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 performanc e in a variety of tasks, including the radial-arm maze to improve memory. T here 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 know ledge concerning the involvement of nicotinic systems with cognitive functi on. The current studies were conducted to assess the actions of three new n icotinic agonists, i.e., bridged nicotine, isonicotine, and norisonicotine, on choice accuracy in the radial-arm maze. Rats were trained on a win-shif t working memory task in the eight-arm radial maze. In Experiment 1, the ra ts were administered (subcutaneously) saline and three doses of bridged nic otine, isonicotine, and norisonicotine (0.5, 1.5, and 4.5 mg/kg). Bridged n icotine did not cause any significant effects on memory performance, althou gh it did significantly increase latency and at the high dose caused severe slowing and nonperformance. Both isonicotine and norisonicotine caused a s ignificant linear dose-related improvement in choice accuracy, indicative o f improved working memory function. In Experiment 2, another set of rats re ceived the effective doses of 4.5 mg/kg of isonicotine and norisonicotine a s well as higher doses of 13.5 mg/kg of each compound. These doses were adm inistered alone or in combination with 5 mg/kg of the nicotinic antagonist mecamylamine to determine the nicotinic nature of the effects. As in Experi ment 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 perform ance, which was not significantly different from control in this experiment . When both experiments were considered together, the 4.5 mg/kg doses of bo th isonicotine and norisonicotine were the most effective in improving work ing memory performance. Significant improvements in working memory were see n with both drugs (P < 0.025). The higher doses of 13.5 mg/kg of both isoni cotine and norisonicotine resulted in nearly control-level performance. Thu s, the typical inverted U-shaped dose-effect function was evident for both isonicotine and norisonicotine. Mecamylamine brought performance improved b y the 4.5 mg/kg dose back to control levels, providing evidence for the nic otinic nature of the effect. Both isonicotine and norisonicotine show promi se for development as memory-improving nicotinic agonist drugs. (C) 1999 Wi ley-Liss, Inc.