Cognitive Enhancing Properties and Tolerability of Cholinergic Agents in Mice: A Comparative Study of Nicotine, Donepezil, and SIB-1553A, a Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

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Abstract
Several studies have demonstrated the importance of nicotinic mechanisms in the pathophysiology of neurodegenerative and cognitive disorders, warranting the search and development of novel nicotinic ligands as potential therapeutic agents. The present study was designed to assess whether the subtype-selective nicotinic acetylcholine receptor (nAChR) ligand SIB-1553A [(+/-)-4-([2-(1-methyl-2-pyrrolidinyl)ethyl]thio)phenol hydrochloride], with predominant agonist activity at beta4 subunit-containing human nAChRs, and no activity at muscle nAChR subtypes, could enhance cognitive performance in rodents with a more desirable safety/tolerability profile as compared to the nonselective prototypic nAChR ligand nicotine. SIB-1553A was equi-efficacious to nicotine in improving working memory performance in scopolamine-treated mice as measured by increased alternation in a T-maze, and was more efficacious than nicotine in improving the baseline cognitive performance of aged mice. This effect on working memory was confirmed in a delayed nonmatching to place task using the eight-arm radial maze. SIB-1553A produced dose-dependent side effects (ie motor deficits and seizures), although these effects were observed at doses 12 to 640-fold above those required to increase cognitive performance. Overall, SIB-1553A was significantly less potent than nicotine in eliciting these undesirable effects. Thus, the subtype-selective profile of SIB-1553A appears to translate into a more efficacious and better tolerated nAChR ligand as compared to nicotine. In the present studies, cognitive enhancement induced by SIB-1553A was similar in magnitude to that produced by the clinically efficacious acetylcholinesterase inhibitor donepezil. Taken together, the present data confirm the importance of nAChR subtypes in modulating cognitive processes, and suggest that activation of nAChR subtypes by selective nAChR ligands may be a viable approach to enhance cognitive performance.