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

Moghaddam, Bita; Adams, Barbara W.; Verma, Anita; Daly, Darron A.

doi:10.1523/jneurosci.17-08-02921.1997

Cited by 1,633 publications

(1,367 citation statements)

References 68 publications

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“…Glutamate and the NMDA-R are essential factors in the plasticity response of the basalganglia (Schmidt, 1998) and glutamatergic activity is secondary only to dopaminergic activity in these structures (Nieoullon, 2002). As NMDA antagonism enhances both glutamate and dopamine release in components of corticostriato-thalamic circuitry (Moghaddam et al, 1997), it is feasible that this enhancement is responsible for the impairment in procedural learning observed in the current study. Previous research has found that administration of a dopamine antagonist can reverse ketamine-induced impairments on the WCST, which has a procedural learning component (Krystal et al, 1999).…”

Section: Discussionmentioning

confidence: 68%

Acute Effects of Ketamine on Memory Systems and Psychotic Symptoms in Healthy Volunteers

Morgan

Mofeez

Brandner

et al. 2003

Neuropsychopharmacol

240

174

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N-methyl-D-aspartate (NMDA) receptor antagonists have been demonstrated to induce schizophrenia-like symptoms and cognitive impairment in humans. The NMDA receptor has been strongly implicated in memory, but research to date on the effects of NMDA antagonists has examined only some aspects of human memory functions. This study used a double-blind, placebo-controlled, independent groups design with 54 healthy volunteers to examine the effects of infusions of two doses (0.4, 0.8 mg/kg) of the NMDA antagonist ketamine upon the five human memory systems, aspects of executive functioning and schizophrenia-like and dissociative symptoms. Ketamine produced a dose-dependent impairment to episodic and working memory and a slowing of semantic processing. Ketamine also impaired recognition memory and procedural learning. Attention, perceptual priming and executive functioning were not affected following the drug. In addition, ketamine induced schizophrenia-like and dissociative symptoms, which were not correlated with the cognitive measures. These data suggest that, in humans, ketamine produces a selective pattern of impairments to working, episodic, and procedural memory but not to perceptual priming, attention or aspects of executive functioning.

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Section: Discussionmentioning

confidence: 68%

Acute Effects of Ketamine on Memory Systems and Psychotic Symptoms in Healthy Volunteers

Morgan

Mofeez

Brandner

et al. 2003

Neuropsychopharmacol

240

174

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“…Likewise, PCP itself increases the firing rate of dopaminergic neurons (Freedman and Bunney 1984; French 1994). The available data suggest that acute administration of PCP may reduce cortical GABAergic function (Grunze et al 1994;Yonezawa et al 1998), disinhibiting glutamatergic transmission in the prefrontal cortex (Moghaddam et al 1997) and ventral tegmental area (Mathe et al 1998). This increase in glutamatergic transmission would then stimulate mesocorticolimbic dopaminergic transmission and locomotor behavior (Jentsch et al 1998d).…”

Section: Neurochemistry Cortical Dopamine Dysfunctionmentioning

confidence: 99%

“…Although acute PCP or ketamine administration may be associated with blockade (and net hypoactivity) of the NMDA receptor, the comprehensive effects of these drugs on cortical circuitry are complicated by the finding that acute administration of ketamine or PCP dramatically increases cortical glutamate (and dopamine) efflux (Moghaddam et al 1997), possibly leading to hyperactivation of non-NMDA glutamate receptors; this hyperactivation of glutamatergic transmission at non-NMDA receptors is a component of Olney and Farber's (1995) "NMDA receptor hypofunction" hypothesis of PCP-induced psychosis. This could also explain the seemingly paradoxical finding that acute ingestion of high doses of PCP, although reducing NMDA-associated transmission, can be proconvulsant (Gorelick and Balster 1994).…”

Section: Glutamatergic and Gabaergic Dysfunctionmentioning

confidence: 99%

“…Indeed, Moghaddam and colleagues (Moghaddam et al 1997) have argued that the increase in cortical glutamate efflux after acute NMDA antagonist administration (a net potentiation of transmission at non-NMDA glutamate receptors) produces the increase in dopamine release since intra-cortical administration of an AMPA receptor antagonist blocked the ketamine-induced increase in cortical dopamine release. This is complementary to the finding that injection of the same AMPA antagonist into the cell body regions of the dopamine neurons likewise attenuates PCP-induced biochemical and behavioral abnormalities (Mathe et al 1998).…”

Section: Glutamatergic and Gabaergic Dysfunctionmentioning

confidence: 99%

“…These ideas are supported by the finding that schizophrenic patients had lower cerebrospinal fluid glutamate concentrations than controls (Kim et al 1980); however, this finding remains controversial (e.g., Perry, 1982 failed to find such an effect). Furthermore, glutamate receptors have been reported to be increased in schizophrenia (an effect presumably secondary to reduced glutamate transmission; Toru et al 1994).Although acute PCP or ketamine administration may be associated with blockade (and net hypoactivity) of the NMDA receptor, the comprehensive effects of these drugs on cortical circuitry are complicated by the finding that acute administration of ketamine or PCP dramatically increases cortical glutamate (and dopamine) efflux (Moghaddam et al 1997), possibly leading to hyperactivation of non-NMDA glutamate receptors; this hyperactivation of glutamatergic transmission at non-NMDA receptors is a component of Olney and Farber's (1995) "NMDA receptor hypofunction" hypothesis of PCP-induced psychosis. This could also explain the seemingly paradoxical finding that acute ingestion of high doses of PCP, although reducing NMDA-associated transmission, can be proconvulsant (Gorelick and Balster 1994).…”

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confidence: 99%

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The Neuropsychopharmacology of Phencyclidine From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia

Jentsch

Roth²

1999

Neuropsychopharmacology

1,203

772

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Administration of noncompetitive NMDA ր glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animalsBiological psychiatric research has seen the development of many putative animal models of schizophrenia. The etiological bases of these models have varied widely from the administration of purportedly psychotomimetic drugs (Snyder 1988; Javitt and Zukin 1991; Jentsch et al. 1998a), to perinatal insults (Lipska et al. 1993;El-Khodor and Boksa 1997;Moore and Grace 1997; Bertolino et al. 1997), to chronic social isolation or stress (Jones et al. 1990), and beyond. The administration of psychotomimetic drugs to humans and animals represents probably the most widely accepted and utilized class of schizophrenia models. These "pharmacological" models seem to represent methods for the induction of psychopathology in humans and aberrant (potentially related) behavior in animals.At the behavioral level, there seems to be some heterogeneity in the effects of different psychotomimetic drug classes. The psychomotor stimulants, such as amphetamine and cocaine, can clearly induce a form of 20 , NO . 3 paranoid psychosis in human subjects after high-dose or long-term administration, but evidence regarding the ability of these agents to induce "deficit" state symptoms is conflicting (Angrist and Gershon 1970;Everitt et al., 1997); moreover, there is evidence that amphetamine may actually alleviate negative and cognitive symptoms in schizophrenic patients (Angrist et al. 1982;Goldberg et al. 1991; Carter et al. 1997). Psychotomimetic indoleamines, such as lysergic acid diethylamide, can induce profound sensory hallucinations without causing any apparent deficit state in normal subjects (Geyer and Markou 1994) and without precipitating symptomatology in schizophrenic patients (Cohen et al. 1962). In contrast, the noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) ր glutamate receptor, including phencyclidine (PCP) and ketamine, seem to be capable of inducing both positive and negative symptoms of schizophrenia, including cognitive dysfunction in normal humans (Snyder 1980; Javitt and Zukin 1991;Tamminga 1998); these drugs also profoundly exacerbate both positive and negative symptoms in schizophrenic patients (Itil et al. 1967;Lahti et al. 1994;Malhotra et al. 1997a).Because of the more comprehensive psychopathology induced by PCP, many researchers have studied the effects of NMDA receptor antagonists in humans and animals to gain insights into the neurobiology of schizophrenia. In this review, the validity of NMDA receptor antagonist-induced models of schizophrenia in humans and animals are considered, and the applicability of acute versus chronic administration of PCP as a more precise model is assessed. The neurobiological substrates of the observed behavior...

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A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression

Diazgranados

Ibrahim

Brutsché

et al. 2010

Arch Gen Psychiatry

855

705

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Context Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects—for instance, within a few hours or days—would have an enormous impact on patient care and public health. Objective To determine whether an N-methyl-d-aspartate–receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression. Design A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009. Setting Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant). Interventions Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion. Main Outcome Measures Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores. Results Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d=0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d=0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point. Conclusion In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-d-aspartate antagonist. Trial Registration clinicaltrials.gov Identifier: NCT00088699

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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

Cited by 1,633 publications

References 68 publications

Acute Effects of Ketamine on Memory Systems and Psychotic Symptoms in Healthy Volunteers

Acute Effects of Ketamine on Memory Systems and Psychotic Symptoms in Healthy Volunteers

The Neuropsychopharmacology of Phencyclidine From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia

A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression

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