Bridged nicotine, isonicotine, and norisonicotine effects on working memory performance of rats in the radial-arm maze
Nicotine and other nicotinic agonists have been found tO improve performance in a variety of tasks, including the radial-arm maze to improve memory. There has been an active effort to develop novel nicotinic agonists for the treatment of cognitive dysfunction such as is seen in Alzheimer's disease. These novel ligands can also serve as tools with which to increase our knowledge concerning the involvement of nicotinic systems with cognitive function. The current studies were conducted to assess the actions of three new nicotinic agonists, i.e., bridged nicotine, isonicotine, and norisonicotine, on choice accuracy in the radial-arm maze. Rats were trained on a win-shift working memory task in the eight-arm radial maze. In Experiment 1, the rats were administered (subcutaneously) saline and three doses of bridged nicotine, isonicotine, and norisonicotine (0.5, 1.5, and 4.5 mg/kg). Bridged nicotine did not cause any significant effects on memory performance, although it did significantly increase latency and at the high dose caused severe slowing and nonperformance. Both isonicotine and norisonicotine caused a significant linear dose-related improvement in choice accuracy, indicative of improved working memory function. In Experiment 2, another set of rats received the effective doses of 4.5 mg/kg of isonicotine and norisonicotine as well as higher doses of 13.5 mg/kg of each compound. These doses were administered alone or in combination with 5 mg/kg of the nicotinic antagonist mecamylamine to determine the nicotinic nature of the effects. As in Experiment 1 the 4.5 mg/kg of isonicotine caused a significant memory improvement. The 4.5 mg/kg dose of norisonicotine caused a more modest rise in performance, which was not significantly different from control in this experiment. When both experiments were considered together, the 4.5 mg/kg doses of both isonicotine and norisonicotine were the most effective in improving working memory performance. Significant improvements in working memory were seen with both drugs (P < 0.025). The higher doses of 13.5 mg/kg of both isonicotine and norisonicotine resulted in nearly control-level performance. Thus, the typical inverted U-shaped dose-effect function was evident for both isonicotine and norisonicotine. Mecamylamine brought performance improved by the 4.5 mg/kg dose back to control levels, providing evidence for the nicotinic nature of the effect. Both isonicotine and norisonicotine show promise for development as memory-improving nicotinic agonist drugs.
Levin, ED; Imad Damaj, M; Glassco, W; May, EL; Martin, BR
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