Ranitidine analog, JWS-USC-751X, enhances memory-related task performance in rats

The purpose of this study was to evaluate potential cognitive effects and nicotinic receptor binding affinity of a ranitidine analog previously found to antagonize M₂ muscarinic-cholinergic receptors and acetylcholinesterase (ACHE) in vitro. Several doses of JWS-USC-751X (JWS) were evaluated in rats in three memory-related tasks, a passive avoidance (PA) paradigm, the Morris Water Maze (MWM), and a delayed stimulus discrimination task (DSDT). Rat groups (n per dose) were as follows: PA = Wistar, n = 2025; MWM = 1-year-old Long-Evans, n = 7-8; and DSDT, Wistar, n = 6. In PA, JWS (1.0 mg/kg) improved scopolamine (SCOP)-induced deficits in learning to avoid an unsafe region of a shuttle box as indicated by both latency and learning frequency analysis. In the MWM, JWS (0.1, 0.5, and 1.0 mg/kg) improved 'spatial navigation learning' as demonstrated by the improved ability of rats to locate a hidden platform on day 2 of an 8-day training schedule. Two doses (0.1 and 0.5 mg/kg) also improved 'spatial bias' for the previous platform location when tested on day 9. JWS was not particularly effective at reducing SCOP-induced deficits in the MWM and failed to improve DSDT accuracy in a dose-dependent manner across delays. However, repeated optimal doses significantly improved DSDT accuracy at medium and long, presumably more difficult, delay intervals. JWS did not demonstrate a high affinity at nicotinic receptors as indicated in [³H]cytisine displacement assays. The data thus indicate moderate improvements in the performance of three memory-related tasks in both young and middle-aged rodents of two strains administered JWS. These results appear to substantiate the hypothesis that antagonizing both M₂ cholinergic receptors and AChE offers a potential means of improving cognition and supports the potential use of this agent (or similar compounds) in disorders of memory.