Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatr 9: 979, 984-997

Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research/New York University School of Medicine, Orangeburg, NY 10962, USA.
Molecular Psychiatry (Impact Factor: 14.5). 12/2004; 9(11):984-97, 979. DOI: 10.1038/
Source: PubMed

ABSTRACT Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD.

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    • "They are known to mediate signal transduction through G-protein second messenger systems including activation of phosphoinositide hydrolysis [Pin and Duvoisin, 1995] and are broadly categorized into three groups namely, Group 1 (GRM1 and GRM5), Group II (GRM2 and GRM3), and Group III (GRM4, GRM6, GRM7, and GRM8). Among these, group II receptor gene GRM3 is considered as potential therapeutic agent for a wide range of psychiatric disorders [Javitt, 2004]. Agonists of group II receptors have been earlier shown to reverse cognitive and motor deficits in NMDA receptor antagonism rodent model of schizophrenia. "
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    ABSTRACT: Literature indicates key role of glutamatergic pathway genes in antipsychotic response among schizophrenia patients. However, molecular basis of their underlying role in antipsychotic response remained unexplained. Thus, to unravel their molecular underpinnings, we sought to investigate interactions amongst GRM3, SLC1A1, SLC1A2, SLC1A3, SLC1A4 gene polymorphisms with drug response in south Indian schizophrenia patients. We genotyped 48 SNPs from these genes in 423 schizophrenia patients stratified into low and high severity of illness groups. The SNPs and haplotypic combinations of associated SNPs were examined for their association with antipsychotic response. Multifactor-dimensionality-reduction was further used to explore gene-gene interaction among these SNPs and 53 SNPs from previously studied genes (BDNF, RGS4, SLC6A3, PI4KA, and PIP4K2A). Single SNP and haplotype analyses revealed no significant association with drug response irrespective of severity of illness. Gene-gene interaction analyses yielded promising leads, including an observed synergistic effect between PI4KA_rs165854 and GRM3_rs1468412 polymorphisms and incomplete antipsychotic response in schizophrenia patients with low severity of illness (OR = 12.4; 95%CI = 3.69–41.69). Further, this interaction was also observed in atypical monotherapy (n = 355) and risperidone (n = 260) treatment subgroups (OR = 11.21; 95%CI = 3.30–38.12 and OR = 13.5; 95%CI = 3.03–121.61 respectively). PI4KA is known to be involved in the biosynthesis of phosphatidylinositol-4, 5-bisphosphate which regulates exocytotic fusion of synaptic vesicles (glutamate, dopamine) with the plasma membrane and regulates duration of signal transduction of GPCRs. Whereas GRM3 regulates glutamate and dopamine transmission. Present findings indicate that PI4KA and GRM3 polymorphisms have potential to jointly modulate antipsychotic response. These results warrant additional replication studies to shed further light on these interactions.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2014; 165(8). DOI:10.1002/ajmg.b.32268 · 3.42 Impact Factor
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    • "Growing evidence suggests that the glutamatergic system plays key roles in the neurobiology and treatment of major depression.6,7,8,9,10,11,12,13) The NMDA receptor antagonist ketamine has been associated with rapid and robust antidepressant effects in patients with treatment-resistant major depression.14,15) "
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    ABSTRACT: Objective Pediatric depression is associated with significant functional impairment at school and at work. Recently, we reported on depression-like behavior in juvenile mice neonatally exposed to dexamethasone (DEX) as a potential animal model for pediatric depression. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has promoted rapid and long-lasting antidepressant effects in patients with treatment-resistant major depression. This study was conducted to examine whether ketamine had antidepressant effects in juvenile mice after neonatal DEX exposure. Methods A single dose (10 mg/kg) of ketamine or vehicle was injected into juvenile mice at days 29-32 after neonatal DEX (or saline) exposure (days 1-3). The sucrose preference test, tail suspension test, and forced swimming test were performed 24, 40, and 46 hours, respectively, after injection of ketamine. Results Ketamine (10 mg/kg) significantly improved depression-like behavior in DEX-treated juvenile mice. Conclusion This finding suggests that ketamine confers antidepressant effects in an animal model of pediatric depression.
    Clinical Psychopharmacology and Neuroscience 08/2014; 12(2):124-7. DOI:10.9758/cpn.2014.12.2.124
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    • "Group II mGluRs function as heteroceptors, regulating the release of other neurotransmitters, including dopamine [5,9]. Since mGluR2/3 activation leads to a net reduction in glutamate neurotransmission, the ligands for these receptors may be potential therapeutic agents for a wide range of psychiatric disorders [10]. Phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor of glutamate receptor, induces schizophrenic symptoms in humans [11]. "
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    ABSTRACT: We previously performed systematic association studies of glutamate receptor gene family members with schizophrenia, and found positive associations of polymorphisms in the GRM3 (a gene of metabotropic glutamate receptor 3: mGluR3) with the disorder. Physiological roles of GRM3 in brain functions and its functional roles in the pathogenesis of schizophrenia remain to be resolved. We generated mGluR3 knockout (KO) mice and conducted comprehensive behavioral analyses. KO mice showed hyperactivity in the open field, light/dark transition, and 24-hour home cage monitoring tests, impaired reference memory for stressful events in the Porsolt forced swim test, impaired contextual memory in cued and contextual fear conditioning test, and impaired working memory in the T-Maze forced alternation task test. Hyperactivity and impaired working memory are known as endophenotypes of schizophrenia. We examined long-term synaptic plasticity by assessing long-term potentiation (LTP) in the CA1 region in the hippocampi of KO and wild-type (WT) mice. We observed no differences in the amplitude of LTP between the two genotypes, suggesting that mGluR3 is not essential for LTP in the CA1 region of the mouse hippocampus. As hyperactivity is typically associated with increased dopaminergic transmission, we performed in vivo microdialysis measurements of extracellular dopamine in the nucleus accumbens of KO and WT mice. We observed enhancements in the methamphetamine (MAP)-induced release of dopamine in KO mice. These results demonstrate that a disturbance in the glutamate-dopamine interaction may be involved in the pathophysiology of schizophrenia-like behavior, such as hyperactivity in mGluR3 KO mice.
    Molecular Brain 04/2014; 7(1):31. DOI:10.1186/1756-6606-7-31 · 4.90 Impact Factor
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