Modulating ketamine-induced thought disorder with lorazepam and haloperidol in humans

Krystal, J.; Karper, Laurence P.; Bennett, Allyson J.; Abi‐Saab, Danielle; D’Souza, Cyril; Abi‐Dargham, Anissa; Ds, Charney

doi:10.1016/0920-9964(95)95485-r

Cited by 9 publications

(9 citation statements)

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“…Another important aspect of the NMDA antagonist model is that PCP psychosis is not responsive to conventional antipsychotic therapy 2,17. This is supported by findings that only selective behavioral effects of PCP and ketamine in basic and clinical studies are ameliorated with dopamine antagonists 19,20. This makes the PCP model especially useful for strategies aimed at developing novel approaches for treatment of schizophrenia.…”

Section: The Nmda Antagonist Animal Model Of Schizophreniamentioning

confidence: 83%

Glutamatergic Animal Models of Schizophrenia

Moghaddam

Jackson

2003

Annals of the New York Academy of Sciences

132

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Several lines of evidence, including recent genetic linkage studies implicating susceptibility genes for schizophrenia, make a strong case that abnormal NMDA receptor-mediated neurotransmission is a major locus for the pathophysiology of schizophrenia. Animal models that are relevant to putative NMDA dysfunction in schizophrenia have excellent face validity for several symptoms of schizophrenia and are important tools for the design of novel pharmacological intervention in schizophrenia. The present chapter includes a brief review of the utility of these models and the search for new medications that have the potential of normalizing glutamate neurotransmission in schizophrenia.

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Section: The Nmda Antagonist Animal Model Of Schizophreniamentioning

confidence: 83%

Glutamatergic Animal Models of Schizophrenia

Moghaddam

Jackson

2003

Annals of the New York Academy of Sciences

132

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“…Although extrapolation of data from rodent models to complex human syndromes such as PCP psychosis or schizophrenia may be problematic, hyperlocomotion in rodents has been generally used as a predictor of the propensity of a drug to elicit or exacerbate psychosis in humans (Castellani & Adams, 1981;Greenburg & Segal, 1985;French, 1986;Carlsson et al, 1993;Jackson et al, 1994;Ogren & Goldstein, 1994;Steinpreis et al, 1994;Krystal et al, 1995;Goldman-Rakic, 1996;Verma & Moghaddam, 1996;Moghaddam & Adams, 1998). Therefore, the ability of a compound to antagonise PCP-induced behaviour and neuronal activation would be predictive of its antipsychotic properties in humans.…”

Section: Discussionmentioning

confidence: 99%

Blockade of phencyclidine‐induced effects by a nitric oxide donor

Bujas‐Bobanovic

Bird

Robertson

et al. 2000

British J Pharmacology

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1 Phencyclidine (PCP) is widely used as an animal model of schizophrenia. The aim of this study was to better understand the role of nitric oxide (NO) in the mechanism of action of PCP and to determine whether positive NO modulators may provide a new approach to the treatment of schizophrenia. 2 The eects of the NO donor, sodium nitroprusside (SNP), were studied in PCP-treated rats. Following drug administration, behavioural changes and the expression of c-fos, a metabolic marker of functional pathways in the brain, were simultaneously monitored. 3 Acute PCP (5 mg kg 71 , i.p.) treatment induced a complex behavioural syndrome, consisting of hyperlocomotion, stereotyped behaviours and ataxia. Treatment with SNP (2 ± 6 mg kg 71 , i.p.) by itself produced no eect on any behaviour studied but completely abolished PCP-induced behaviour in a dose-and time-dependent manner. 4 PCP had dierential regional eects on c-fos expression in rat brain, suggesting regionally dierent patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. Pre-treatment with SNP blocked PCP-induced c-fos expression at doses similar to those that suppress PCP-induced behavioural eects. 5 These results implicate the NO system in the mechanism of action of PCP. The fact that SNP abolished eects of PCP suggests that drugs targeting the glutamate-NO system may represent a novel approach to the treatment of PCP-induced psychosis and schizophrenia.

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“…Historically, attempts have been made to attribute PCP-and ketamine-induced psychosis to a wide variety of targets including dopaminergic, monoaminergic, cholinergic, GABAergic, opiatergic, sigma (Javitt and Zukin, 1991), and, most recently, to high D2 receptors (Seeman, 2010). However, the behavioral effects of NMDAR antagonists that are relevant to schizophrenia persist in the absence of dopamine activity (Carlsson and Carlsson, 1989;Adams and Moghaddam, 1998) or dopamine antagonists (Krystal et al, 1995). Furthermore, both the absolute concentrations and the rank-order potency with which a range of compounds induce psychotomimetic effects in humans and animal models conforms to their rank order of potency at NMDAR but not other receptor types (Javitt and Zukin, 1991;Seeman, 2010).…”

Section: The Revolutionmentioning

confidence: 99%

From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment

Moghaddam

Javitt

2011

Neuropsychopharmacol

859

642

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Glutamate is the primary excitatory neurotransmitter in mammalian brain. Disturbances in glutamate-mediated neurotransmission have been increasingly documented in a range of neuropsychiatric disorders including schizophrenia, substance abuse, mood disorders, Alzheimer's disease, and autism-spectrum disorders. Glutamatergic theories of schizophrenia are based on the ability of N-methyl-D-aspartate receptor (NMDAR) antagonists to induce schizophrenia-like symptoms, as well as emergent literature documenting disturbances of NMDAR-related gene expression and metabolic pathways in schizophrenia. Research over the past two decades has highlighted promising new targets for drug development based on potential pre- and postsynaptic, and glial mechanisms leading to NMDAR dysfunction. Reduced NMDAR activity on inhibitory neurons leads to disinhibition of glutamate neurons increasing synaptic activity of glutamate, especially in the prefrontal cortex. Based on this mechanism, normalizing excess glutamate levels by metabotropic glutamate group 2/3 receptor agonists has led to potential identification of the first non-monoaminergic target with comparable efficacy as conventional antipsychotic drugs for treating positive and negative symptoms of schizophrenia. In addition, NMDAR has intrinsic modulatory sites that are active targets for drug development, several of which show promise in preclinical/early clinical trials targeting both symptoms and cognition. To date, most studies have been done with orthosteric agonists and/or antagonists at specific sites. However, allosteric modulators, both positive and negative, may offer superior efficacy with less danger of downregulation.

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Modulating ketamine-induced thought disorder with lorazepam and haloperidol in humans

Cited by 9 publications

References 0 publications

Glutamatergic Animal Models of Schizophrenia

Glutamatergic Animal Models of Schizophrenia

Blockade of phencyclidine‐induced effects by a nitric oxide donor

From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment

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