Differential impact of N-Methyl-D-Aspartate Receptor antagonists on genes involved in synaptic plasticity and neural glucose metabolism: implication for psychosis.
Sarappa, Chiara (2011) Differential impact of N-Methyl-D-Aspartate Receptor antagonists on genes involved in synaptic plasticity and neural glucose metabolism: implication for psychosis. [Tesi di dottorato] (Inedito)
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Background: NMDA-R-hypofunction (NRH) is considered one of the putative molecular mechanism involved in psychosis. Several studies show that an imbalance of dopamine–glutamate transmission has a key role in psychosis pathophysiology. Preclinical and clinical data indicate that NMDA-Rs antagonists may affect cortical and striatal pathways and animal models of NRH suggest profound changes in synaptic gene expression and in expression of genes involved in neural glucose metabolism. Our aim was to investigate the molecular changes putatively occurring in multiple biological systems in an animal model that has been widely used to resemble psychotic-like behaviors in preclinical studies. Methods: 1) Gene expression of Hk1 (coding for the enzyme catalyzing glycolysis) and GLUT3 (coding for the main membrane transporter involved in glucose intake within neurons) were investigated in an acute paradigm after the administration of Ketamine (12mg/kg and 50mg/kg). 2) Gene expression of D1R-D2R-DAT were investigated in an acute paradigm after the administration of Ketamine (12mg/kg and 50mg/kg) and in a subchronic paradigm after the administration of ketamine (12mg/kg). 3) Gene expression of PSD-genes (Homer 1a, Homer 1b, Arc and PSD-95) and c-fos were investigated in an acute paradigm after the administration of Memantine (5mg/kg), MK-801 (0,8mg/kg), Ketamine (25mg/kg and 50mg/kg). We used male Sprague-Dawley rats and performed In Situ Hybridization Histochemistry in order to analyze gene expression for its quantitative and topographical pattern. Results: Glucose metabolism may be impaired by ketamine, causing an increase in the expression of Hk1 gene, and a decrease in the expression of the GLUT3 as adaptive changes in glucose metabolism; acute ketamine reduces D1R expression while subchronic ketamine increases dopamine D2R and DAT expression as feedback mechanism to avoid hyperdopaminergia; memantine induces different and somewhat opposite molecular changes in PSD gene expression when compared to the fully NMDA-R antagonists ketamine and MK-801 activating, probably, divergent intracellular pathways and so explaining the divergent clinical outcomes of these compounds. Conclusions: The overall conclusion that stems from the different paradigms investigated in this study and based on subanaesthetic ketamine administration model of psychosis in rats is that multiple changes in gene expression occur after NMDA-R-blockade in cortical and subcortical regions and affect the transcription of genes involved in glucose metabolism and dopamine-glutamate interaction.
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