RT Journal Article
SR Electronic
T1 SIB-1553A, (±)-4-{[2-(1-Methyl-2-pyrrolidinyl)ethyl]thio}phenol Hydrochloride, a Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors with Putative Cognitive-Enhancing Properties: Effects on Working and Reference Memory Performances in Aged Rodents and Nonhuman Primates
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 297
OP 306
VO 299
IS 1
A1 Bruno Bontempi
A1 Kevin T. Whelan
A1 Victoria B. Risbrough
A1 Tadimeti S. Rao
A1 Jerry J. Buccafusco
A1 G. Kenneth Lloyd
A1 Frédérique Menzaghi
YR 2001
UL http://jpet.aspetjournals.org/content/299/1/297.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics