Psychopharmacology

, Volume 179, Issue 1, pp 303–309

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
Original Investigation

DOI: 10.1007/s00213-004-1982-8

Cite this article as:
Krystal, J.H., Abi-Saab, W., Perry, E. et al. Psychopharmacology (2005) 179: 303. doi:10.1007/s00213-004-1982-8

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.

Keywords

GlutamateN-Methyl-d-aspartate receptorAttentionWorking memoryPrefrontal cortexSchizophreniaPsychosisEuphoriaAnxiety

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • John H. Krystal
    • 1
    • 2
  • Walid Abi-Saab
    • 1
    • 2
    • 3
  • Edward Perry
    • 1
    • 2
  • D. Cyril D’Souza
    • 1
    • 2
  • Nianjin Liu
    • 2
    • 4
  • Ralitza Gueorguieva
    • 2
    • 4
  • Lisa McDougall
    • 1
    • 2
  • Tracy Hunsberger
    • 1
    • 2
  • Aysenil Belger
    • 1
    • 5
  • Louise Levine
    • 6
  • Alan Breier
    • 6
  1. 1.Schizophrenia Biological Research Center (116-A)VA Connecticut Healthcare SystemWest HavenUSA
  2. 2.Abraham Ribicoff Research FacilitiesConnecticut Mental Health CenterNew HavenUSA
  3. 3.Pfizer Global Research and DevelopmentGrotonUSA
  4. 4.Division of Biostatistics, Department of Epidemiology and Public HealthYale University School of MedicineNew HavenUSA
  5. 5.Department of PsychiatryUniversity of North CarolinaChapel HillUSA
  6. 6.Lilly Research LaboratoriesIndianapolisUSA