Abstract
Preclinical and clinical data have suggested the potential use of nicotinic acetylcholine receptor (nAChR) ligands for treating cognitive dysfunction associated with neurodegenerative diseases, such as Alzheimer's disease. SIB-1553A, (±)-4-{[2-(1-methyl-2-pyrrolidinyl)ethyl]thio}phenol hydrochloride, a novel nAChR ligand with predominant agonist subtype selectivity for β4 subunit-containing human neuronal nAChRs, was tested in a variety of cognitive paradigms in aged rodents and nonhuman primates after acute and repeated administration. Subcutaneous administration of SIB-1553A improved delayed nonmatching to place performance in aged mice. In aged rhesus monkeys, intramuscular and oral administration of SIB-1553A improved choice accuracy in a delayed matching to sample task. SIB-1553A improved performances in these spatial and nonspatial working memory tasks but was less effective at improving performances in spatial reference memory tasks (i.e., aged rodents exposed to a discrimination task in a T-maze or trained to locate a hidden platform in a water maze). These data suggest that SIB-1553A has a predominant effect on attention/working memory processes. SIB-1553A also induced the release of acetylcholine in the hippocampus of aged rats and was equally effective whether administered acutely or repeatedly (6 weeks of daily subcutaneous administration). Thus, rats repeatedly treated with SIB-1553A exhibit neither tolerance nor sensitization to the effects of the compound. The SIB-1553A-induced cognitive improvement may be in part related to an increase in cholinergic function. The present study provides additional support for the use of subtype-selective nAChR ligands as a potential therapy for the symptomatic treatment of specific cognitive deficits (such as attention/working memory deficits) associated with aging and neurological diseases.
Footnotes
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↵1 Current address: Laboratoire de Neurosciences Cognitives, UMR CNRS 5106, Avenue des Facultés, 33405 Talence, France.
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↵2 Current address: Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Dr., San Diego, CA 92121.
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This work was funded by Merck Research Laboratories (formerly SIBIA Neurosciences, Inc.). The primate study was supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs, and funds provided by Merck Research Laboratories. B.B. was supported in part by a grant from the Pôle Aquitaine Santé, Secteur Médicament (Pessac, France).
- Abbreviations:
- ANOVA
- analysis of variance
- DMTS
- delayed matching to sample
- DNMTP
- delayed nonmatching to place
- nAChR
- nicotinic acetylcholine receptor
- Received January 18, 2001.
- Accepted June 12, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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