A reversible model of the cognitive impairment associated with schizophrenia in monkeys

Potential therapeutic effects of two nicotinic acetylcholine receptor agonists

Jerry J. Buccafusco, Alvin V Terry

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

In monkeys proficient in the performance of a computer-assisted delayed response task, administration of sub-sedative doses of ketamine significantly impaired task performance after the 2 mg/kg dose, producing a decrease in accuracies across all four delay intervals. Ketamine elicited occasional and inconsistent increases in task latencies. But in general processing speed was not dramatically affected by the test dose. Pretreatment with the α7 nicotinic receptor agonist GTS-21 (DMXB-A) [3-[(3E)-3-[(2,4-dimethoxyphenyl) methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine] produced a dose-dependent attenuation of ketamine-induced decreases in task accuracies. In fact, the best dose of GTS-21 completely reversed the effects of ketamine. The nicotine metabolite cotinine is a cognitive-enhancer, and active in models predictive of antipsychotic activity. Pretreatment with cotinine did not reverse the task deficits produced by ketamine, and selection of a best dose was necessary to show the activity of cotinine. However, the best dose of cotinine, like GTS-21, completely reversed the ketamine-induced task deficits. Task accuracies were increased relative to their non-ketamine baselines during sessions run 24 h later. The cotinine-ketamine order of administration was reversed to provide a more clinically relevant model, and cotinine post-treatment regimen produced a clear reversal of the ketamine-induced task deficits. The protracted task improvement also was still evident. The DMTS task impairment induced by ketamine was capable of being completely reversed by two compounds that are known to improve working memory and cognition. The model could provide a means of late stage preclinical evaluation of new compounds that address the cognitive impairment associated with major psychotic disease.

Original languageEnglish (US)
Pages (from-to)852-862
Number of pages11
JournalBiochemical Pharmacology
Volume78
Issue number7
DOIs
StatePublished - Oct 1 2009

Fingerprint

Cholinergic Agonists
Ketamine
Nicotinic Receptors
Therapeutic Uses
Haplorhini
Cotinine
Schizophrenia
Nicotinic Agonists
Nootropic Agents
Cognitive Dysfunction
Task Performance and Analysis
Metabolites
Hypnotics and Sedatives
Nicotine
Short-Term Memory
Cognition
Antipsychotic Agents
Data storage equipment

Keywords

  • Cognition
  • Delayed matching
  • Hallucinogen
  • Nicotinic receptor agonist
  • Non-human primate
  • Schizophrenia

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

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title = "A reversible model of the cognitive impairment associated with schizophrenia in monkeys: Potential therapeutic effects of two nicotinic acetylcholine receptor agonists",
abstract = "In monkeys proficient in the performance of a computer-assisted delayed response task, administration of sub-sedative doses of ketamine significantly impaired task performance after the 2 mg/kg dose, producing a decrease in accuracies across all four delay intervals. Ketamine elicited occasional and inconsistent increases in task latencies. But in general processing speed was not dramatically affected by the test dose. Pretreatment with the α7 nicotinic receptor agonist GTS-21 (DMXB-A) [3-[(3E)-3-[(2,4-dimethoxyphenyl) methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine] produced a dose-dependent attenuation of ketamine-induced decreases in task accuracies. In fact, the best dose of GTS-21 completely reversed the effects of ketamine. The nicotine metabolite cotinine is a cognitive-enhancer, and active in models predictive of antipsychotic activity. Pretreatment with cotinine did not reverse the task deficits produced by ketamine, and selection of a best dose was necessary to show the activity of cotinine. However, the best dose of cotinine, like GTS-21, completely reversed the ketamine-induced task deficits. Task accuracies were increased relative to their non-ketamine baselines during sessions run 24 h later. The cotinine-ketamine order of administration was reversed to provide a more clinically relevant model, and cotinine post-treatment regimen produced a clear reversal of the ketamine-induced task deficits. The protracted task improvement also was still evident. The DMTS task impairment induced by ketamine was capable of being completely reversed by two compounds that are known to improve working memory and cognition. The model could provide a means of late stage preclinical evaluation of new compounds that address the cognitive impairment associated with major psychotic disease.",
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