Effect of R3487/MEM3454, a novel nicotinic a7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats

It is well established that nicotinic systems in the brain are critically involved in attentional processes in both animals and humans. The current study assessed the effects of a novel nicotinic a7 receptor partial agonist and 5-HT3 antagonist, R3487/MEM3454 (also referred to as R3487 or MEM 3454) on sustained attention in rats performing an operant visual signal detection task. The effects of R3487/MEM3454 were compared to those of the acetylcholinesterase inhibitor/nicotinic a7 allosteric positive modulator galanthamine. Adult female Sprague-Dawley rats were injected subcutaneously with R3487/MEM3454 (0.0,0.,0.1,0.3 and 0.6 mg/kg), galanthamine (0.2,0.5, 1, 2 mg/kg) or vehicle 30 min before the attentional test. In the second study, the time-dependent effects of R3487/MEM3454 were assessed by injecting the compound (0.6 mg/kg, s.c.) at different pretreatment intervals (30, 60 or 90 min) before the start of the attentional task. Our results show a significant dose-effect for R3487/MEM3454 on percent hit accuracy performance without any significant alteration on percent correct rejection performance. In the time-dependent test, R3487/MEM3454 significantly increased the percent hit accuracy performance when animals were injected 60 min before the start of the attentional task. Administration of galanthamine failed to significantly increase percent hit accuracy performance and increasing the dose of galanthamine produced a decrease in percent correct rejection performance. The present findings with R3487/MEM3454 suggest that nicotinic a7 receptors and/or 5-HT3 receptors may play an important role in modulating sustained attention and that R3487/MEM3454 may have therapeutic potential in improving sustained attention in humans.