PMID- 11561092
DA - 20010918
DCOM- 20011018
IS - 0022-3565
VI - 299
IP - 1
DP - 2001 Oct
TI - 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.
PG - 297-306 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 beta4 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.
AD - Merck Research Laboratories, La Jolla, California, USA.
FAU - Bontempi, B
AU - Bontempi B
FAU - Whelan, K T
AU - Whelan KT
FAU - Risbrough, V B
AU - Risbrough VB
FAU - Rao, T S
AU - Rao TS
FAU - Buccafusco, J J
AU - Buccafusco JJ
FAU - Lloyd, G K
AU - Lloyd GK
FAU - Menzaghi, F
AU - Menzaghi F
LA - eng
PT - Journal Article
CY - United States
TA - J Pharmacol Exp Ther
JID - 0376362
RN - 0 (Nicotinic Agonists)
RN - 0 (Phenols)
RN - 0 (Pyrrolidines)
RN - 0 (Receptors, Nicotinic)
RN - 0 (SIB 1553A)
SB - IM
MH - Aging/*psychology
MH - Animal
MH - Cognition/*drug effects
MH - Conditioning, Operant/drug effects
MH - Discrimination Learning/drug effects
MH - Dose-Response Relationship, Drug
MH - Female
MH - Macaca mulatta
MH - Male
MH - Memory/*drug effects
MH - Memory, Short-Term/*drug effects
MH - Mice
MH - Mice, Inbred C57BL
MH - Microdialysis
MH - Nicotinic Agonists/*pharmacology
MH - Phenols/*pharmacology
MH - Pyrrolidines/*pharmacology
MH - Rats
MH - Receptors, Nicotinic/*drug effects
MH - Support, Non-U.S. Gov't
MH - Support, U.S. Gov't, Non-P.H.S.
EDAT- 2001/09/19 10:00
MHDA- 2001/10/19 10:01
URLF- http://www.jpet.org/cgi/content/full/299/1/297
URLS- http://www.jpet.org/cgi/content/abstract/299/1/297
PST - ppublish
SO - J Pharmacol Exp Ther 2001 Oct;299(1):297-306.