NMDA receptor antagonist - Wikipedia
0197-4580(94)00185-5 COMMENTARY NMDA RECEPTOR HYPOFUNCTION, EXCITOTOXICITY, AND ALZHEIMER'S DISEASE J O H N W.
Aspects of the NMDA receptor hypofunction hypothesis …
The past two decades have produced a wealth of evidence for dysfunction of both GABAergic interneurons and NMDARs in schizophrenia (). While deficits were first seen in postmortem studies, recent experiments using electrophysiology, neuroimaging, and animal models have provided mechanistic links between these two abnormalities. Recent studies have shown that NMDAR activity is critical for proper development and adult function of GABAergic interneurons, and that both micro and macroscopic functional brain organization is dependent on proper inhibition. The relationship between NMDAR and GABAR, clearly seen on different scales of analysis, can provide insight into how they are normally required for cognition and how their dysfunction contributes to schizophrenia phenomenology. Specifically, we hypothesize that NMDAR hypofunction on GABAergic interneurons may result in underdeveloped GABAergic circuitry and reduced inhibition, and thus support many symptoms of schizophrenia. This overview unifies findings from multiple fields and thus provides a schizophrenia framework that can help launch novel therapeutic directions.
Hypofunction of the N-methyl-D-aspartic (NMDA) receptor at a subpopulation of the cortical GABAergic interneuronsmay explain, at least in part, schizophrenia like symptoms.
Overview The Hypothesis of NMDA Receptor Hypofunction …
On a global level, it is therefore interesting to speculate that the behavioral phenotypes seen in schizophrenia can be explained by deficits in functional connectivity among large scale networks, a phenomenon which depends on GABAergic inhibition in the motor cortex () and NMDAR activity in the PFC and striatum (; ). Functional connectivity is critical for the emergence of the default mode network (DMN, also referred to as the task-negative network), a collection of correlated cortical regions including the medial PFC, which is active when the brain is at wakeful rest and is associated with stimulus-independent thought and internally guided cognition (). DMN is known to be hyperactive in schizophrenia patients, a measure that is correlated with both positive and negative symptoms (). When the brain shifts its information processing mode to externally-guided cognition, DMN is suppressed, and instead the dorsal attentional network (DAN, also referred to as task-positive network, which includes dorsolateral PFC (dlPFC) is activated (). DMN and DAN are mutually anticorrelated networks, whose respective engagement may reflect the dominant mode of information processing in the brain. Similar to DMN, DAN is also disrupted in schizophrenia at rest, evident by its aberrant interactions with executive cortical regions (). During working memory tasks, appropriate DAN activation and DMN suppression is impaired in schizophrenia (; ; ), a phenomenon that is mimicked by ketamine administration to healthy subjects (). These findings are highly significant, as they suggest a mechanism by which hypo-NMDA states translate to clinical phenomenology. In addition, augmenting inhibition with a GABA agonist in humans () or optogenetics in mice () results in increased functional connectivity in the cortex. By impairing large scale cortical networks involved in telling apart internal vs. external stimuli, such states may help explain hallucinations in schizophrenia where it is often difficult to distinguish internal from external events.
While current pharmacologic management of schizophrenia is dependent on D2 blockers, the evolving understanding of NMDAR and GABA interactions in schizophrenia holds promise for future therapeutics. As subunit-specific positive and negative allosteric modulators become available, this approach will increasingly be guided by selective targeting of subpopulations of NMDARs in an approach consistent with their neurodevelopmental expression. Several drugs acting at the glycine binding site of NMDARs have been tested with mixed results over the past 20 years (). Increasing glycine via dietary supplementation (; ; ; ) or by inhibiting glycine reuptake with the competitive inhibitors sarcosine () or bitopertin () has been shown to ameliorate negative symptoms of schizophrenia, although results have been inconsistent (; ). Other trials have supported the efficacy of high dose D-serine (; ; ) and low dose D-cycloserine () but again, negative results have also been reported (; ; ). The difficulty in replicating early positive findings may reflect the larger problem of heterogeneity in schizophrenia and the unreliability of clinical trials in this population. In addition, clozapine and possibly other second generation antipsychotics may enhance glutamatergic transmission, thereby complicating pharmacologic add-on strategies (; ; ; ). Repeated dosing with glycine site agonists may produce tachyphylaxis via endocytosis of NMDARs (; ) which has led to intermittent dosing strategies (; ). Intracellular pathways downstream of NMDARs may also present targets for pharmacologic intervention, as exemplified by nitric oxide augmentation by nitroprusside infusion (). Of note, clozapine reverses the loss of PV in interneurons produced by repeated administration of NMDAR antagonists in adult mice () and differs from other antipsychotics in showing efficacy for the glycine site of the NMDAR (). Another promising new pharmacologic approach targets the Kv3.1 channel which is primarily localized on PV+ interneurons (). It remains to be established whether newer strategies, such as interneuron precursor transplants () and transcranial electrical stimulation () will prove effective in correcting interneuron functional deficits. Given the many genetic links between schizophrenia and NMDAR pathways, a personalized medicine approach may produce larger and more consistent therapeutic benefits which could fundamentally advance our understanding of the illness and expand our available therapeutic options.
NMDA receptor hypofunction model of schizophrenia …
Early models of schizophrenia posited a hyperdopaminergic state, based on the finding that affinity of D2 receptor antagonists correlates with their clinical potency (; ). Excessive activity at D2 receptors was demonstrated by the dysregulation of amphetamine-induced striatal dopamine release (; ; ; ). The dopamine model subsequently was extended to include a reciprocal hypoactivation of D1 receptors in prefrontal cortex (PFC) (). Abnormal dopamine release remains highly relevant to deficits in reward response, novelty detection, attention and neuroplasticity in schizophrenia (; ). However, abnormal dopamine signaling may be a consequence of other primary modulatory abnormalities, including NMDAR dysregulation (). Among relevant receptor systems, NMDARs have drawn attention in large part due to historical observations that the NMDAR antagonist phencyclidine (PCP) produces a syndrome resembling schizophrenia in healthy individuals (). More than 20 years ago, investigators proposed models linking NMDAR hypofunction to schizophrenia (; ; ; ). The model proposed by Carlsson () emphasized interactions between glutamate and dopamine signaling in the processing and transmission of sensory information. Experiments by Olney and Farber () demonstrated corticolimbic neurodegenerative changes following exposure to NMDAR antagonists and focused attention on midline structures, including anterior cingulate and thalamus, while providing evidence for a developmental vulnerability consistent with the neurodevelopmental pattern of onset of schizophrenia. Of note is the discovery by Benes and colleagues of a reduced density of small interneurons in cingulate cortex (), followed by their finding of a 73% reduction in GABAergic neurons expressing the NR2A subunit of the NMDAR in cingulate cortex, identified by co-localization of glutamic acid decarboxylase 67 (GAD67) and NR2A mRNA (). These studies of brain samples from affected individuals provided critical evidence linking NMDARs and GABAergic interneurons to schizophrenia.
To put NMDARs into context, excitatory synaptic transmission is mediated by multiple ionotropic glutamate receptors, including NMDA, AMPA, and kainate receptors. Several characteristics make NMDARs unique (see ). In contrast to AMPARs, which mediate current flow across the membrane in response to glutamate, NMDARs act as coincidence detectors of pre- and post-synaptic activity due to a voltage dependent Mg2+ blockade, allowing ion flux only at depolarized membrane potentials (). In addition, NMDARs require the presence of a co-agonist along with glutamate. At the glycine binding site, D-serine potentiates NMDAR function (; ; ) whereas kynurenic acid, a metabolite of tryptophan, acts as an antagonist at the glycine binding site (). Both D-serine and kynurenic acid are released from astrocytes and dysregulation of their synthesis and release has been implicated in schizophrenia (; ). The functional properties are rooted in molecular structure. NMDARs are tetrameric complexes assembled from obligatory NR1 subunits which contain the glycine binding site and variable NR2 subunits which contain the glutamate binding site. The various NR2 subunits confer distinct functional properties (). NR2A subunits, which are present mainly at synaptic sites, are associated with neuroprotection and synaptic potentiation (). In contrast, NR2B subunits are mainly extrasynaptic (), and their activation promotes cell death () and synaptic depression (). The synaptic NR2A/ NR2B ratio is known to increase in excitatory cortical neurons throughout development (; ), which is important for novel forms of synaptic plasticity involved in transferring new information into long term memories (). NR2C and NR2D subunits are both expressed in forebrain interneurons and likely distributed at both synaptic and extrasynaptic sites (; ; ; ). NR2C/ NR2D-containing NMDARs exhibit a particularly high affinity for ketamine, which may be mechanistically related to ketamine-induced psychosis (; ; ; ). NR3A and NR3B subunits are much less studied and their functional role remains to be clarified ().
The NMDA Receptor Hypofunction Model of Psychosis …
Antagonists of the NMDA glutamate receptor, ..
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NMDA receptor hypofunction model of schizophrenia | …
The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia.
Can We Link Perception And Cognition? | Slate Star …
NMDA Receptor and Schizophrenia: NMDA glutamate glutamate hypofunction hypothesis of schizophrenia receptor hypofunction hypothesis Theories of Etiology of Schizophrenia.
Signaling pathways underlying the pathophysiology …
1 The Glutamate Hypothesis of Schizophrenia Dr Khalid Mansour 17 GLUTAMATE SYSTEM AND SCHIZOPHRENIA pro con stadiums NMDA-R Hypofunction Hypothesis of Schizophrenia.
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Electrophysiological findings provide additional support for a link between NMDA and GABA in schizophrenia, as reduced NMDAR-dependent inhibitory drive results in the increased excitability that characterizes schizophrenia (). In the cortical slice preparation, exposure to MK-801 reduces inhibitory post-synaptic currents (IPSCs) on pyramidal neurons (). In animal models, the administration of ketamine enhances excitability of PFC (). This is surprising, as one would expect a blocker of excitatory transmission to reduce excitability. It has been proposed that NMDAR antagonists preferentially impact inhibitory interneurons, partially because of their higher baseline activity compared to pyramidal neurons, which lessens Mg2+ dependent block of their NMDARs (). Consequently, MK-801 decreases activity of GABAergic interneurons and thereby increases pyramidal neuron excitability in prefrontal regions, which may contribute to the disinhibition associated with psychosis (; ).
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