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Glutamatergic Dysfunction (glutamatergic + dysfunction)
Selected AbstractsAn update on the role of glutamate in the pathophysiology of depressionACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2010N. D. Mitchell Mitchell ND, Baker GB. An update on the role of glutamate in the pathophysiology of depression. Objective:, To review the literature on the involvement of glutamate (Glu), including its interactions with other neurochemical systems, in the pathophysiology of depression. Method:, A MEDLINE search using the terms glutamate, depression and major depressive disorder, was performed. Results:, Alterations in proteins involved in glutamatergic signalling are implicated in variations in behaviour in animal models of depression. Drugs acting at Glu receptors appear to have antidepressant-like effects in these models, and traditional antidepressant pharmacotherapies act on the glutamatergic system. Recent evidence from genetic studies and in vivo spectroscopy also correlate glutamatergic dysfunction with depression. Trials of N -methyl- d -aspartate receptor antagonists in humans have provided mixed results. Conclusion:, A growing body of evidence indicates that the glutamatergic system is involved in the pathophysiology of depression, and may represent a target for intervention. [source] The type 1 cannabinoid receptor is highly expressed in embryonic cortical projection neurons and negatively regulates neurite growth in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2008Tania Vitalis Abstract In the rodent and human embryonic brains, the cerebral cortex and hippocampus transiently express high levels of type 1 cannabinoid receptors (CB1Rs), at a developmental stage when these areas are composed mainly of glutamatergic neurons. However, the precise cellular and subcellular localization of CB1R expression as well as effects of CB1R modulation in this cell population remain largely unknown. We report that, starting from embryonic day 12.5, CB1Rs are strongly expressed in both reelin-expressing Cajal-Retzius cells and newly differentiated postmitotic glutamatergic neurons of the mouse telencephalon. CB1R protein is localized first to somato-dendritic endosomes and at later developmental stages it localizes mostly to developing axons. In young axons, CB1Rs are localized both to the axolemma and to large, often multivesicular endosomes. Acute maternal injection of agonist CP-55940 results in the relocation of receptors from axons to somato-dendritic endosomes, indicating the functional competence of embryonic CB1Rs. The adult phenotype of CB1R expression is established around postnatal day 5. By using pharmacological and mutational modulation of CB1R activity in isolated cultured rat hippocampal neurons, we also show that basal activation of CB1R acts as a negative regulatory signal for dendritogenesis, dendritic and axonal outgrowth, and branching. Together, the overall negative regulatory role in neurite development suggests that embryonic CB1R signaling may participate in the correct establishment of neuronal connectivity and suggests a possible mechanism for the development of reported glutamatergic dysfunction in the offspring following maternal cannabis consumption. [source] Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implicationsJOURNAL OF NEUROCHEMISTRY, Issue 4 2009Pablo A. Gaspar Abstract Early models for the etiology of schizophrenia focused on dopamine neurotransmission because of the powerful anti-psychotic action of dopamine antagonists. Nevertheless, recent evidence increasingly supports a primarily glutamatergic dysfunction in this condition, where dopaminergic disbalance is a secondary effect. A current model for the pathophysiology of schizophrenia involves a dysfunctional mechanism by which the NMDA receptor (NMDAR) hypofunction leads to a dysregulation of GABA fast- spiking interneurons, consequently disinhibiting pyramidal glutamatergic output and disturbing the signal-to-noise ratio. This mechanism might explain better than other models some cognitive deficits observed in this disease, as well as the dopaminergic alterations and therapeutic effect of anti-psychotics. Although the modulation of glutamate activity has, in principle, great therapeutic potential, a side effect of NMDAR overactivation is neurotoxicity, which accelerates neuropathological alterations in this illness. We propose that metabotropic glutamate receptors can have a modulatory effect over the NMDAR and regulate excitotoxity mechanisms. Therefore, in our view metabotropic glutamate receptors constitute a highly promising target for future drug treatment in this disease. [source] Searching for Responders to Acamprosate and Naltrexone in Alcoholism Treatment: Rationale and Design of the Predict StudyALCOHOLISM, Issue 4 2009Karl Mann Background:, Alcoholism represents a major public health issue and treating alcohol dependent patients remains an imminent challenge. Evidence based psychotherapies and pharmacotherapies are available. However, when administered to heterogeneous populations of patients effect sizes are only modest. We present the rationale and design of a double-blind randomized trial comparing acamprosate, naltrexone, and placebo. Additionally we subtype patients on the basis of biological and psychometric measures and explore their treatment response to both acamprosate and naltrexone. According to our initial hypothesis, the "relief drinker/craver" is an endophenotype associated with glutamatergic dysfunction who responds to acamprosate. The "reward drinker/craver" is mainly associated with alterations in the dopaminergic and opioidergic system and responds to naltrexone. Methods:, The study is planned for 430 patients (2:2:1 for both drugs and placebo) over 12 weeks of medication. All receive manualized counselling to improve compliance (Medical Management) which is extended to 6 months. Subtyping is primarily done using the acoustic startle reflex, functional magnetic resonance imaging, positron emission tomography (in a subset of patients), and the Inventory of Drinking Situations. Relapsers will be re-randomized into a second study where additional psychotherapy (Cognitive Behavioral Intervention) is used in a stepped care approach. Genotyping and additional analyses such as health economy are being done as well. The study follows the assessment methods, treatments, and medications used in the U.S. based COMBINE study, which will allow for a direct comparison between this U.S. study trial and a study performed in Europe. [source] | |||||||||||||