Relation of nimodipine dose and serum concentration to learning enhancement in aging rabbits

Nimodipine, a 1,4-dihydropyridine calcium channel blocker, has been shown to enhance learning in aging rats, rabbits, and monkeys. Using an intravenous drug model, the relations among nimodipine dosage, nimodipine plasma concentration, and acquisition rate of the conditioned eyeblink response in aging rabbits were observed. Animals treated with nimodipine reached a behavioral criterion of 80% conditioned responses more quickly than did vehicle-treated control animals. Nimodipine doses produced marked behavioral effects, with statistically significant values starting at 0.5 micrograms/kg/min and reaching maximum efficacy at the minimal dose of 1 microgram/kg/min. Nimodipine at this dose exhibited an effect from the first day of infusion and facilitated learning rate threefold in comparison to control animals. Increasing the nimodipine dose to 3 and 5 micrograms/kg/min did not further facilitate learning rate. As nimodipine doses were augmented, the concentration of the nimodipine in plasma increased in a dose-related fashion. The most effective serum concentration for enhancing learning seemed to be distributed between 10 and 50 ng/ml. Concentrations above 50 ng/ml did not exert a more pronounced effect on the hippocampally dependent trace eyeblink conditioning task. The results of this study suggest that nimodipine may be useful in enhancing learning abilities in aging brain and have established the minimal serum concentration of nimodipine which must be achieved for this effect.