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Abstract: It is well known that in certain disease states, including ischemia and Alzheimer''s disease, neurodegeneration occurs in the hippocampus and that vulnerability to neuronal death is area dependent. The present study investigated the mechanism of area-dependent vulnerability to neuronal death under endoplasmic reticulum stress conditions induced by tunicamycin (TM), using rat organotypic hippocampal cultures (OHC) and hippocampal slices. Analysis of propidium iodide uptake showed that TM-induced neuronal death in a concentration-dependent manner (20–80μg/mL) and that the rank order of vulnerability among hippocampal subregions was dentate gyrus (DG)>CA1>CA3. Results of immunohistochemistry using hippocampal slices also showed that procaspase-12-positive cells in area CA3 were significantly fewer than those in area CA1 and the DG. Moreover, procurement of neurons in areas CA1, CA3 and the DG by laser microdissection, followed by Western blot analysis, also revealed that the level of procaspase-12 in area CA3 was significantly lower than those in area CA1 and the DG. Pretreatment with z-ATAD-fmk, a cell-permeable caspase-12-selective inhibitor significantly attenuated the TM-induced increase of PI fluorescence in the CA1 and DG subregion but not in area CA3. These results suggest that TM elicits subregion-specific neuronal toxicity in OHC and that the vulnerability to TM-induced toxicity is at least partly dependent on the expression level of endogenous procaspase-12 in each area of the hippocampus. [Copyright &y& Elsevier]

Abstract: We have evaluated the effect of the systemic administration of MK-801 (0.4 mg/kg) on the gene expression of d-amino acid oxidase (DAO) in several brain areas of the rat. The levels of DAO mRNA in all the brain areas significantly increased and peaked at 4 h after the administration. The present results suggest that there is a link between the expression of DAO mRNA and the N-methyl-d-aspartate (NMDA) receptor activity. [Copyright &y& Elsevier]

Abstract: This study investigated the influence of diazepam on the binding characteristics of adrenoceptor, muscarinic and benzodiazepine receptors in rat parotid gland membrane using a radioligand binding assay. At a concentration of >10−6 M, diazepam competed with [3H]dihydroalprenolol for β-adrenoceptor, but not [3H]prazosin for α-adrenoceptor or [3H]quinuclidinyl benzilate for muscarinic receptor. Continuous administration of diazepam at doses of 0.4mg/kg/day, i.p. for 7days in rat significantly decreased pilocarpine (4.0mg/kg, i.p.)-induced parotid salivary flow. Diazepam also produced a significant increase in the dissociation constant (Kd) value for [3H]dihydroalprenolol binding, but no change in the maximal binding capacity (Bmax) value, and a decrease in the Kd value for [3H]diazepam binding to benzodiazepine receptors, but no change in the Kd or Bmax values for [3H]prazosin or [3H]quinuclidinyl benzilate binding. These results suggest that continuous administration of diazepam modifies affinity for β-adrenoceptor and benzodiazepine receptor binding sites in parotid gland membrane and that changes in these binding sites may be closely related to diazepam-induced suppression of salivary secretion. [Copyright &y& Elsevier]

Abstract: We have investigated the acute effects of the increasing doses of non-competitive N-methyl-d-aspartate receptor antagonist MK-801 (0.2–1.6 mg/kg) on the expression of serine racemase and d-amino acid oxidase (DAO) mRNAs in several brain areas of rats. We have also evaluated the effects of the chronic administration of MK-801 (0.4 mg/kg) on the gene expression of serine racemase and DAO and on the d-serine concentrations. A dose-dependent augmentation of the expression of serine racemase mRNA was seen in most brain areas at both 1 and 4 h after the administration. In contrast, a drastic decline in the expression of DAO mRNA was observed in most brain areas 1 h after the MK-801 administration, whereas a dose-dependent elevation in the expression of DAO mRNA was observed in most brain areas 4 h after the administration. The chronic MK-801 administration produced a significant increase in the expression of serine racemase mRNA in almost all brain areas, whereas no significant changes were found in the level of DAO mRNA in most brain areas. In addition, the chronic administration caused a slight but significant elevation in the concentrations of d-serine in the cortex and striatum. These present findings indicate that increasing the serine racemase mRNA and no changes in the DAO mRNA after the chronic administration could contribute to the elevation of the d-serine level in the forebrain, and that serine racemase and DAO could play an important role in the regulation of N-methyl-d-aspartate receptors via the d-serine metabolism. [Copyright &y& Elsevier]

Abstract: We have evaluated the effects of the acute administration of noncompetitive N-methyl-d-aspartate receptor antagonist, ketamine, on the expression of serine racemase and d-amino acid oxidase mRNAs in several brain areas of rats. The ketamine administration produced a dose-dependent and transient elevation in the levels of serine racemase and d-amino acid oxidase mRNAs in all the brain areas. These findings suggest that there is a relationship between the gene expression of the d-serine-related enzymes and the blockade of the N-methyl-d-aspartate receptors. [Copyright &y& Elsevier]

Abstract: To obtain further insight into the interactions between the N-methyl-d-aspartate receptor and opioid receptor systems, we have investigated the effects of the acute treatment of morphine on the expression of serine racemase and d-amino acid oxidase mRNAs in several brain areas of rats. The morphine administration produced a dose-dependent and transient elevation in the levels of serine racemase and d-amino acid oxidase mRNAs in all the brain areas. The present results are the first to suggest an interaction between the expression of the mRNAs for the d-serine-related enzymes and the opioid receptor activation. [Copyright &y& Elsevier]

We have used real-time quantitative PCR methods to evaluate the effect of the systemic administration of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801; 0.4 mg/kg) on the gene expression of serine racemase in several brain areas of the rat. The levels of serine racemase mRNA in all the brain areas transiently increased after the administration. The present findings suggest that there is a link between the expression of serine racemase mRNA and the activity of the NMDA receptors. [Copyright &y& Elsevier]

Abstract: Real-time quantitative PCR, Western blot and in situ hybridization techniques were employed to clarify the presence of serine racemase in the primary cultures of rat neurons. We have detected both serine racemase mRNA and protein in the cultured neurons. Both the mRNA and the protein levels in the neurons are higher than those in the astrocytes. Sequential detection of serine racemase mRNA and MAP2 immunoreactivity also revealed that serine racemase and MAP2 are co-localized in the cultured neurons. These data are the first to demonstrate that a substantial amount of serine racemase exists in the cultured neurons. [Copyright &y& Elsevier]