Motor dysfunction produced by tacrine administration in rats.

Abstract

In the present study, three experiments were conducted to provide a characterization of some of the motor effects of the anticholinesterase tacrine (1.25-5.0 mg/kg I.P.) in rats. In the first experiment, tacrine was found to produce tremulous jaw movements in the dose range of 1.25-5.0 mg/kg. The second experiment examined the effects of tacrine on locomotion, and it was demonstrated that tacrine produced a dose-related suppression of open-field motor activity. In the third experiment, the effects of tacrine were assessed using operant conditioning procedures. Behavioral output during lever pressing on a fixed ratio 5 schedule was recorded by a computerized system that measured response initiation time (time from offset of one response to onset of the next) and duration for each lever press. Tacrine administration substantially depressed lever pressing response rate. This deficit was largely due to a substantial increase in the average response initiation time. Analysis of the distribution of response initiation times indicated that tacrine-treated rats made relatively few responses with fast initiation times (e.g., 0-125 ms), and also that tacrine led to a dramatic increase in the number of pauses in responding (i.e., response initiation times greater than 2.5 s). Tacrine-treated rats showed a slight increase in the average initiation time for fast responses (i.e., a slight decrease in the local rate of responding), and also showed a substantial increase in the average length of pauses greater than 2.5 s. Analysis of response durations indicated that there was an overall increase in average response duration among animals that received the higher doses of tacrine. Although tacrine-induced decreases in the local rate of responding and increases in response duration contribute to the overall deficit, the major reason why tacrine-treated animals responded less was because they took much longer breaks in responding. It is possible that the tacrine-induced increases in pausing reflect a drug-induced akinesia. Thus, the present experiments indicate that tacrine impairs several aspects of motor function in the dose range tested. In view of the fact that tremor and motor slowing are classic symptoms of Parkinsonism, the present results in rats are consistent with the human literature indicating that tacrine (Cognex) can produce Parkinsonian side effects. Studies of the motor dysfunctions produced by tacrine in rats could be useful for investigating the motor side effects of tacrine in humans.