RESUMEN
The role of excitotoxicity in the cerebral damage of glutaryl-CoA dehydrogenase deficiency (GDD) is under intense debate. We therefore investigated the in vitro effect of glutaric (GA) and 3-hydroxyglutaric (3-OHGA) acids, which accumulate in GDD, on [(3)H]glutamate uptake by slices and synaptosomal preparations from cerebral cortex and striatum of rats aged 7, 15 and 30 days. Glutamate uptake was significantly decreased by high concentrations of GA in cortical slices of 7-day-old rats, but not in cerebral cortex from 15- and 30-day-old rats and in striatum from all studied ages. Furthermore, this effect was not due to cellular death and was prevented by N-acetylcysteine preadministration, suggesting the involvement of oxidative damage. In contrast, glutamate uptake by brain slices was not affected by 3-OHGA exposure. Immunoblot analysis revealed that GLAST transporters were more abundant in the cerebral cortex compared to the striatum of 7-day-old rats. Moreover, the simultaneous addition of GA and dihydrokainate (DHK), a specific inhibitor of GLT1, resulted in a significantly higher inhibition of [(3)H]glutamate uptake by cortical slices of 7-day-old rats than that induced by the sole presence of DHK. We also observed that both GA and 3-OHGA exposure did not alter the incorporation of glutamate into synaptosomal preparations from cerebral cortex and striatum of rats aged 7, 15 and 30 days. Finally, GA in vivo administration did not alter glutamate uptake into cortical slices from 7-day-old rats. Our findings may explain at least in part why cortical neurons are more vulnerable to damage at birth as evidenced by the frontotemporal cortical atrophy observed in newborns affected by GDD.
Asunto(s)
Animales Recién Nacidos/metabolismo , Corteza Cerebral/metabolismo , Glutamatos/farmacocinética , Glutaratos/administración & dosificación , Glutaratos/metabolismo , Acetilcisteína/administración & dosificación , Acetilcisteína/metabolismo , Animales , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/metabolismo , Glutamatos/metabolismo , Glutaril-CoA Deshidrogenasa/deficiencia , Técnicas In Vitro , Ácido Kaínico/análogos & derivados , Ácido Kaínico/metabolismo , Neostriado/metabolismo , Ratas , Ratas Wistar , Sinaptosomas/metabolismoRESUMEN
The excitotoxicity of the neurotransmitter glutamate has been shown to be connected with many acute and chronic diseases of the CNS. High affinity sodium-dependent glutamate transporters play a key role in maintaining adequate levels of extracellular glutamate. In the present study, we used slices of striatum, hippocampus and cortex from rat brain to describe the in vitro profile of glutamate uptake during development and ageing, and its sensitivity to guanosine. In all structures, glutamate uptake was higher in immature animals. There was a maximum decrease in glutamate uptake in striatum and hippocampus in 15-month-old rats, which later increased, while in cortex there was a significant decrease in rats aged 60 days old. The effect of guanosine seems to be age and structure dependent since the increase in basal glutamate uptake was only seen in slices of cortex from 10-day-old animals.
Asunto(s)
Envejecimiento/fisiología , Encéfalo/metabolismo , Glutamatos/farmacocinética , Guanosina/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Técnicas In Vitro , Masculino , Ratas , Ratas WistarRESUMEN
Este artículo constituye una revisión del substrato neuroquímico de los efectos conductuales del etanol (ETOH), en especial sus propiedades gratificantes positivas y la tolerancia y dependencia física que su consumo produce, a partir de estudios en animales, haciendo referencia también a resultados obtenidos en humanos. La mayoría de los sistemas de neurotransmisión están involucrados en las acciones conductuales del ETOH, principalmente las monoaminas y los opioides. Sus efectos depresores a altas dosis, estimulantes a bajas dosis e hipotérmicos parecen tener bases distintas. Mientras que la activación catecolaminérgica está relacionada con los efectos estimulantes, los mecanismos gabérgicos están más involucrados con los depresores