Dose-related effects of the NMDA antagonist, ketamine, in healthy humans

Krystal, J.; Karper, Laurence P.; Seibyl, J; Delaney, Richard; Bremner, J. Douglas; Bowers, MalcolmB.; Ds, Charney

doi:10.1016/0920-9964(93)90538-t

Cited by 23 publications

(20 citation statements)

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“…Recent studies have suggested that motor function in certain animal models of PD may be altered by drugs that affect glutamatergic systems (Klockgether et al, 1991;see Greenamyre and O'Brien, 1991). Challenge protocols with ketamine have resulted in schizophreniform symptomatology (Krystal et al, 1992) and initial clinical trials of agents that act at sites on the excitatory amino acid receptor complex in schizophrenia have been performed. Unfortunately, the systemic administration of these pharmacological agents precludes the definition of sites of action (e.g, subthalamic nucleus as opposed to cerebral cortex or striatum).…”

Section: Discussionmentioning

confidence: 99%

Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease

1993

J. Neural Transmission

205

101

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The dopaminergic innervation of the prefrontal cortex is able to transsynaptically regulate the activity of subcortical dopamine innervations. Disruption of the prefrontal cortical DA innervation results in the enhanced biochemical responsiveness of the dopamine innervation of the nucleus accumbens. We present recent data indicating that distinct prefrontal cortical dopamine innervations can be functionally dissociated on the basis of responsiveness to stress. The ventral striatal projection target (nucleus accumbens shell) of the prefrontal cortical region that is stress sensitive is also responsive to stress. In this manner interconnected cortico-striato-pallido-mesencephalic loops can be defined on the basis of the biochemical responsive of local dopamine systems to stress and on the basis of responsiveness to antipsychotic drugs. These data suggest the functional derangement of a distinct corticofugal loops in schizophrenia and in certain aspects of Parkinson's disease.

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Section: Discussionmentioning

confidence: 99%

Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease

1993

J. Neural Transmission

205

101

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“…Ketamine and MK-801, which act at the same target within the NMDA receptor complex as 'open channel blockers', provoke the same psychotic symptoms (Krystal et al, 1993;1994) as PCP. Other substances, however, acting at the NMDA receptor complex as antagonists, but not at the PCP site of the NMDA receptor, have psychotogenic properties, too.…”

Section: Nmda-receptor Hypofunction and Schizophreniamentioning

confidence: 98%

Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

2006

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This overview tries to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. Schizophrenia is a disorder of dopaminergic neurotransmission, but modulation of the dopaminergic system by glutamatergic neurotransmission seems to play a key role. This view is supported by genetic findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction, however, is mediated by the N-methyl-D-aspartate (NMDA)-receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYNA). Despite the NMDA receptor antagonism, KYNA also blocks, in lower doses, the nicotinergic acetycholine receptor, i.e., increased KYNA levels can explain psychotic symptoms and cognitive deterioration. KYNA levels are described to be higher in the cerebrospinal fluid (CSF) and in critical central nervous system (CNS) regions of schizophrenics as compared to controls. Another line of evidence suggests that a (prenatal) infection is involved in the pathogenesis of schizophrenia. Due to an early sensitization process of the immune system or to a (chronic) infection, which is not cleared through the immune response, an immune imbalance between the type-1 and the type-2 immune responses takes place in schizophrenia. The type-1 response is partially inhibited, while the type-2 response is over-activated. This immune constellation is associated with inhibition of the enzyme indoleamine dioxygenase (IDO), because IDO - located in astrocytes and microglial cells - is inhibited by type-2 cytokines. IDO catalyzes the first step in tryptophan metabolism, the degradation from tryptophan to kynurenine, as does tryptophan 2,3-dioxygenase (TDO). Due to the inhibition of IDO, tryptophan-kynurenine is predominantly metabolized by TDO, which is located in astrocytes, not in microglial or other CNS cells. In schizophrenia, astrocytes in particular are activated, as increased levels of S100B appear. Additionally, they do not have the enzymatic equipment for the normal metabolism-route of tryptophan. Due to the lack of kynurenine hydroxylase (KYN-OHase) in astrocytes, KYNA accumulates in the CNS, while the metabolic pathway in microglial cells is blocked. Accordingly, an increase of TDO activity has been observed in critical CNS regions of schizophrenics. These mechanisms result in an accumulation of KYNA in critical CNS regions. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g., the use of anti-inflammatory cyclo-oxygenase-2 inhibitors, which can also decrease KYNA directly, are discussed.

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“…NMDA-R antagonists such as phencyclidine (PCP) and ketamine are well-known for their ability to produce schizophrenia-like symptoms when administered acutely in both healthy individuals (Krystal et al, 1994) or in remitted schizophrenia patients (Lahti et al, 1995), and when administered chronically (Morris et al, 2005). Assessing the impact of these antagonists on functional connectivity is also particularly pertinent given the suggested central role for altered NMDA-R mediated synaptic plasticity in the functional dysconnectivity seen in schizophrenia (Stephan et al, 2006;).…”

Section: Altered Brain Connectivity Following Nmda-r Antagonist Adminmentioning

confidence: 99%

Functional brain connectivity phenotypes for schizophrenia drug discovery

2015

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While our knowledge of the pathophysiology of schizophrenia has increased dramatically this has not translated into the development of new and improved drugs to treat this disorder. Human brain imaging and electrophysiological studies have provided dramatic new insight into the mechanisms of brain dysfunction in the disease, with a swathe of recent studies highlighting the differences in functional brain network and neural system connectivity present in the disorder. Only recently has the value of applying these approaches in preclinical rodent models relevant to the disorder started to be recognised.Here we highlight recent findings of altered functional brain connectivity in preclinical rodent models and consider their relevance to those alterations seen in the brains of schizophrenia patients. Furthermore, we highlight the potential translational value of using the paradigm of functional brain connectivity phenotypes in the context of preclinical schizophrenia drug discovery, as a means both to understand the mechanisms of brain dysfunction in the disorder and to reduce the current high attrition rate in schizophrenia drug discovery.3

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Dose-related effects of the NMDA antagonist, ketamine, in healthy humans

Cited by 23 publications

References 0 publications

Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease

Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease

Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

Functional brain connectivity phenotypes for schizophrenia drug discovery

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