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Prevention of Ketamine-Induced Working Memory Impairments by AMPA Potentiators in a Nonhuman Primate Model of Cognitive Dysfunction

Brooke M Roberts, Daniel E Holden, Christopher L Shaffer, Patricia A Seymour, Frank S Menniti, Christopher J Schmidt, Graham V Williams, Stacy A Castner

Behav Brain Res. 2010 Sep 1;212(1):41-8.

PMID: 20347881

Abstract:

Working memory impairments are a core aspect of schizophrenia, yet current medicines do not address such cognitive dysfunction. We have developed a model of these working memory deficits by acutely disrupting glutamatergic synaptic transmission by administration of the N-methyl-d-aspartate (NMDA) antagonist ketamine in the nonhuman primate. The current studies evaluated the effect of positive allosteric modulators ("potentiators") of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors on the working memory and behavioral effects of ketamine. AMPA receptors mediate fast excitatory synaptic transmission throughout the brain and play a critical role in the activity-dependent regulation of NMDA receptors. We find that positive modulation of AMPA receptors with LY451646 (0.1-1.0mg/kg, SC) and structurally distinct PF-4778574 (0.01mg/kg, SC) robustly ameliorates ketamine-induced working memory impairments without altering behavioral effects of acute ketamine we consider related to positive- and negative-like symptoms. These results support AMPA receptor potentiators as a potential adjunctive treatment for cognitive impairment associated with schizophrenia (CIAS).

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
AP1219633994 PF-4778574 PF-4778574 1219633-99-4 Price
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