No association of G72 and D-amino acid oxidase genes with schizophrenia

The genes of D-amino acid oxidase (DAAO) activator (DAOA or G72; 13q34) and DAAO (12q24) have been suggested as candidate genes and involved in the N-methyl-D-aspartate receptor regulation pathway for schizophrenia. In order to evaluate the potential association of these two genes with schizophrenia in a Taiwanese sample, three single nucleotide polymorphisms (SNPs) for DAAO (rs2111902, rs3918346, rs3741775) and eleven SNPs for G72 (rs3916965, rs3916966, rs3916967, rs2391191, rs3916968, rs947267, rs778294, rs3916970, rs3916971, rs778293, rs3918342) were genotyped by the MALDI-TOF mass spectrometry method in 218 families (864 individuals) containing at least two siblings affected with schizophrenia. In SNP-based single locus association analyses, neither G72 nor DAAO showed significant association with schizophrenia. Additionally, a three-SNP haplotype in DAAO, and a four-SNP as well as a two-SNP haplotype in G72, showed no significant associations with schizophrenia. These results suggest that the DAAO and G72 genes are not susceptibility genes for schizophrenia in a Taiwanese sample.     

Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia

Müller DJ, Zai CC, Shinkai T, Strauss J, Kennedy JL. Association between the DAOA/G72 gene and bipolar disorder and meta‐analyses in bipolar disorder and schizophrenia.
Bipolar Disord 2011: 13: 198–207. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objective: The d ‐amino acid oxidase activator (DAOA, or G72) is involved in the oxidation of d ‐serine, an endogenous modulator of N‐methyl‐d ‐aspartate receptors and thus represents an important candidate in psychotic disorders. Several studies reported the DAOA/G72 gene to be associated with schizophrenia (SZ) and bipolar disorder (BD); however, the associated polymorphisms varied between SZ and BD. This study attempts to replicate the DAOA/G72 findings in BD and to conduct subgroup analyses based on the presence or absence of psychotic symptoms. Methods: Five polymorphisms of the DAOA/G72 gene (rs1341402, rs1935062, rs2391191, rs947267, and rs778294) were analysed for association with BD in a family‐based study design (303 core families including 916 individuals). We also conducted a meta‐analysis of DAOA/G72 polymorphisms in BD and SZ. Results: Marker rs1935062 was significantly associated with BD diagnosis in our sample (Z‐score for C‐allele = ?2.33, p = 0.02, uncorrected for genome‐wide multiple comparisons). When we examined the subset of BD patients with psychotic symptoms (157 families), no significant results were obtained. Our meta‐analysis yielded negative findings for DAOA/G72 markers in BD and positive findings for marker rs2391191 in SZ in East Asians. However, significant heterogeneity across studies limits interpretation. Conclusions: Our results provide evidence that suggests a possible role of the DAOA/G72 gene in BD and SZ. Marker rs1935062 may be specifically associated with BD, while marker rs2391191 may be associated with SZ but not with BD. Together with previous studies, these findings suggest that the DAOA/G72 gene confers susceptibility to both BD and SZ, but that different polymorphisms may potentially differentiate between these two disorders.     

Adjunctive sarcosine plus benzoate improved cognitive function in chronic schizophrenia patients with constant clinical symptoms: A randomised,double-blind,placebo-controlled trial

Objectives Hypofunction of NMDA receptor is implicated in the pathophysiology, particularly cognitive impairment, of schizophrenia. Sarcosine, a glycine transporter I (GlyT-1) inhibitor, and sodium benzoate, a d-amino acid oxidase (DAAO) inhibitor, can both enhance NMDA receptor-mediated neurotransmission. We proposed simultaneously inhibiting DAAO and GlyT-1 may be more effective than inhibition of either in improving the cognitive and global functioning of schizophrenia patients. Methods This study compared add-on sarcosine (2?g/day) plus benzoate (1?g/day) vs. sarcosine (2?g/day) for the clinical symptoms, as well as the cognitive and global functioning, of chronic schizophrenia patients in a 12-week, double-blind, randomised, placebo-controlled trial. Participants were measured with the Positive and Negative Syndrome Scale and the Global Assessment of Functioning Scale every 3 weeks. Seven cognitive domains, recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Committee, were measured at weeks 0 and 12. Results Adjunctive sarcosine plus benzoate, but not sarcosine alone, improved the cognitive and global functioning of patients with schizophrenia, even when their clinical symptoms had not improved. Conclusions This finding suggests N-methyl-d-aspartate receptor-enhancement therapy can improve the cognitive function of patients with schizophrenia, further indicating this pro-cognitive effect can be primary without improvement in clinical symptoms.     

Increased brain D-amino acid oxidase (DAAO) activity in schizophrenia

D-serine has been shown to be a major endogenous coagonist of the N-methyl D-aspartate (NMDA) type of glutamate receptors. Accumulating evidence suggests that NMDA receptor hypofunction contributes to the symptomatic features of schizophrenia. d-serine degradation can be mediated by the enzyme d-amino acid oxidase (DAAO). An involvement of d-serine in the etiology of schizophrenia is suggested by the association of the disease with single nucleotide polymorphisms in the DAAO and its regulator (G72). The present study aims to further elucidate whether the DAAO activity is altered in schizophrenia. Specific DAAO activity was measured in postmortem cortex samples of bipolar disorder, major depression and schizophrenia patients, and normal controls (n=15 per group). The mean DAAO activity was two-fold higher in the schizophrenia patients group compared with the control group. There was no correlation between DAAO activity and age, age of onset, duration of disease, pH of the tissue and tissue storage time and no effect of gender, cause of death and history of alcohol and substance abuse. The group of neuroleptics users (including bipolar disorder patients) showed significantly higher D-amino acid oxidase activity. However, there was no correlation between the cumulative life-time antipsychotic usage and D-amino acid oxidase levels. In mice, either chronic exposure to antipsychotics or acute administration of the NMDA receptor blocker MK-801, did not change d-amino acid oxidase activity. These findings provide indications that D-serine availability in the nervous system may be altered in schizophrenia because of increased D-amino acid degradation by DAAO.     

G72 gene is associated with susceptibility to methamphetamine psychosis

Methamphetamine psychosis is considered as one of the pharmacological models of schizophrenia, and a hyperdopaminergic one. However, many lines of experimental evidence indicate that glutamatergic signaling is also involved in development of methamphetamine psychosis. Several genes related to glutamate function, e.g. the DTNBP1, G72, and GRM3 genes, were shown to be associated with schizophrenia susceptibility. Recently, we found significant association of the DTNBP1 gene with methamphetamine psychosis. This finding prompted us to examine the G72 gene encoding the d-amino acid oxidase activator (DAOA), which metabolizes d-serine, an NMDA co-agonist, in methamphetamine psychosis. Six SNPs of the G72 gene, which previously showed significant association with schizophrenia, were analyzed in 209 patients with methamphetamine psychosis and 291 age- and sex-matched normal controls. One SNP of M22 (rs778293) showed a significant association with methamphetamine psychosis (genotype: p = 0.00016, allele: p = 0.0015). Two haplotypes G-A of M12 (rs3916965)-M15 (rs2391191) (p = 0.00024) and T-T of M23 (rs947267)-M24 (rs1421292) (p = 0.00085) also showed associations with methamphetamine psychosis. The present findings suggest that the G72 gene may contribute to a predisposition to not only schizophrenia but also to methamphetamine psychosis.     

Family-based association study between G72/G30 genetic polymorphism and schizophrenia

Genetic variations in G72/G30 have been reported to be associated with schizophrenia and bipolar disorders in several case-control studies. This gene is located in a genomic region known to contain susceptibility genes for schizophrenia. As case-control studies carry an increased risk of confounding through population stratification, we investigate whether the rs947267 (A/C) polymorphism is associated with schizophrenia in a family-based association study. This polymorphism is located within the G72/G30 gene and has been previously associated with bipolar disorders. The sample consisted of a total of 216 Chinese families that included an affected offspring and parents. Transmission disequilibrium analysis revealed a significant association between the G72/G30 rs947267 polymorphism and schizophrenia (P=0.016), with the A allele more commonly transmitted to patients. Further analysis stratified by sex showed that the A allele was significantly more overtransmitted than nontransmitted in the trios of male probands (P=0.031), but not in the trios of female probands. Our family-based association study supports the suggestion that the G72/G30 gene may be implicated in susceptibility to schizophrenia and there may be an interaction between this gene and sex in the pathogenesis of schizophrenia.     

Significant association between the genetic variations in the 5' end of the N-methyl-D-aspartate receptor subunit gene GRIN1 and schizophrenia.

BACKGROUND: N-methyl-D-aspartate (NMDA) receptors play important roles in many neurophysiological processes. Evidence from previous studies indicate that NMDA receptors contribute to the pathophysiology of schizophrenia. Two NMDA receptor subunit genes, GRIN1 and GRIN2A, are both good candidate genes for schizophrenia. METHOD: We genotyped five single nucleotide polymorphisms (SNPs) in GRIN1 and two in GRIN2A in 2455 Han Chinese subjects, including population- and family-based samples, and performed case-control and transmission disequilibrium test (TDT) analyses. A microsatellite in GRIN2A was genotyped in population-based samples and a Mann-Whitney U test was performed. RESULTS: A highly significant association was detected at the 5' end of GRIN1. Analyses of single variants and multiple-locus haplotypes indicate that the association is mainly generated by rs11146020 (case-control study: p = .0000013, odds ratio = .61, 95% confidence interval .50-.74; TDT: p = .0019, T/NT = 79/123). No association was found in the GRIN2A polymorphisms. CONCLUSIONS: Our results provide support for the hypothesis that NMDA receptors are an important factor in schizophrenia. Moreover, rs11146020 is located in 5' untranslated region where several functional elements have been found. Hence, the SNP is a potential candidate in altering risk for schizophrenia and worthy of further replication and functional study.     

Genetic variation in the DAOA gene complex: impact on susceptibility for schizophrenia and on cognitive performance

INTRODUCTION: The genetic region coding for d-amino acid oxidase activator (DAOA) is considered an intriguing susceptibility locus for schizophrenia. However, association studies have often resulted in conflicting findings, and the risk-conferring variants and their biological impact remain elusive. Our aim in this study was to investigate the relationship between DAOA variation and schizophrenia, and the influence of DAOA on cognitive performance. METHODS: We analyzed block structure and association patterns of an approximately 173 kb region on chromosome 13q33, applying genotype data of 55 SNPs derived from Caucasian North American sample (178 cases, 144 healthy controls). Haplotypes were assigned using the program PHASE and frequencies compared between cases and controls. We applied MANOVA to investigate the relationship between the identified risk haplotype on cognitive performance. RESULTS: We identified multiple haplotypes within the region containing the DAOA gene. Of these, one was significantly associated with schizophrenia, being over-represented in schizophrenia versus healthy controls. This haplotype was also associated with one aspect of cognitive performance, semantic fluency. Carriers of the risk haplotype showed better semantic fluency than non-carriers. CONCLUSIONS: We report a significant effect of DAOA variation on risk for schizophrenia. Moreover, we identified a relationship between DAOA genetic variation and specific aspects of neurocognitive function. As the identified DAOA risk haplotype was associated with better performance on a semantic fluency measure, further work is required to identify the mechanism of DAOA action on CNS function, including the possibility of a role for balanced selection at this locus.     

Vascular changes in the spinal cord in N-methyl-d-aspartate-induced excitotoxicity: morphological and permeability studies

Summary Our previous studies have demonstrated toxicity in spinal cord neuronal systems of middle-aged rats with continuous intrathecal infusion of N-methyl-d-aspartate (NMDA). The present study was undertaken to determine when during the course of excitotoxicity vascular changes occur. The model used was intrathecal infusion of NMDA in the region of the lumbar enlargement of the spinal cord. Horseradish peroxidase (HRP) was used as a marker of vascular permeability alterations occurring in this model. Pathological changes were observed in the cord gray matter of all rats infused with 30–60 g/min NMDA for 30 or 60 min. The changes consisted of swelling of dendrited which gave the neuropil a vacuolated appearance. There was expansion of the extracellular spaces in these areas and neurons were shrunken with pyknotic nuclei. These changes were more frequently encountered in the posterior than anterior horns and were specific for NMDA since they did not occur in NMDA-infused rats pretreated with MK-801, a specific NMDA antagonist. Endothelial dysfunction manifested as increased permeability to HRP. This was a consistent finding in all rats infused with the higher dose of NMDA and was less frequent in those infused with 30 g/min and no vascular changes were observed in rats infused with NMDA for 30 min despite the presence of tissue changes. Increased permeability affected all types of vessels but principally, capilaries and venules. There was no evidence of endothelial necrosis or vascular occlusion.This study demonstrates that in excitotoxin-mediated tissue damage, breakdown of the blood-brain barrier follows the development of nervous tissue damage. Thus, edema is not a significant feature of early lesions in excitotoxin-induced brain injury.Supported by the Heart and Stroke Foundation of Ontario     

Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder

CONTEXT: Variation at the DAOA/G30 locus has been described to be associated with both schizophrenia and bipolar disorder, but there is little consistency between studies of the tested polymorphisms or variants showing association. OBJECTIVES: To obtain a stringent replication of association in large samples of both disorders using consistent clinical and laboratory methods, and to test the hypothesis that association at DAOA/G30 identifies an underlying domain of psychopathological abnormalities that cuts across traditional diagnostic categories. DESIGN: A systematic study of polymorphisms at DAOA/G30 using genetic case-control association analysis. SETTING: Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. PARTICIPANTS: White persons from the United Kingdom meeting criteria for DSM-IV schizophrenia (n = 709) or bipolar I disorder (n = 706) and 1416 ethnically matched controls. METHODS: Nine polymorphisms that tag common genetic variations at DAOA/G30 were genotyped in all of the individuals, and comparisons were made between affected and unaffected individuals. RESULTS: We identified significant association (P = .01-.047) between 3 single-nucleotide polymorphisms and bipolar disorder but failed to find association with schizophrenia. Analyses across the traditional diagnostic categories revealed significant evidence (P = .002-.02) for association with 4 single-nucleotide polymorphisms in the subset of cases (n = 818) in which episodes of major mood disorder had occurred (gene-wide P = .009). We found a similar pattern of association in bipolar cases and in schizophrenia cases in which individuals had experienced major mood disorder. In contrast, we found no evidence for association in the subset of cases (n = 1153) in which psychotic features occurred (all P>.08). CONCLUSIONS: Despite being originally described as a schizophrenia susceptibility locus, our data suggest that variation at the DAOA/G30 locus does not primarily increase susceptibility for prototypical schizophrenia or psychosis. Instead, our results imply that variation at the DAOA/G30 locus influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories.     

Association study of polymorphisms in glycine transporter with schizophrenia

Summary. Glycine acts as an obligatory co-agonist with glutamate on N-methyl-D-aspartate (NMDA) receptors. Brain glycine availability is determined by glycine transporters (GlyT1 or SLC6A9), which mediate glycine reuptake into nerve terminals. Since hypofunction of NMDA receptors has been implicated in the pathophysiology of schizophrenia, this study tests the hypothesis that GlyT1 genetic variants confer susceptibility to schizophrenia. Four GlyT1 polymorphisms were studied in a sample population of 249 people with schizophrenia and 210 normal controls. One polymorphism (rs16831541) was not informative in our Chinese population while the other three polymorphisms (rs1766967, rs2248632 and rs2248253) were analysed with chi-square tests and haplotype analysis. Significant linkage disequilibrium was obtained among the three polymorphisms. Neither single marker nor haplotype analysis revealed an association between variants at the GlyT1 locus and schizophrenia, suggesting that it is unlikely that the GlyT1 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further studies with other GlyT1 variants, relating either to schizophrenia, psychotic symptoms or to therapeutic response in schizophrenia, are suggested.     

The genes for schizophrenia: Finally a breakthrough?

A number of susceptibility genes for schizophrenia have recently been identified. They have engendered excitement because replicate studies have attained greater consistency than in the past. In this review, we outline gene mapping methods, and briefly review their strengths and challenges. We also evaluate peer-reviewed genetic association studies that have implicated six selected genes: catechol-O-methyl transferase (COMT), neuregulin I (NRGI), dysbindin (DTNBPI), regulator of G-protein signaling 4 (RGS4), andG72 and D-amino-acid oxidase (DAAO). The available supporting evidence is variable. Though credible evidence is available for all of these genes, it is strongest forNRGI andDTNBPI. Further studies, particularly exhaustive analyses of all polymorphisms at each locus, meta-analyses, and investigations of the likely function of risk alleles (variants) are desirable.     

Spinal neuronal pathology associated with continuous intrathecal infusion ofN-methyl-d-aspartate in the rat

Summary Continuous intrathecal infusion ofN-methyl-d-aspartate (NMDA) at the level of the lumbar enlargement of the spinal cord in middle-aged rats produced dose-dependent toxicity of spinal cord neuronal systems. Toxicity was enhanced by coadministration of glycine, but was significantly reduced when NMDA was coadministered with the competitive inhibitordl-2-amino-5-phosphovaleric acid or the noncompetitive inhibitor MgSO₄. The toxic effects of NMDA were manifest most dramatically and at the lowest concentrations in the neuropil, while neuronal loss was obvious at higher concentrations. The distribution and intensity of reactive astrocytosis was consistent with the known regional and subcellular distribution of NMDA receptors in the spinal cord of rats. The increase in ribosomes and rough endoplasmic reticulum observed in anterior horn cells suggested an increase of cell metabolism reflecting either a nonspecific response to injury or a specific increase in cell metabolism secondary to sustained activation of NMDA receptors. The present studies implicate excitatory amino acid receptors of the NMDA type in producing toxicity to selected neuronal populations of the spinal cord. This model provides a system for studies of the protective effects and rescue of neuronal populations susceptible to the toxic effects of excitatory amino acids.Supported by the ALS Society of Canada     

ARVCF single marker and haplotypic association with schizophrenia

We present a schizophrenia association study using an extensive linkage disequilibrium (LD) mapping approach in seven candidate genes with a well established link to dopamine, including receptors (DRD2, DRD3) and genes involved in its metabolism and transport (ACE, COMT, DAT, MAO-A, MAO-B). The sample included 242 subjects diagnosed with schizophrenia and related disorders and 373 hospital-based controls. 84 tag SNPs in candidate genes were genotyped. After extensive data cleaning 70 SNPs were analyzed for association of single markers and haplotypes. One block of four SNPs (rs165849, rs2518823, rs887199 and rs2239395) in the 3′ downstream region of the COMT gene which included a non-dopaminergic candidate gene, the ARVCF (Armadillo like VeloCardio Facial) gene, was associated with the risk of schizophrenia. The genetic region including the ARVCF gene in the 22q11.21 chromosome is associated with schizophrenia in a Spanish series. Our results will assist in the interpretation of the controversy generated by genetic associations of COMT and schizophrenia, which could be the result of different LD patterns between COMT markers and the 3′ region of the ARVCF gene.     

Genetic association analysis of tagging SNPs in alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptor genes (<Emphasis Type="Italic">CHRNA4</Emphasis> and <Emphasis Type="Italic">CHRNB2</Emphasis>) with schizophrenia in the Japanese population

Several lines of evidence suggest that nicotinic cholinergic dysfunction may contribute to the cognitive impairments in schizophrenia. The majority of high affinity nicotine binding sites in the human brain have been implicated in heteropentameric alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptors; therefore, these two neuronal nicotinic acetylcholine receptors genes (CHRNA4 and CHRNB2) are considered to be attractive candidate genes for the pathophysiology of schizophrenia. To represent these two genes in a gene-wide manner, we first evaluated the linkage disequilibrium structure using our own control samples. Thirteen SNPs (7 SNPs for CHRNA4 and 5 SNPs for CHRNB2) were selected as tagging SNPs. Using these tagging SNPs, we then conducted genetic association analysis of case-control samples (738 schizophrenia and 753 controls) in the Japanese population. No significant association was detected in the allele/genotype-wise or haplotype-wise analysis. Our results suggest that CHRNA4 and CHRNB2 do not play a major role in Japanese schizophrenia.     

Dopamine and glutamate dysfunctions in schizophrenia: Role of the dopamine D<Subscript>3</Subscript> receptor

Symptoms of schizophrenia are improved by dopamine antagonists and exacerbated by dopamine-releasing agents, suggesting hyperactivity of dopamine. However, chronic blockade of glutamate neurotransmission by antagonists at theN-methyl-D-aspartate (NMDA) receptor subtype produces a pathophysiological state resembling schizophrenia. A link between cortical glutamate/NMDA deficiency and subcortical dopamine hyperactivity, particularly in the mesolimbic pathway, has been hypothesized in schizophrenia. Here we show that hyperactivity produced by NMDA receptor blockade is dependent upon stimulation of the dopamine D₃ receptor subtype. Since D₃ receptor antagonists and antipsychotics produced very similar effects, our results add to the growing evidence suggesting that D₃ receptor blockade might produce antipsychotic effects.     

Glutamate receptors communicate with Na+/K+-ATPase in rat cerebellum granule cells

Two glutamate receptor agonists, NMDA (N-methyl-d-aspartic acid) and ACPD (cis-(1S/3R)-1-aminocyclopentane-1,3-dicarboxylic acid), induce the reactive oxygen species (ROS) production in rat cerebellum granule cells, whereas the third one, 3-HPG (3-hydroxyphenylglycine), decreases this parameter. The simultaneous presence of 3-HPG, together with NMDA or ACPD, prevents the generation of ROS by neuronal cells. A similar effect of these ligands on Na⁺/K⁺-ATPase can be demonstrated: NMDA and ACPD inhibited the enzyme activity, but 3-HPG activated Na⁺/K⁺-ATPase and prevented its inhibition by NMDA or ACPD. In terms of current classification, NMDA is an agonist of ionotropic glutamate receptors of the so-called NMDA class, whereas ACPD and 3-HPG belong to metabotropic agonists, the former primarily being an activator of metabotropic glutamate receptors (mGluRs) of groups 2 and 3, and the latter, that of mGluRs of groups 1 and 5. Thus, the data presented illustrate the existence of diverse mechanisms of the cross talk between Na⁺/K⁺-ATPase and different glutamate receptors, as well as that between glutamate receptors of different classes.     

Effect of D-amino acid oxidase activator (DAOA; G72) on brain function during verbal fluency

Background. The D ‐Amino acid oxidase activator (G72 or DAOA) is believed to play a key role in the regulation of central glutamatergic transmission which is seen to be altered in psychosis. It is thought to regulate D ‐amino acid oxidase (DAO), which metabolizes D ‐serine, a co‐agonist of NMDA‐type glutamate receptors and to be involved in dendritic arborization. Linkage, genetic association and expression studies have implicated the G72 gene in both schizophrenia and bipolar disorder. Aims. To examine the influence of G72 variation on brain function in the healthy population. Method. Fifty healthy volunteers were assessed using functional magnetic resonance imaging while performing a verbal fluency task. Regional brain activation and task‐dependent functional connectivity during word generation was compared between different rs746187 genotypes. Results. G72 rs746187 genotype had a significant effect on activation in the left postcentral and supramarginal gyri (FWE P < 0.05), and on the task‐dependent functional coupling of this region with the retrosplenial cingulate gyrus (FWE P < 0.05). Conclusions. Our results may reflect an effect of G72 on glutamatergic transmission, mediated by an influence on D ‐amino acid oxidase activity, on brain areas particularly relevant to the hypoglutamatergic model of psychosis. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Intraventricular infusion of N-methyl-d-aspartate

Summary The purpose of this study was to document the early cerebrovascular consequences of excessive N-methyl-d-aspartate (NMDA) receptor activation. Five microliters of NMDA (100 nmol/l) or vehicle was infused over a 15-min period into the lateral ventricle of adult rats. The protein tracer horseradisch peroxidase (HRP) was injected intravenously for blood-brain bartier (BBB) studies. The intraventricular infusion of vehicle (n=5) caused no alterations in arterial blood pressure or microvascular damage away from the intraventicular probe tract. In contrast, NMDA infusion (n=8) led to a gradual increase in arterial blood pressure (mean 36 mm Hg). Multifocal regions of HRP extravasation were observed bilaterally throughout the neuraxis following NMDA infusion. Sites of BBB disruption and hemorrhage included brain regions bordering ventricular spaces. In addition, isolated foci of protein extravasation were commonly detected in the cerebral cortex, thalamus, basal forebrain, septum and cerebellum. Pretreatment with the noncompetitive NMDA antagonist MK-801 (2 mg/kg) substantially reduced the BBB responses to NMDA. However, microvascular abnormalities were seen in NMDA-infused rats where blood pressure elevations were inhibited by blood removal. In addition to neurons, cerebral blood vessels are also acutely affected by NMDA receptor activation. Blockage of NMDA receptor channels following brain injury may potentially provide protection by attenuating BBB breakdown and subsequent brain edema.Supported by USPHS Grants NS-05820, NS-30291 and NS-27127 and by the American Heart Association Grant-in-Aid 90-1133, with funds contributed by the Flordia Affiliate.