of 24.6% (28.3 s) in individuals over age 50 years compared to individuals under age 30 years.

RESUMO Nosso sistema de relógio interno é predominantemente dopaminérgico, mas a memória é predominantemente colinérgica. Neste estudo, examinamos a assertiva comum que “o tempo passa mais rápido para pessoas mais velhas”. Objetivo Medir o intervalo de tempo 2 min contados mentalmente em pessoas de diferentes faixas etárias. Método 233 pessoas saudáveis (129 mulheres) foram divididos em três grupos: G1, 15-29 anos; G2, 30-49 anos; e G3, 50-89 anos. Foi solicitado que contassem mentalmente, com os olhos fechados, a passagem de 120 s. Resultados Os tempos aferidos foram: G1, média = 114,9 ± 35 s; G2, média = 96,0 ± 34,3 s; G3, média = 86,6 ± 34,9 s. A comparação entre os tempos de G3 e G1 (teste de comparação múltipla ANOVA-Bonferroni) foi muito significante (P < 0,001). Conclusão Cálculo mental de 120 s foi encurtado em média 24,6% (28,3 s) em pessoas maiores que 50 anos quando comparado com pessoas menores que 30 anos.

Análise do jitter com agulha concêntrica em pacientes com miastenia gravis autoimune adquirida / Concentric needle jitter analysis in patients with autoimmune acquired myasthenia gravis

A técnica de eletromiografia de fibra única (EMGFU), mediante análise do jitter, é o método neurofisiológico mais sensível para a confirmação do distúrbio da junção neuromuscular na miastenia gravis (MG). Os registros são tradicionalmente obtidos com agulha de fibra única, de alto custo e reutilizável. Por causa da necessidade atual do uso de material descartável, a agulha concêntrica vem sendo utilizada em substituição à agulha de fibra única. A técnica utilizada é semelhante, porém os potencias de ação para a análise do jitter são obtidos com eletrodo de agulha concêntrica (Eletromiografia de fibra única - jitter com agulha concêntrica, EMGFU-JAC). Contudo, os estudos são escassos e as metodologias utilizadas são heterogêneas com a utilização dessa agulha. OBJETIVOS: Este estudo tem por objetivo mensurar os valores de jitter obtidos com agulha concêntrica, no músculo Orbicularis Oculi, em sujeitos saudáveis e em pacientes com MG autoimune adquirida e avaliar a validade do método nas formas generalizada e ocular da doença. MÉTODOS: Foram estudados 20 sujeitos saudáveis, 20 pacientes com miastenia gravis forma generalizada (grupo MGG) e 13 com a forma ocular da doença (grupo MGO). A EMGFU-JAC foi realizada em todos os participantes, idealmente com 20 medidas de jitter em cada estudo. O jitter foi expresso como a média das diferenças consecutivas (MCD). Em todos os pacientes do estudo foram realizados o teste de estimulação repetitiva e dosagem sérica de anticorpo antirreceptor de acetilcolina (ac-AChR) no momento da análise do jitter. Nos pacientes soronegativos para ac-AChR, foi pesquisado o anticorpo antimúsculo específico tirosina-quinase (ac-MuSK). Foram definidos o limite superior da normalidade (LSN) para a média do MCD de cada estudo e para valores individuais de MCD. Os critérios de anormalidade foram: (1) média do MCD acima do LSN; ou (2) mais de 10% dos valores individuais de MCD acima do LSN. A definição do LSN para valores...

Single fiber electromyography (SFEMG) technique, through jitter analysis, is the most sensitive neurophysiological method for confirmation of neuromuscular junction disorder in myasthenia gravis (MG). Records are traditionally obtained with single fiber needle, which is reusable and has a high-cost. Due to the current need of using disposable material, concentric needle has been used to replace single fiber needle. The technique is similar, but the action potential for jitter analysis is obtained with concentric needle electrode (SFEMG - concentric needle jitter, SFEMG-CNJ). However, studies are scarce and methodologies used are heterogeneous with the use of this needle. OBJECTIVES: This study aims to measure jitter values obtained with concentric needle in the Orbicularis Occuli muscle in healthy subjects and in patients with autoimmune acquired MG and to assess the validity of the method in generalized and ocular forms of the disease. METHODS: 20 healthy subjects, 20 patients with generalized myasthenia gravis (GMG group) and 13 with the ocular form of the disease (OMG group) were studied. SFEMG-CNJ was performed on all participants, ideally with 20 jitter values in each study. Jitter was expressed as the mean consecutive difference (MCD). Repetitive nerve stimulation and serum acetylcholine receptor antibody (AChR-ab) were performed in all patients in the study, by the time of jitter analysis. Tyrosine kinase specific antibody muscle antibodies (MuSK-ab) were performed in AChR-ab negative patients. The upper limit of normality (ULN) for the mean MCD and for individual jitter values were defined. The abnormality criteria were: (1) mean MCD above ULN; or (2) more than 10% of individual jitter values above ULN. The definition of ULN for individual jitter values was based on the concept that two out of 20 jitter values above ULN are acceptable in a healthy muscle for voluntary contraction technique. Therefore, the ULN for the 18th highest...

Ocorrência do SNP c.767G>T no gene DNM1responsável pelo colapso induzido pelo exercício em cães da raça Labrador Retriever no estado de São Paulo / Occurrence of DNM1 SNP c.767G>T responsible for exercise-induced collapse in Labrador Retriever in the Sao Paulo state

O colapso induzido pelo exercício (EIC) é considerado uma síndrome autossômica recessiva que afeta principalmente cães da raça Labrador Retriever. A doença é caracterizada por fraqueza muscular e colapso após exercício intenso. Usualmente, ocorre recuperação clínica após o episódio, mas alguns animais podem vir a óbito. Os sinais clínicos são decorrentes do polimorfismo de base única (SNP) c.767G>T no gene Dynamin 1 (DNM1). O objetivo deste trabalho foi determinar a ocorrência deste SNP em 321 cães da raça Labrador Retriever do Estado de São Paulo. Primers específicos para a amplificação de todo o exon 6 do gene DNM1 foram usados nas PCRs utilizando DNA a partir de amostras de sangue ou swab bucal, a avaliação final foi realizada com sequenciamento direto dos produtos da PCR. Dentre os 321 animais estudados, 3,4 % (11/321) eram homozigotos para o SNP c.767G>T no gene DNM1 e 24,6% (79/321) eram heterozigotos. Somente um dos 11 animais homozigotos apresentavam sinais clínicos compatíveis com a EIC. Este é o primeiro estudo sobre a ocorrência deste SNP no Brasil e considerando que quase 25% dos animais estudados eram heterozigotos, a genotipagem dos animais para este SNP pode ser importante antes dos acasalamentos para cães desta raça. A EIC deve ser considerada nos diagnósticos diferenciais de enfermidades neuromusculares em cães da raça Labrador Retriever.

The exercise-induced collapse (EIC) is considered an autosomal recessive syndrome that mainly affects Labrador Retriever dogs. The disease is characterized by muscle weakness and collapse after intense exercise. Recovery usually occurs after exercise but some animals may die. The clinical signs occurs due to the single-nucleotide polymorphism (SNP) c.767G>T in Dynamin 1 (DNM1) gene. The aim of this study was to evaluate the occurrence of this SNP in 321 Labrador Retriever dogs from São Paulo state. Specific primers for amplification of the entire exon 6 of the DNM1 gene were used in a PCR performed with DNA from blood or buccal swab samples, direct sequencing was performed for the final evaluation. Among 321 animals studied, 3.4% (11/321) of animals were homozygous for the DNM1 SNP (c.767G>T) and 24.6% (79/321) were heterozygous. Only one of the 11 homozygous animals in this study had previous clinical signs compatible with this disease. This is the first study that evaluated the occurrence of DNM1 SNP (c.767G>T) gene in Brazil and considering that almost 25% of the studied animals were heterozygous, the routinely evaluation of this SNP may be important before this breed mating The EIC should be include in the differential diagnosis of neuromuscular diseases in Labrador Retriever dogs.

Different Extracts of Zingiber officinale Decrease Enterococcus faecalis Infection in Galleria mellonella

Dried, fresh and glycolic extracts of Zingiber officinale were obtained to evaluate the action against G. mellonella survival assay against Enterococcus faecalis infection. Eighty larvae were divided into: 1) E. faecalis suspension (control); 2) E. faecalis + fresh extract of Z. officinale (FEO); 3) E. faecalis + dried extract of Z. officinale (DEO); 4) E. faecalis + glycolic extract of Z. officinale (GEO); 5) Phosphate buffered saline (PBS). For control group, a 5 μL inoculum of standardized suspension (107 cells/mL) of E. faecalis (ATCC 29212) was injected into the last left proleg of each larva. For the treatment groups, after E. faecalis inoculation, the extracts were also injected, but into the last right proleg. The larvae were stored at 37 °C and the number of dead larvae was recorded daily for 168 h (7 days) to analyze the survival curve. The larvae were considered dead when they did not show any movement after touching. E. faecalis infection led to the death of 85% of the larvae after 168 h. Notwithstanding, in treatment groups with association of extracts, there was an increase in the survival rates of 50% (GEO), 61% (FEO) and 66% (DEO) of the larvae. In all treatment groups, the larvae exhibited a survival increase with statistically significant difference in relation to control group (p=0.0029). There were no statistically significant differences among treatment groups with different extracts (p=0.3859). It may be concluded that the tested extracts showed antimicrobial activity against E. faecalis infection by increasing the survival of Galleria mellonella larvae.

Extratos seco, fresco e glicólico de Zingiber officinale foram obtidos para avaliar suas ações por meio de ensaio de sobrevivência em G. mellonella contra infecção por Enterococcus faecalis. Oitenta larvas foram divididas em: 1) Suspensão de E. faecalis (controle); 2) E. faecalis + extrato fresco de Z. officinale (FEO); 3) E. faecalis + extrato seco de Z. officinale (DEO); 4) E. faecalis + extrato glicólico de Z. officinale (GEO); 5) Solução tampão fosfato salina (PBS). Para o grupo de controle, 5 µL de inóculo de suspensão padronizada (107 células/mL) de E. faecalis (ATCC 29212) foi injetado na última proleg esquerda de cada lagarta. Para os grupos com tratamento, após a injeção de E. faecalis, os extratos foram injetados na última proleg direita. Após as injeções, as lagartas foram armazenadas a 37 °C e o número de animais mortos foi registrado diariamente em 168 h (7 dias) para analisar a curva de sobrevivência. As lagartas foram consideradas mortas quando elas não mostraram qualquer movimento após o toque. A infecção por E. faecalis levou à morte de 85% das lagartas após 168 h. Não obstante, nos grupos de tratamento com associação dos extratos, houve um aumento nas taxas de sobrevivência de 50% (GEO), 61% (FEO) e 66% (DEO) das lagartas. Em todos os grupos com tratamento, as lagartas apresentaram um aumento na sobrevivência, com diferença estatisticamente significativa em relação ao grupo controle (p=0,0029). Não houve diferença estatisticamente significativa entre os tratamentos com os diferentes extratos (p=0,3859). Pode concluir-se que os extratos testados mostraram atividade antimicrobiana contra a infecção por E. faecalis, aumentando a sobrevivência das lagartas de G. mellonella.

Un primer análisis de la investigación en México sobre los determinantes sociales de la salud: 2005-2012 / A first analysis of research on social determinants of health in Mexico: 2005-2012

Objetivo. Examinar la investigación hecha en México sobre los determinantes sociales de la salud (DSS) durante el periodo 2005-2012 con base en la caracterización del sistema nacional de investigación en salud y la producción científica sobre este tema. Material y métodos. Análisis en dos etapas: revisión documental de fuentes oficiales sobre investigación en salud en México y búsqueda sistemática de literatura sobre DSS. Resultados. Los DSS fueron mencionados en el Programa de Acción Específico de Investigación en Salud 2007-2012, pero no figuran en las estrategias y objetivos; en su lugar, se enfatizan primordialmente aspectos de infraestructura y administrativos. En el periodo se publicaron 145 artículos sobre DSS, cuyas temáticas más abordadas fueron "condiciones de salud", "sistemas de salud" y "nutrición y obesidad". Conclusiones. A pesar de que existe investigación en México sobre DSS, la instrumentación de esos hallazgos en políticas de salud no se ha implementado. El Programa Sectorial de Salud 2013-2018 representa una ventana de oportunidad para posicionar resultados de investigación que promuevan políticas de equidad en salud.

Objective. To examine the research on social determinants of health (SDH) produced in Mexico during the period 2005-2012, based on the characterization of the national health research system and the scientific production on this topic. Materials and methods. Two-stage analyses: Review of Mexican documents and official sources on health research and systematic bibliographic review of the literature on SDH. Results. Although SDH were mentioned in the Specific Action Plan for Health Research 2007-2012, they are not implemented in strategies and goals, as the emphasis is put mostly in infrastructure and administrative aspects of research. In the period studied, 145 articles were published on SDH topics such as health conditions, health systems and nutrition and obesity. Conclusions. In spite of the availability of research on SDH in Mexico, the operationalization of such findings into health policies has not been possible. The current Sectorial Program on Health 2013-2018 represents a window of opportunity to position research findings that promote health equity policies.

Nuevos blancos terapéuticos en el tratamiento de las depresiones resistentes: Moduladores glutamatérgicos / New Therapeutic Targets in the Treatment of Resistant Depression: glutamatergic modulators

Dentro de los trastornos del estado de ánimo, los trastornos depresivos son padecimientos generalmente recurrentes que tienen, según las estadísticas, una prevalencia anual de un 3 % a un 6 % en la población. Desde la década de los 60' la hipótesis aminérgica de Schildkraut y posteriores, establecieron que las depresiones estaban vinculadas a alteraciones en la neurotransmisión catecolaminérgica y serotoninérgica. Los fármacos antidepresivos apuntaron a esas disfunciones pero las dificultades terapéuticas, retraso en el inicio de la acción y limitaciones en la eficacia, llevaron a la búsqueda de otras posibilidades, que surgieron de las investigaciones sobre la neurotransmisión glutamatérgica. En modelos animales se descubrió en los comienzos de los 90' la acción antidepresiva de los fármacos que antagonizaban la neurotransmisión de los receptores N-metil-D-aspartato (NMDA). El objetivo de este trabajo se orienta a establecer los fundamentos de la teoría glutamatérgica de las depresiones y a describir los fármacos que potencialmente podrían utilizarse en la clínica...

Depressive disorders are usually recurrent diseases that, according to statistics, afects from 3 % to 6 % of the population. Since the early '60s the Schildkraut aminergic hypothesis and subsequent, established that depressions were associated with alterations in cahtecolaminegic and serotonergic neurotransmission. Antidepressant drugs aimed at these dysfunctions but the therapeutic difficulties, delayed onset of action and efficacy limitations, led to the search of other possibilities that emerged from the research on glutamatergic neurotransmission. In animal models it was discovered in the early 90's the antidepressant action of drugs antagonized the NMDA receptor neurotransmission. The objective of this work is aimed at establishing the foundations of the glutamatergic theory of depressions and describe drugs that potentially could be used in the clinic...

Cardiac 123I-MIBG uptake in de novo Brazilian patients with Parkinson's disease without clinically defined dysautonomia / Cintilografia Miocárdica com 123I-MIBG em pacientes brasileiros com doença de Parkinson recentemente diagnosticada sem disautonomia clinicamente manifesta

Myocardial scintigraphy with meta-iodo-benzyl-guanidine (123I cMIBG) has been studied in Parkinson's disease (PD), especially in Asian countries, but not in Latin America. Most of these studies include individuals with PD associated to a defined dysautonomia. Our goal is to report the cardiac sympathetic neurotransmission in de novo Brazilian patients with sporadic PD, without clinically defined dysautonomia. We evaluated retrospectively a series of 21 consecutive cases with PD without symptoms or signs of dysautonomia assessed by the standard bedside tests. This number was reduced to 14 with the application of exclusion criteria. 123I cMIBG SPECT up-take was low or absent in all of them and the heart/mediastinum ratio was low in 12 of 14. We concluded that 123I cMIBG has been able to identify cardiac sympathetic neurotransmission disorder in Brazilian de novo PD patients without clinically defined dysautonomia.

A cintilografia miocárdica com meta-iodo-benzil-guanidina (123I cMIBG) foi estudada na doença de Parkinson (DP), especialmente nos países asiáticos, mas não na América Latina. A quase totalidade desses estudos inclui indivíduos com DP com disautonomia definida. Nosso objetivo é relatar a neurotransmissão simpática cardíaca em doentes brasileiros com DP de novo esporádica, sem disautonomia clinicamente definida. Foi avaliada retrospectivamente uma série de 21 casos consecutivos com DP sem sintomas ou sinais de disautonomia observáveis pelos testes de beira-de-leito. Com a aplicação dos critérios de exclusão, este número foi reduzido para 14. A captação do 123I MIBG pelo SPECT foi baixa ou ausente em todos os pacientese; a relação coração / mediastino foi baixa em 12 dos 14. Concluímos que a 123c MIBG é capaz de identificar alteração da neurotransmissão simpática cardíaca em doentes com DP de novo sem disautonomia clinicamente definida.

Receptores NMDA: plasticidad sináptica y supervivencia neuronal / NMDA Receptors: Synaptic Plasticity and Neuronal Survival

Un objetivo clave de las investigaciones actuales es el estudio de las redes de señalización intracelular vinculadas a la plasticidad sináptica, así como a la supervivencia y a la muerte neuronal. Haremos una revisión bibliográfica acerca de la neurotransmisión glutamatérgica, en especial de los receptores NMDA, de las variantes en la composición de sus subunidades, y de su localización sináptica o extrasináptica que nos acerca a la comprensión de los mecanismos paradigmáticos de plasticidad sináptica como la potenciación de largo plazo (LTP) y la depresión de largo plazo (LTD), relacionados con la memoria y el aprendizaje, así como con las enfermedades neurodegenerativas generadas por la excitotoxicidad. También analizaremos las diferencias y roles opuestos del factor neurotrófico derivado del cerebro (BDNF) y del pro-BDNF en la supervivencia neuronal y la apoptosis. Y en una aplicación clínica de estos conceptos, revisaremos su influencia en el desarrollo de la enfermedad de Huntington...

A key goal of current research is to study the intracellular signaling networks associated with synaptic plasticity and survival and neuronal death. We will do a bibliographic review on glutamatergic neurotransmission, especially NMDA receptors, the variations in the composition of its subunits, and its synaptic or extrasynaptic localization, bringing us closer to understanding the paradigmatic mechanisms of LTP and LTD, related with memory and learning, as well as neurodegenerative diseases generated by excitotoxicity. We will also analyze the differences and opposing roles of BDNF and pro-BDNF in neuronal survival and apoptosis. And by clinically applying these concepts, we shall review its influece in the development of Huntington's disease...

Activation of group II metabotropic glutamate receptors blocks zinc release from hippocampal mossy fibers

BACKGROUND: The hippocampal CA3 area contains large amounts of vesicular zinc in the mossy fiber terminals which is released during synaptic activity, depending on presynaptic calcium. Another characteristic of these synapses is the presynaptic localization of high concentrations of group II metabotropic glutamate receptors, specifically activated by DCG-IV. Previous work has shown that DCG-IV affects only mossy fiber-evoked responses but not the signals from associational-commissural afferents, blocking mossy fiber synaptic transmission. Since zinc is released from mossy fibers even for single stimuli and it is generally assumed to be co-released with glutamate, the aim of the work was to investigate the effect of DCG-IV on mossy fiber zinc signals. RESULTS: Studies were performed using the membrane-permeant fluorescent zinc probe TSQ, and indicate that DCG-IV almost completely abolishes mossy fiber zinc changes as it does with synaptic transmission. CONCLUSIONS: Zinc signaling is regulated by the activation of type II metabotropic receptors, as it has been previously shown for glutamate, further supporting the corelease of glutamate and zinc from mossy fibers.

Evidence of presynaptic and postsynaptic action of local anesthetics in rats

PURPOSE: To assess the probable actions of ropivacaine, 50% enantiomeric excess bupivacaine mixture (S75-R25) and levobupivacaine on neuromuscular transmission in vitro. METHODS: Thirty rats were distributed into groups (n=5) according to the drug used: ropivacaine, bupivacaine (S75-R25) and levobupivacaine. The concentration used for the three local anesthetics (LA) was 5 µg.mL.-1The following parameters were evaluated: 1) LA effects on membrane potential (MP) and miniature end plate potential (MEPP). A chick biventer cervicis preparation was also used to evaluate LA effects on the contracture response to acetylcholine. RESULTS: LA did not alter MP values and decreased the frequency and amplitude of MEPP. In a chick biventer cervicis preparation, bupivacaine (S75-R25) and levobupivacaine decreased the contracture response to acetylcholine with statistical significance, in comparison to ropivacaine. CONCLUSIONS: In the concentrations used, levobupivacaine and bupivacaine (S75-R25) exhibited presynaptic and postsynaptic actions evidenced by alterations in miniature end plate potentials and contracture response to acetylcholine. Ropivacaine only had a presynaptic action.

Sleep pattern and learning in knockdown mice with reduced cholinergic neurotransmission

Impaired cholinergic neurotransmission can affect memory formation and influence sleep-wake cycles (SWC). In the present study, we describe the SWC in mice with a deficient vesicular acetylcholine transporter (VAChT) system, previously characterized as presenting reduced acetylcholine release and cognitive and behavioral dysfunctions. Continuous, chronic ECoG and EMG recordings were used to evaluate the SWC pattern during light and dark phases in VAChT knockdown heterozygous (VAChT-KDHET, n=7) and wild-type (WT, n=7) mice. SWC were evaluated for sleep efficiency, total amount and mean duration of slow-wave, intermediate and paradoxical sleep, as well as the number of awakenings from sleep. After recording SWC, contextual fear-conditioning tests were used as an acetylcholine-dependent learning paradigm. The results showed that sleep efficiency in VAChT-KDHET animals was similar to that of WT mice, but that the SWC was more fragmented. Fragmentation was characterized by an increase in the number of awakenings, mainly during intermediate sleep. VAChT-KDHET animals performed poorly in the contextual fear-conditioning paradigm (mean freezing time: 34.4±3.1 and 44.5±3.3 s for WT and VAChT-KDHET animals, respectively), which was followed by a 45% reduction in the number of paradoxical sleep episodes after the training session. Taken together, the results show that reduced cholinergic transmission led to sleep fragmentation and learning impairment. We discuss the results on the basis of cholinergic plasticity and its relevance to sleep homeostasis. We suggest that VAChT-KDHET mice could be a useful model to test cholinergic drugs used to treat sleep dysfunction in neurodegenerative disorders.

Trastorno Bipola: respuesta paradojar a la supresión de antidepresivos y neurotransmisión colinérgica / Bipolar disorder: paradoxical response to antidepressants withdrawal and cholinergic neurotransmission

El tratamiento farmacológico de los episodios depresivos en el trastorno bipolar resulta más complejo que el de los episodios maníacos. Además de restituir a un paciente a su estado eutímico, se pretende que su tratamiento no produzca virajes a la manía, ciclado rápido o episodios mixtos. Cuando los fármacos considerados de 1ª línea, litio, lamotrigina, fluoxetina asociada con olanzapina o quetiapina no han dado resultados adecuados, se han ensayado otras asociaciones, entre las que se encuentran aquellas controversiales con los antidepresivos. De manera muy poco frecuente, la aparición paradojal de hipomanías o manías, cuando se suspenden los antidepresivos que están asociados a antirecurrenciales, ha dado lugar a explicaciones que abordan el problema de la neurotransmisión colinérgica en el trastorno bipolar. Este trabajo pretende realizar una revisión sobre ese tema y mencionar posibilidades terapéuticas actuales que se sostienen en dicha neurotransmisión.

The pharmacological treatment of depressive episodes in bipolar disorder is more complex than the pharmacological treatment of manic episodes. In addition to returning a patient to their euthymic state, its treatment is intended not to produce returns to mania, rapid cycling, or mixed episodes. When drugs considered first line, like Lithium, Lamotrigine, Fluoxetine associated with Olanzapine, or Quetiapine, did not show adequate results, other associations have been tested, among which are those ones controversial with antidepressants. Infrequently, the paradoxical appearance of hypomania or mania, whenever the antidepressants which are associated to mood stabilizers are suspended, has led to explanations that address the problem of cholinergic neurotransmission in bipolar disorder. This paper aims to provide a review on the subject and to mention current therapeutic options that are held in such neurotransmission.

La intoxicación con cobre disminuye la sobrevida e induce alteraciones neurológicas en Drosophila melanogaster / Copper intoxication decreases lifespan and induces neurologic alterations in Drosophila melanogaster

La enfermedad de Wilson, es un trastorno hereditario autosómico recesivo causado por mutaciones del gen de la trifosfatasa de adenosina (ATP7B). Dicha mutación ocasiona intoxicación con cobre, generando manifestaciones clínicas por los efectos tóxicos del metal, principalmente a nivel del hígado y el encéfalo. Recientemente se han desarrollado modelos genéticos de la enfermedad para su estudio clínico. Sin embargo, la utilidad de los mismos es limitada por el hecho de que en tales modelos no se observan manifestaciones neurológicas. El presente estudio tuvo como objetivo desarrollar un modelo de la enfermedad de Wilson en Drosophila melanogaster. Inicialmente se evaluó el efecto de la suplementación con concentraciones de 31 µM y 47 µM de cobre en la sobrevida. Posteriormente se realizaron estudios de conducta para determinar si existían alteraciones en el desempeño motor asociadas al tratamiento con la dosis de 47 µM de cobre. Los resultados obtenidos sugieren que el tratamiento con cobre disminuye la viabilidad de la Drosophila. La disminución de la sobrevida estuvo asociada a un aumento y una disminución de los registros de actividad motora en las etapas tempranas y tardías de la intoxicación respectivamente. Por último, se evaluó el papel del sistema de neurotransmisión dopaminérgico sobre las alteraciones conductuales inducidas por el cobre. El tratamiento con el precursor de la dopamina, L-dopa, indujo un aumento de la actividad motora similar al inducido por el cobre. Por el contrario, el tratamiento con Flufenazina, un antagonista de los receptores dopaminérgicos D2, fue capaz de impedir las alteraciones conductuales en todas las edades evaluadas. Estos resultados sugieren que la Drosophila melanogaster podría ser empleada como modelo para el estudio de posibles intervenciones con potencial terapéutico en la enfermedad de Wilson.

Wilson disease is a hereditary disorder caused by mutations of the ATP7B gene, which leads to intoxication with copper as a result of an unbalance of copper homeostasis. The clinical manifestations resulting from this intoxication are related to the affectation of liver and the encephalon in most cases. Several animal models are currently available for the study of the malady. However, in such models no neurological symptoms are observed, which limits their use for the study of pathogenic effects of this disease on the central nervous system. The aim of the present study was to evaluate if copper feeding could induce a disease state in Drosophila melanogaster to model Wilson disease. The effect of the feeding of copper at the doses of 31 µM and 47 µM on the survival was initially evaluated. Next, behavioral experiments were conducted to determine whether the motor performance was altered by the 47 µM concentration. The results suggest that copper treatment decreases the viability of the flies. In addition, the decrease of viability was associated to an increase and decrease of spontaneous motor activity at early and late stages of the intoxication, respectively. Finally, the role of the dopaminergic neurotransmission system on the observed motor alterations was evaluated. The dopamine precursor L-dopa increased motor activity. In contrast, D2 receptor antagonist, Fluphenazine, was able to block both the increase and decrease of motor activity scores induced by copper. These results suggest that Drosophila melanogaster could be used as a model organism for the study of possible interventions with potential neuroprotective effects in Wilson disease.