Differential Effects of Donepezil and Tacrine on Recall-Phase Exploratory Behavior in Healthy Male Wistar Rats: A Two-Trial Y-Maze Study

Abstract

Cholinesterase inhibitors with distinct pharmacological profiles may influence exploratory behavior, yet their effects on recall-related exploration in physiologically intact animals remain insufficiently characterized. The present study aimed to directly compare the effects of donepezil, a relatively selective acetylcholinesterase inhibitor, and tacrine, a cholinesterase inhibitor with broader enzymatic and pharmacological activity, on exploratory allocation during memory recall in healthy rats. Male Wistar rats were assigned to five groups (n = 8/group): control, donepezil 1 mg/kg, donepezil 3 mg/kg, tacrine 3 mg/kg, and tacrine 5 mg/kg. Treatments were administered intraperitoneally 50 min before the acquisition trial, while recall performance was evaluated 24 h later without additional treatment using a two-trial Y-maze paradigm. Time spent and entries into the familiar and novel arms, novel-to-familiar ratios, and mean time per entry were analyzed. Control animals showed no marked preference for the novel arm, whereas donepezil produced only limited, non-significant behavioral changes. Tacrine 5 mg/kg significantly increased the U/K time ratio compared with controls (p = 0.0006) and the U/K entry ratio (p = 0.001), primarily through reduced time spent in the familiar arm (p = 0.0004) and fewer familiar-arm entries (p = 0.025). Absolute time spent in, and entries into, the novel arm did not differ significantly among groups (p = 0.689 and p = 0.883, respectively). Overall, these findings suggest that tacrine, but not donepezil, modified recall-phase exploratory preference in healthy rats, predominantly by reducing persistence in the familiar arm.