Antipsychotiques, dopamine et glutamate, une relation à établir

Plus de 50 ans après leur découverte, nous savons encore très peu du mécanisme d’action des agents antipsychotiques. D’autre part, il est surprenant de constater que nous savons également bien peu de choses à propos du fonctionnement normal des systèmes de neurotransmission qui sont ciblés par ces molécules. Dans le cadre de cette brève réflexion, nous aborderons deux sujets principaux : d’une part, nous discuterons du mode d’action des antipsychotiques afin d’en arriver au constat qu’une meilleure compréhension de la plasticité structurale du cerveau induite par les antipsychotiques est nécessaire. D’autre part, nous lèverons le voile sur le comportement mystérieux d’une des populations neuronales ciblées par les antipsychotiques, à savoir les neurones produisant le neurotransmetteur dopamine. Nous verrons que des découvertes récentes ont montré que ces neurones sont en quelque sorte polygame, utilisant non seulement la dopamine, mais aussi le glutamate comme neurotransmetteur. Dans le contexte des théories récentes suggérant que la schizophrénie implique une perturbation à la fois de la neurotransmission dopaminergique et glutamatergique, cette découverte ouvre de nouvelles pistes quant aux relations entre schizophrénie, dopamine et glutamate.More than 50 years after their discovery, we still know very little about the mechanism of action of antipsychotic drugs. Moreover, it is surprising to realize that we also know very little about the basic functioning of the neuronal systems that are targeted by such pharmacological agents in the central nervous system. In this brief commentary, we will address two major issues: first, we will consider the mechanisms of action of antipsychotic drugs and reach the conclusion that a better understanding of the structural plasticity induced by chronic administration of such agents in the brain is required. Second, we will highlight some of the peculiar properties of one of the neuronal populations targeted by antipsychotics, namely the neurons that produce the neurotransmitter dopamine. We will see that recent discoveries have demonstrated that such neurons are in some ways polygamous, producing and releasing not only dopamine, but also glutamate as a neurotransmitter. In the context of recent theories suggesting that schizophrenia involves perturbations of not only dopamine but also glutamate-mediated neurotransmission, these recent findings open new opportunities in our quest to explain the complicated interrelations between schizophrenia, dopamine and glutamate.Más de 50 años después de su descubrimiento, sabemos todavía muy poco del mecanismo de acción de los agentes antipsicóticos. Por otra parte, es sorprendente constatar que también sabemos muy poco de las cosas al respecto del funcionamiento normal de los sistemas de neurotransmisión que son el blanco de estas moléculas. En el marco de esta breve reflexión, abordaremos dos temas principales: por una parte, trataremos el modo de acción de los antipsicóticos a fin de llegar a constatar que es necesaria una mejor comprensión de la plasticidad estructural del cerebro inducida por los antipsicóticos. Por otra parte, develaremos el comportamiento misterioso de una de las poblaciones neuronales blanco de los antipsicóticos, es decir, las neuronas que producen el neurotransmisor dopamina. Veremos que los descubrimientos recientes han mostrado que estas neuronas son de cierta forma polígamas, que no sólo utilizan la dopamina sino también el glutamato como neurotransmisor. En el contexto de las teorías recientes, que sugieren que la esquizofrenia implica una perturbación a la vez de la neurotransmisión dopaminérgica y glutaminérgica, este descubrimiento presenta pistas nuevas en cuanto a las relaciones entre esquizofrenia, dopamina y glutamato.Há mais de 50 anos após sua descoberta, ainda sabemos muito pouco sobre o mecanismo de ação dos agentes antipsicóticos. Por outro lado, é surpreendente constatar que também sabemos muito pouco a respeito do funcionamento normal dos sistemas de neurotransmissão que são escolhidos por estas moléculas. Dentro desta breve reflexão, abordaremos dois assuntos principais: por um lado, discutiremos o modo de ação dos antipsicóticos, a fim de chegar a uma constatação de que uma melhor compreensão da plasticidade estrutural do cérebro induzida pelos antipsicóticos é necessária. Por outro lado, esclareceremos sobre o comportamento misterioso de uma das populações neuronais buscadas pelos antipsicóticos, a saber, os neurônios que produzem o neurotransmissor dopamina. Veremos que descobertas recentes demonstraram que estes neurônios são, de alguma maneira, polígamos, utilizando não apenas a dopamina, mas também o glutamato como neurotransmissor. No contexto das teorias recentes que sugerem que a esquizofrenia implica em uma perturbação ao mesmo tempo da neurotransmissão dopaminérgica e glutamatérgica, esta descoberta abre novas pistas quanto às relações entre esquizofrenia, dopamina e glutamato

Pendidikan Kewarganegaraan untuk Membangun Wawasan Global Warga Negara Muda

Penelitian ini bertujuan untuk menemukan nilai-nilai dasar yang perlu dikembangkan dalam pendidikan kewarganegaraan untuk membangun wawasan global warga negara muda. Penelitian menggunakan pendekatan kualitatif dengan metode grounded theory. Sumber data terdiri atas sumber kepustakaan dan responden yang dipilih dengan menggunakan metode purposive sampling.Teknik pengumpulan data menggunakan studi dokumentasi, wawancara, dan observasi. Analisis data menggunakan analisis induktif. Hasil penelitian menunjukkan bahwa nilai-nilai dasar yang perlu dikembangkan dalam pendidikan kewarganegaraan untuk membangun wawasan global warga negara muda dalam konteks Indonesia antara lain adalah ketuhanan, kemanusiaan, persatuan, kerakyatan, keadilan sosial, kompetisi, menghormati orang lain, kemerdekaan, dan perdamaian

Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons

SummaryAlthough the mechanisms underlying the loss of neurons in Parkinson’s disease are not well understood, impaired mitochondrial function and pathological protein aggregation are suspected as playing a major role. Why DA (dopamine) neurons and a select small subset of brain nuclei are particularly vulnerable to such ubiquitous cellular dysfunctions is presently one of the key unanswered questions in Parkinson’s disease research. One intriguing hypothesis is that their heightened vulnerability is a consequence of their elevated bioenergetic requirements. Here, we show for the first time that vulnerable nigral DA neurons differ from less vulnerable DA neurons such as those of the VTA (ventral tegmental area) by having a higher basal rate of mitochondrial OXPHOS (oxidative phosphorylation), a smaller reserve capacity, a higher density of axonal mitochondria, an elevated level of basal oxidative stress, and a considerably more complex axonal arborization. Furthermore, we demonstrate that reducing axonal arborization by acting on axon guidance pathways with Semaphorin 7A reduces in parallel the basal rate of mitochondrial OXPHOS and the vulnerability of nigral DA neurons to the neurotoxic agents MPP+ (1-methyl-4-phenylpyridinium) and rotenone. Blocking L-type calcium channels with isradipine was protective against MPP+ but not rotenone. Our data provide the most direct demonstration to date in favor of the hypothesis that the heightened vulnerability of nigral DA neurons in Parkinson’s disease is directly due to their particular bioenergetic and morphological characteristics

Découvertes récentes sur la fonction et la plasticité des voies dopaminergiques du cerveau

Bien que la dopamine ait été découverte il y a plus de 50 ans, l’étendue des connaissances sur ses fonctions physiologiques et sur ses dérèglements pathologiques demeure restreinte. Des travaux récents ont levé le voile sur de nouvelles et surprenantes propriétés des neurones à dopamine, ainsi que sur celles d’autres partenaires de la régulation du système dopaminergique. Par exemple, on a observé que l’intégration du signal de la dopamine par ses récepteurs dépend de plusieurs protéines engagées dans diverses cascades de signalisation. On a remarqué qu’elle dépend aussi d’autres types de récepteurs qui interagissent fonctionnellement avec les récepteurs à dopamine. De plus, nous constatons graduellement que le traitement à long terme de certaines maladies à l’aide de nombreux médicaments qui agissent sur le système dopaminergique entraîne à la longue des adaptations d’ordre fonctionnel, structurel et moléculaire au sein de ce système. Ces nouvelles observations pourraient aider à déceler de nouvelles cibles thérapeutiques. Enfin, la découverte de la co-libération du glutamate par les neurones à dopamine nous amène à reconsidérer certains aspects de la physiologie fondamentale de ces neurones

Evaluation of D1 and D2 dopamine receptor segregation in the developing striatum using BAC transgenic mice.

The striatum is predominantly composed of medium spiny neurons (MSNs) that send their axons along two parallel pathways known as the direct and indirect pathways. MSNs from the direct pathway express high levels of D1 dopamine receptors, while MSNs from the indirect pathway express high levels of D2 dopamine receptors. There has been much debate over the extent of colocalization of these two major dopamine receptors in MSNs of adult animals. In addition, the ontogeny of the segregation process has never been investigated. In this paper, we crossed bacterial artificial chromosome drd1a-tdTomato and drd2-GFP reporter transgenic mice to characterize these models and estimate D1-D2 co-expression in the developing striatum as well as in striatal primary cultures. We show that segregation is already extensive at E18 and that the degree of co-expression further decreases at P0 and P14. Finally, we also demonstrate that cultured MSNs maintain their very high degree of D1-D2 reporter protein segregation, thus validating them as a relevant in vitro model