Prevention of ketamine-induced working memory impairments by AMPA potentiators in a nonhuman primate model of cognitive dysfunction

• Published in: Behavioural brain research Vol. 212; no. 1; pp. 41 - 48
• Main Authors: Roberts, Brooke M., Holden, Daniel E., Shaffer, Christopher L., Seymour, Patricia A., Menniti, Frank S., Schmidt, Christopher J., Williams, Graham V., Castner, Stacy A.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 01.09.2010; Elsevier
• Subjects: Adult and adolescent clinical studies; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism; AMPA; Analysis of Variance; Animals; Animals, Newborn; Area Under Curve; Behavioral psychophysiology; Biological and medical sciences; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Excitatory Amino Acid Agonists - chemistry; Excitatory Amino Acid Agonists - therapeutic use; Fundamental and applied biological sciences. Psychology; Ketamine; Macaca fascicularis; Macaca mulatta; Medical sciences; Memory Disorders - blood; Memory Disorders - chemically induced; Memory Disorders - prevention & control; Memory, Short-Term - drug effects; Monkey; Motor Activity - drug effects; Neuropsychological Tests; NMDA; Primates; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Psychopathology. Psychiatry; Psychoses; Reaction Time - drug effects; Schizophrenia; Spatial working memory; Sulfonamides - blood; Sulfonamides - chemistry; Sulfonamides - therapeutic use; Thiophenes - pharmacology; Thiophenes - therapeutic use; Time Factors; Spatial working memory; NMDA; Schizophrenia; AMPA; Ketamine; Monkey; Memory disorder; Cognitive disorder; Glutamate receptor; Psychosis; Prevention; Cognitive theory; Vertebrata; Mammalia; Theoretical model; General anesthetic; Animal; Primates; Antagonist; Working memory; NMDA receptor; Public health; Spatial memory
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2010.03.039

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 α-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 (0.1–1.0 mg/kg, SC) and structurally distinct PF-4778574 (0.01 mg/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).