Human GRIN2B blocking peptide

The dopamine and glutamate hypotheses reflect only some of the pathophysiological changes associated with schizophrenia. We have proposed a new comprehensive progressive pathophysiology model based on the dopamine to glutamate hypothesis. Repeated administration of methamphetamine (METH) at a dose of 2.5mg/kg in rats has been used to assess dynamic changes in the pathophysiology of schizophrenia. Previous use of this model suggested N-methyl-d-aspartate receptor (NMDA-R) dysfunction, but the mechanism could only be inferred from limited, indirect observations. In the present study, we used this model to investigate changes in the expression of NMDA-R subunits. Repeated administration of METH significantly decreased the gene expression levels of glutamate ionotropic receptor NMDA type subunit (Grin) subtypes Grin1 and Grin2c in the prefrontal cortex (PFC), Grin1 and Grin2a in the hippocampus (HPC), and Grin1, Grin2b, and Grin2d in the striatum (ST).We observed a significant difference in Grin1 expression between the PFC and ST. Furthermore, repeated administration of METH significantly decreased the protein expression of GluN1 in both cytosolic and synaptosomal fractions isolated from the PFC, and significantly decreased the protein expression of GluN1 in the cytosolic fraction, but not the synaptosomal fraction from the ST. These regional differences may be due to variations in the synthesis of GluN1 or intracellular trafficking events in each area of the brain. Considering that knockdown of Grin1 in mice affects vulnerability to develop schizophrenia, these results suggest that this model reflects some of the pathophysiological changes of schizophrenia, combining both the dopamine and glutamate hypotheses.

We aimed to assess whether allelic variants of dopamine receptor, glutamate receptor, and serotonin transporter genes are associated with the appearance of impulse control and related behaviors (ICRB) in Parkinson's disease (PD) with dopamine replacement therapy (DRT). We surveyed ICRB in consecutive Korean patients with PD who were treated with stable DRT using modified Minnesota Impulsive Disorders Interview over a period of 4 months. In the 404 patients who completed the interview and the 559 Korean healthy normal controls, genotyping was performed for variants of the DRD3 p.S9G, DRD2 TaqlA, GRIN2B c.366C>G, c.2664C>T and c.-200T>G, and the promoter region of the serotonin transporter gene (5-HTTLPR). Behavioral abnormalities suggestive of ICPB including compulsive buying, gambling, sexual behavior and eating, and punding, were present in 14.4% of the patients. Variants of DRD2 and 5-HTTLPR were not associated with the risk of developing ICRB. However, the AA genotype of DRD3 p.S9G and the CC genotype of GRIN2B c.366C>G were more frequent in patients with ICRB than in nonaffected patients (odds ratio [OR] = 2.21, P = 0.0094; and 2.14, P = 0.0087, after adjusting for age and sex). After controlling for clinical variables in the multivariate analysis, carriage of either AA genotype of DRD3 or CC genotype of GRIN2B was identified as in independent risk factor for ICRB (adjusted OR: 2.57, P = 0.0087). Variants of DRD3 p.S9G and GRIN2B c.366C>G may be associated with the appearance of ICRB in PD. (C) 2009 Movement Disorder Society