Excitatory Amino Acid Receptors in Schizophrenia

Ułas, J.; Cotman, Carl W.

doi:10.1093/schbul/19.1.105

Cited by 85 publications

(46 citation statements)

References 64 publications

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“…In agreement with clinical studies, basic findings indicate that subanesthetic doses of ketamine and other noncompetitive NMDA receptor antagonists produce deficits in acquisition and performance of cognitive tasks, including those that are sensitive to the functional integrity of the PFC (Danysz et al, 1988;Hauber and Schmidt, 1989;Heale and Harley, 1990;Parada-Turska and Turski, 1990;Wesierska et al, 1990;Hauber, 1993;Verma and Moghaddam, 1996). These actions of ketamine are similar to those observed decades ago with phencyclidine (Luby et al, 1959;Davies and Beech, 1960;Bakker and Amini, 1961), which led to the "phencyclidine model of schizophrenia" and, more recently, to several glutamate-and NMDA-related hypotheses of schizophrenia (Kim et al, 1980;Deakin et al, 1989;Wachtel and Turski, 1990;Javitt and Zukin, 1991;Ulas and Cotman, 1993;Olney and Farber, 1995;Akbarian et al, 1996;Coyle, 1996).…”

mentioning

confidence: 81%

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex

et al. 1997

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Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.Key words: microdialysis; phencyclidine; schizophrenia; working memory; antipsychotic drugs; AMPA receptors Recent clinical trials with ketamine, a noncompetitive antagonist of the NMDA receptor (Thomson et al., 1985), have demonstrated that subanesthetic doses of this drug exacerbate preexisting symptoms of schizophrenia (Lahti et al., 1995a,b) and produce behaviors in healthy individuals that bear a resemblance to a broad range of symptoms associated with schizophrenia, including impaired performance in psychological tests sensitive to prefrontal cortex (PFC) function (Ghoneim et al., 1985;Oye et al., 1992;Krystal et al., 1994; Malhorta et al., 1996). In agreement with clinical studies, basic findings indicate that subanesthetic doses of ketamine and other noncompetitive NMDA receptor antagonists produce deficits in acquisition and performance of cognitive tasks, including those that are sensitive to the functional integrity of the PFC (Danysz et al

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mentioning

confidence: 81%

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex

et al. 1997

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“…Thus, technical and conceptual issues may be relevant to the failure to replicate findings. Perhaps the variety of disparate hippocampal glutamatergic findings themselves may be important as suggested by Ulas and Cotman, 163 leading to a final common blockade or inhibition of hippocampal efferent pathway activity in schizophrenia.…”

Section: Characteristics Of Postmortem Tissuementioning

confidence: 99%

Phenotype of schizophrenia: a review and formulation

2004

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The discovery of the pathophysiology(ies) for schizophrenia is necessary to direct rational treatment directions for this brain disorder. Firm knowledge about this illness is limited to areas of phenomenology, clinical electrophysiology, and genetic risk; some aspects of dopamine pharmacology, cognitive symptoms, and risk genes are known. Basic questions remain about diagnostic heterogeneity, tissue neurochemistry, and in vivo brain function. It is an illness ripe for molecular characterization using a rational approach with a confirmatory strategy; drug discovery based on knowledge is the only way to advance fully effective treatments. This paper reviews the status of general knowledge in this area and proposes an approach to discovery, including identifying brain regions of dysfunction and subsequent localized, hypothesis-driven molecular screening.

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“…Some magnetic resonance imaging (MRI) studies have found a decrease in prefrontal cortical volume (Harvey et al 1993;Andreasen et al 1994&). Postmortem studies show that schizophrenia patients exhibit alterations in cytoarchitecture of the dorsolateral PFC (Daviss and Lewis 1995;Selemon et al 1995), a loss of glutamate receptor binding (Kerwin et al 1990;Ulas and Cotman 1993), and a decrease in DA fibers in the PFC (Akil and Lewis 1996). From a clinical perspective, many symptoms of schizophrenia resemble those that occur as a result of a lesion in the PFC (Buchanan et al 1994).…”

Section: Cortical Disturbances In Schizophreniamentioning

confidence: 99%

Dysfunctions in Multiple Interrelated Systems as the Neurobiological Bases of Schizophrenic Symptom Clusters

O’Donnell

Grace

1998

Schizophrenia Bulletin

176

115

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The absence of an animal model that accurately approximates schizophrenia limits current research into the pathophysiology of this disorder. Obviously, the cognitive disturbances associated with schizophrenia are difficult to evaluate in laboratory animals. Nonetheless, animal studies have provided insight into the anatomy and physiology of the brain systems that have been implicated in schizophrenia. These studies also suggest how brain systems may be involved in information processing in normal and pathological conditions. Thus, a careful assessment of the properties and functions of the brain regions suggested to be involved in schizophrenic symptoms has been a primary objective in several laboratories. In this review, we discuss the interactions among the brain regions implicated in schizophrenia-the ventral striatum, prefrontal cortex, hippocampus, and dopamine systems-and provide an integrative model linking altered function in these regions with specific clusters of symptoms of schizophrenia.Key words: Nucleus accumbens, hippocampus, prefrontal cortex, thalamus, dopamine, negative symptoms, positive symptoms, thought disorder. Schizophrenia Bulletin, 24(2):267-283,1998.Schizophrenia is a complex disorder characterized by a profound disturbance of cognitive functions. A major problem in the study of schizophrenia is the diversity of its symptoms, leading to the suggestion that schizophrenia is actually a cluster of diseases. An integrative clinical view was brought up by Liddle, who used factor analysis to segregate symptoms of schizophrenia into three clusters-reality distortion, psychomotor poverty, and disorganization (Liddle et al. 1992fc)-and proposed that dysfunctions in specific brain regions were involved in each cluster of symptoms (Liddle et al. 1992a). This interpretation is reinforced by a number of studies that implicate a variety of structures in the pathophysiology of schizophrenia. These structures include the prefrontal cortex (PFC), medial temporal lobe (including the hippocampus), ventral striatum, and mesolimbic dopamine (DA) system. In this review, we will link information regarding the physiological interactions among these systems with clinical investigations, in an attempt to analyze these symptom clusters from an anatomical perspective.

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Excitatory Amino Acid Receptors in Schizophrenia

Cited by 85 publications

References 64 publications

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex

Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex

Phenotype of schizophrenia: a review and formulation

Dysfunctions in Multiple Interrelated Systems as the Neurobiological Bases of Schizophrenic Symptom Clusters

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