Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects

John H. Krystal, Walid Abi-Saab, Edward Perry, D. Cyril D'Souza, Nianjin Liu, Ralitza Gueorguieva, Lisa McDougall, Tracy Hunsberger, Aysenil Belger, Louise Levine, Alan Breier

Research output: Contribution to journalArticle

216 Citations (Scopus)

Abstract

Rationale: Some of the behavioral consequences of deficits in N-methyl-d-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry. Objective: This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects. Methods: Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions. Results: Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion. Conclusions: These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.

Original languageEnglish (US)
Pages (from-to)303-309
Number of pages7
JournalPsychopharmacology
Volume179
Issue number1
DOIs
StatePublished - Apr 2005
Externally publishedYes

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eglumetad
Excitatory Amino Acid Agonists
Excitatory Amino Acid Antagonists
Metabotropic Glutamate Receptors
Ketamine
Short-Term Memory
Healthy Volunteers
Placebos
Glutamate Receptors
Intravenous Administration
aspartic acid receptor
Pharmaceutical Preparations

Keywords

  • Anxiety
  • Attention
  • Euphoria
  • Glutamate
  • N-Methyl-D-aspartate receptor
  • Prefrontal cortex
  • Psychosis
  • Schizophrenia
  • Working memory

ASJC Scopus subject areas

  • Pharmacology

Cite this

Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. / Krystal, John H.; Abi-Saab, Walid; Perry, Edward; D'Souza, D. Cyril; Liu, Nianjin; Gueorguieva, Ralitza; McDougall, Lisa; Hunsberger, Tracy; Belger, Aysenil; Levine, Louise; Breier, Alan.

In: Psychopharmacology, Vol. 179, No. 1, 04.2005, p. 303-309.

Research output: Contribution to journalArticle

Krystal, John H. ; Abi-Saab, Walid ; Perry, Edward ; D'Souza, D. Cyril ; Liu, Nianjin ; Gueorguieva, Ralitza ; McDougall, Lisa ; Hunsberger, Tracy ; Belger, Aysenil ; Levine, Louise ; Breier, Alan. / Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. In: Psychopharmacology. 2005 ; Vol. 179, No. 1. pp. 303-309.
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abstract = "Rationale: Some of the behavioral consequences of deficits in N-methyl-d-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry. Objective: This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects. Methods: Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions. Results: Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion. Conclusions: These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.",
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AU - Abi-Saab, Walid

AU - Perry, Edward

AU - D'Souza, D. Cyril

AU - Liu, Nianjin

AU - Gueorguieva, Ralitza

AU - McDougall, Lisa

AU - Hunsberger, Tracy

AU - Belger, Aysenil

AU - Levine, Louise

AU - Breier, Alan

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N2 - Rationale: Some of the behavioral consequences of deficits in N-methyl-d-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry. Objective: This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects. Methods: Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions. Results: Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion. Conclusions: These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.

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KW - Prefrontal cortex

KW - Psychosis

KW - Schizophrenia

KW - Working memory

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