Effect of a Novel CNS-Selective Cholinesterase Inhibitor, SM-10888, on Habituation and Passive Avoidance Responses in Mice

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Abstract
The effects of the tacrine (THA) derivatives SM-10888 (9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate) on habituation and passive avoidance responses were studied in mice. We examined its effects on habituation of exploratory activity, measured by photo-cell beam interruptions in a small, simple cage and cycloheximide (CXM)- or electroconvulsive shock (ECS)-induced stepdown type passive avoidance response (PAR) failures in comparison with those of THA, amiridin, HP-029 and physostigmine. SM-10888 (6 mg/kg, p.o.) administered post-acquisition session enhanced the retention of habituation. CXM- and ECS-induced PAR failures were improved by SM-10888 (6 mg/kg, p.o.) administered at pre-training or post-training, respectively. THA enhanced the retention of habituation and improved CXM-induced PAR failure at 30 mg/kg, p.o., but did not affect ECS-induced PAR failure at 1-15 mg/kg, p.o. Amiridin and HP-029 were also effective on habituation and CXm-induced PAR failure at 40-50 mg/kg, p.o., but did not affect ECS-induced PAR failure at the tested doses. Physostigmine showed a moderate improvement only in CXM-induced PAR failure. The results indicate that SM-10888 enhanced habituation and improved PAR failures at much lower doses than THA. This seems to depend on its high selectivity to the central nervous system.