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Salud mental

versão impressa ISSN 0185-3325

Salud Ment vol.29 no.3 México Mai./Jun. 2006

 

Artículos originales

5-Hydroxytryptaminie and plasticity in rodents

María Guadalupe Flores Cruz1 

Alfonso Escobar Izquierdo1 

1Depto de Biología Celular y Fisiología. Instituto de Investigaciones Biomédicas. UNAM. Ciudad Universitaria, 04510, México DF.


Abstract:

The attributes that characterize a molecule as neurotransmitter at CNS are: i . neuronal synthesis, ii . being present at presynapsis, iii. Ca2+-dependent release, iv. postsynaptic actions mediated by receptors, v. an elimination mechanism at synapse. Since 1964, 5-hydroxytryptamine (5-HT) was included as a neurotransmitter and is part of a set of neurotransmitters named biogenic amines.

In rodents, the 5-hydroxytryptaminergic system is constituted by nine nuclei at brainstem, and divided in two groups, rostral and caudal by ther localization. The rostral group projects mainly to the telencephalon and diencephalon, while the caudal group does it to the spinal cord. 5-HT innervation to brainstem and cerebellar nuclei have been also described.

The most well-known function of 5-hydroxytryptamine (5-HT) in the CNS is neuromodulation, in processes such as memory, learning, mood, sleep-wake cycle; all of these are regulated by this biogenic amine through a wide family of receptors. All the receptors are metabotropic with the sole exception of 5-HT1, which is an ionotropic receptor.

The 5-HT system differentiates early in ontogenesis; 5-HT immunoreactive neurons are evident in rat fetuses at embryonic day 12 (E12), when almost any other neuronal lineage possesses a cellular commitment. This fact highlights the importance 5-HT has at neurodevelopment.

Scientific works are focused in the 5-HT auto-regulatory signalling for neuropil outgrowth at ontogeny, another remarkable trait of the 5-HT system. In addition, 5-HT releases astrocyte neurotrophic factor S-100 beta, necessary for dendritic maintenance. The 5-HT set point at different stages during ontogeny remains unknown.

Several target structures of the 5-HT system are dependent on the level of 5-HT activity in newborn rodents; e.g. the somatosensory cortex where proper barrel field arrangement requires an active 5-HT innervation.

Moreover, besides the 5-HT level, other factors, such as the level of reelin, are determinant for the proper cytoarchitectonic organization of the neocortex. The use of 5-methoxytryptamine, an unespecific 5-HT agonist, in the prenatal period, which negatively affects the reelin level, leads to cytoarchitectonic derangement, as it has been described to occur in the presubicular cortex.

5-HT and plasticity are also related to neurogenesis in adulthood. Neurogenesis in adulthood is influenced by several factors. Some of them, such as exercise and an enriched environment, increase the rate of newly born neurons in the dentate gyrus and olfactory bulb; while others, such as mood depression (in humans), low 5-HT levels, 5-HT1A receptor blockade by antagonists, or down-regulation, account for a poor neurogenesis rate.

Chronic administration of 5-HT reuptake inhibitors, such as fluoxetine, increases the number of bromodeoxiuridine- labelled (BrdU) granule cells at the dentate gyrus and hilus versus control rats. This means that fluoxetine increases the neurogenesis rate. Newly born granule cells at dentate gyrus are more likely to survive, thus contributing to maintaining the hippocampal volume unchanged.

On the contrary, following chronic 5-HT antagonist administration, specifically 5-HT1A receptor blockade BrdU-labelled granule cells in dentate gyrus are 30% reduced.

Reduced hippocampal volume develops in humans affected by major depression, concomitant in some cases with a decrease in 5-HT neurotransmiter level. Recent studies linking 5-HT neurogenesis stimulation in dentate gyrus explain why plastic phenomena associated to pathology could be reversed by 5-HT reuptake inhibitors like fluoxetine. These works contribute to a better understanding of both depression etiology and clinical approach.

Key words: 5-Hydroxytrypamine; neurodevelopment; neurogenesis; fluoxetine; BrdU

Resumen:

Se considera que la 5-hidroxitriptamina (5-HT) como un neurotransmisor en el SNC si cubre los siguientes criterios: i. síntesis y vesiculación al interior de la neurona, ii. presencia de la molécula en la presinapsis, iii . liberación en un mecanismo dependiente de Ca+2, iv. acción postsináptica mediada por receptores para la molécula y v. presencia de mecanismos de recaptura y degradación.

Los cuerpos celulares de las neuronas que sintetizan 5-HT se agrupan en nueve núcleos distribuidos en el tallo cerebral. A su vez, estos núcleos se dividen en dos grandes grupos, rostral y caudal, de acuerdo con su localización.

El grupo rostral inerva principalmente el telencéfalo y el diencéfalo, mientras que el grupo caudal hace lo propio con la médula espinal.

La actividad del sistema 5-HT es neuromoduladora, esto es, interviene en la regulación de la actividad neuronal por medio de receptores, todos ellos metabotrópicos, con excepción del receptor 5-HT 3, que es ionotrópico. Los procesos relacionados con el sistema 5-HT comprenden la regulación del talante emocional, el aprendizaje, la memoria, la regulación del tono muscular, la ingesta de alimentos, la conducta sexual y la regulación del ciclo sueño-vigilia en humanos.

Durante el desarrollo, las primeras neuronas inmunorreactivas a 5-HT se observan en el día 12 de la gestación de ratas a lo largo del borde entre el metencéfalo y el mielencéfalo rostral, en la región externa de la zona ventricular. El pico de proliferación celular para este fenotipo ocurre en E15 y, pese a que la inervación completa del SNC concluye en la tercera semana de vida post natal, al nacimiento están presentes la totalidad de las neuronas 5-HT, así como las principales proyecciones de este sistema.

La relevancia de la 5-HT es notoria al observarse los procesos con que se relaciona durante el desarrollo. Uno de ellos es la elongación axónica en función de un gradiente de concentración. Al momento en que los neuroblastos intervienen en el nivel celular y se diferencian en neuronas 5-HT, sintetizan y secretan el neurotransmisor. De esta forma, el milieu posee un gradiente 5-HT que influye en la elongación axónica por medio de un asa de retroalimentación negativa.

Otra forma en que la 5-HT incide en el neurodesarrollo es al promover la secreción del factor neurotrófico derivado de astrositos: S-100p. Esta proteína estimula el crecimiento neurítico en las neuronas 5-HT y contribuye a mantener la inervación 5-HT a las estructuras blanco.

La administración prenatal de 5-metoxitriptamina, agonista específico 5-HT, provocó alteraciones citoarquitectónicas en la corteza presubicular de las crías evaluadas en P7. Con lo anterior se sugiere, por último, que la 5-HT influye en el desarrollo de sus estructuras blanco.

El vínculo entre 5-HT y plasticidad continúa en la vida adulta, cuando la 5-HT sostiene una estrecha relación con la neurogénesis en el giro dentado.

Trastornos y procesos como el estrés crónico, la depresión (en humanos) y la disminución en el nivel de 5-HT, así como la administración de antagonistas del receptor 5-HT1A, disminuyen la tasa de proliferación neuronal, evaluada mediante el marcaje de células recién generadas con bromodeoxiuridina. Esto lo efectúan en una magnitud similar a la que se observa tras la administración de un inhibidor de la síntesis de 5-HT. Por otra parte, la administración crónica de inhibidores de la recaptura de 5-HT, como la fluoxetina, incrementa la tasa de neurogénesis en ratas adultas. Estos trabajos resaltan la importancia del sistema 5-HT a lo largo de toda la vida del individuo en los fenómenos de plasticidad.

Palabras clave: 5-Hidroxitriptamina; neurodesarrollo; neurogénesis; fluoxetina; BrdU

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Received: May 09, 2006; Accepted: May 26, 2006

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