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 referencememory performances in aged rodents and nonhuman primates

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. SI B-1553A, (+/-)-4-{[2-(1-methyl-2-pyrrolidinyl)ethyl]thio}phenol hydrochlori de, a novel nAChR ligand with predominant agonist subtype selectivity for b eta4 subunit-containing human neuronal nAChRs, was tested in a variety of c ognitive paradigms in aged rodents and nonhuman primates after acute and re peated administration. Subcutaneous administration of SIB-1553A improved de layed nonmatching to place performance in aged mice. In aged rhesus monkeys , intramuscular and oral administration of SIB-1553A improved choice accura cy in a delayed matching to sample task. SIB-1553A improved performances in these spatial and nonspatial working memory tasks but was less effective a t improving performances in spatial reference memory tasks (i.e., aged rode nts exposed to a discrimination task in a T-maze or trained to locate a hid den platform in a water maze). These data suggest that SIB-1553A has a pred ominant effect on attention/working memory processes. SIB-1553A also induce d the release of acetylcholine in the hippocampus of aged rats and was equa lly 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 i ncrease in cholinergic function. The present study provides additional supp ort for the use of subtype-selective nAChR ligands as a potential therapy f or the symptomatic treatment of specific cognitive deficits (such as attent ion/working memory deficits) associated with aging and neurological disease s.