TY - JOUR
T1 - A reversible model of the cognitive impairment associated with schizophrenia in monkeys
T2 - Potential therapeutic effects of two nicotinic acetylcholine receptor agonists
AU - Buccafusco, Jerry J.
AU - Terry, Alvin V.
N1 - Funding Information:
This study was supported by the National Institutes of Health National Institute on Aging [Grant AG029617] and by the Office of Research and Development, Department of Veterans Administration through partial salary support to J.J.B. The authors would also like to thank primate technicians Nancy Kille and Donna Blessing for conducting the study, and primate veterinarian Dr. Nancy Rodriguez for her clinical expertise pertaining to the care of our non-human primate subjects.
PY - 2009/10/1
Y1 - 2009/10/1
N2 - 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.
AB - 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.
KW - Cognition
KW - Delayed matching
KW - Hallucinogen
KW - Nicotinic receptor agonist
KW - Non-human primate
KW - Schizophrenia
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UR - http://www.scopus.com/inward/citedby.url?scp=68349131633&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2009.06.102
DO - 10.1016/j.bcp.2009.06.102
M3 - Article
C2 - 19577545
AN - SCOPUS:68349131633
SN - 0006-2952
VL - 78
SP - 852
EP - 862
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 7
ER -