• John H Krystal, Walid Abi-Saab, Edward Perry, D Cyril D'Souza, Nianjin Liu, Ralitza Gueorguieva, Lisa McDougall, Tracy Hunsberger, Aysenil Belger, Louise Levine, and Alan Breier.
• Schizophrenia Biological Research Center (116-A), VA Connecticut Healthcare System, West Haven, CT 06516, USA. john.krystal@yale.edu
• Psychopharmacology (Berl.). 2005 Apr 1;179(1):303-9.

RationaleSome 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.ObjectiveThis 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.MethodsNineteen 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.ResultsKetamine 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.ConclusionsThese 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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