Evaluation of acute bis(7)-tacrine treatment on behavioral functions in 17-day-old and 30-day-old mice, with attention to drug toxicity.

摘要

Bis(7)-tacrine was evaluated for efficacy on memory retention in mice 17 days of age and 30 days of age. The tests used were a passive-avoidance response test and a measure of spontaneous motor activity. Also, possible drug-induced hepatotoxicity and acute drug toxicity were evaluated. Behavioral studies were performed using a step-through task and an open-field test with a 24-h interval between training and evaluation tests. Bis(7)-tacrine (0.06-20 micromol/kg) was subcutaneously injected 30 min prior to the first session of both test types. During the training session of the step-through task, bis(7)-tacrine treatment reduced (by 46%, P<0.01) the number of avoidable electric shocks (footshocks) only at a high dose of 20 micromol/kg in mice 17 days of age, but dose-dependently decreased the number of footshocks (10-56%, P<0.001) in mice 30 days of age. Bis(7)-tacrine treatment at all doses tested did not produce any detectable changes in retention latency in mice 17 days of age, but the drug significantly prolonged retention latency at low doses (1.25 and 2.50 micromol/kg), and not high doses (5-20 micromol/kg), in mice 30 days of age. In the open-field test, bis(7)-tacrine decreased spontaneous motor activity in the acquisition session only at a high dose of 20 micromol/kg in mice 17 days of age and 30 days of age (by 28 and 45%, respectively), but did not affect spontaneous motor activity in the recall session. Bis(7)-tacrine treatment at a dose of 20 micromol/kg produced a more potent hepatotoxic effect in mice 30 days of age than in mice 17 days of age, (P<0.05), and the drug caused acute toxicity with comparable potencies in mice of both age groups. In conclusion, mice 30 days of age seemed to be more sensitive than mice 17 days of age to bis(7)-tacrine-induced cognitive function enhancement and hepatotoxicity. Bis(7)-tacrine appears to be more potent and more selective as a cognitive function-enhancing agent than tacrine.