TY - JOUR
T1 - Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains
AU - Weed, Michael R.
AU - Bookbinder, Mark
AU - Polino, Joseph
AU - Keavy, Deborah
AU - Cardinal, Rudolf N.
AU - Simmermacher-Mayer, Jean
AU - Cometa, Fu Ni L.
AU - King, Dalton
AU - Thangathirupathy, Srinivasan
AU - Macor, John E.
AU - Bristow, Linda J.
N1 - Funding Information:
This work was funded by Bristol-Myers Squibb, and all authors except for Fu-Ni Cometa and Rudolf Cardinal were BMS employees during their contribution to this project. In the prior three years Fu-ni Cometa has been employed by Aerotek Scientific (during these studies) and Manpower. Dr Cardinal was compensated by BMS for his role in the development of the novel version of the nonhuman primate-CANTAB delayed-match-to-sample procedure and software used in these studies. In addition, Dr Cardinal has received salary from the University of Cambridge as a full-time employee; payments for teaching and clinical work from Cambridgeshire and Peterborough NHS Foundation Trust; royalties from software sales via the University of Cambridge; consultancy fees from Campden Instruments Ltd; royalties from books from Taylor Francis Group and Cambridge University Press; a lecture fee from the Neuroscience Education Institute; and payment for clinical services from UK government agencies.
Publisher Copyright:
© 2016 American College of Neuropsychopharmacology. All rights reserved.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.
AB - Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.
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U2 - 10.1038/npp.2015.184
DO - 10.1038/npp.2015.184
M3 - Article
C2 - 26105137
AN - SCOPUS:84949599459
VL - 41
SP - 568
EP - 577
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 2
ER -