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This research characterizes the cholinergic challenge induced by trihexyphenidyl in memory tasks and compares the effects of donepezil and tacrine.

April 22, 2026Open Access

Differential Effects of Donepezil and Tacrine on Recall-Phase Exploration in a Trihexyphenidyl-Induced Cholinergic Impairment Y-Maze Model

Key Points

This research characterizes the cholinergic challenge induced by trihexyphenidyl in memory tasks and compares the effects of donepezil and tacrine.
Conducted a two-trial Y-maze evaluation with a 24-hour interval using male Wistar rats.
Tested multiple treatment groups including control, donepezil, tacrine, and trihexyphenidyl.
Analyzed recall-phase behaviors and exploratory patterns using various behavioral metrics.
THP increased familiar-arm exploration and decreased novel-arm exploration at 10 mg/kg.
Donepezil showed clearer positive effects at a dose of 3 mg/kg under THP challenge.
Tacrine exhibited a dose-dependent effect, with optimal improvement in exploratory allocation at 5 mg/kg.

Abstract

Background/Objectives: Cholinergic dysfunction plays a central role in memory impairment, yet trihexyphenidyl (THP)-based paradigms remain less explored than scopolamine-based models. This study aimed to characterize a THP-induced cholinergic challenge in a two-trial Y-maze with a 24 h interval and to compare the effects of donepezil and tacrine on recall-phase exploratory allocation. Methods: Male Wistar rats (n = 9/group) were studied in a validation phase including saline, THP 5 mg/kg, and THP 10 mg/kg groups, followed by an intervention phase including control, THP 10 mg/kg, donepezil 1 and 3 mg/kg + THP, and tacrine 3 and 5 mg/kg + THP groups. All treatments were administered intraperitoneally (i.p.). Acquisition- and recall-phase behavior was analyzed. Recall outcomes included arm times, arm entries, the novel-to-familiar arm time ratio (U/K time ratio), the novel-to-familiar arm entry ratio (U/K entry ratio), discrimination indices and time-per-entry indices. Data were analyzed by one-way ANOVA; Tukey’s post hoc test was used in the validation experiment, whereas Dunnett’s test was used in the intervention experiment for comparisons against THP 10. Results: THP at 10 mg/kg produced a robust recall-phase phenotype, with increased familiar-arm exploration, reduced novel-arm exploration and lower normalized indices. Under THP challenge, donepezil was associated with clearer effects at 3 mg/kg, whereas tacrine displayed a broader dose-dependent profile, with the strongest shift in recall-phase exploratory allocation toward the novel arm observed at 5 mg/kg. Conclusions: THP 10 mg/kg produced a robust recall-phase exploratory phenotype in a 24 h two-trial Y-maze paradigm. Under THP challenge, donepezil and tacrine were associated with shifts in recall-phase exploratory allocation. These findings support the potential utility of THP-based paradigms for studying cholinergic disruption in Y-maze settings, while direct comparison with scopolamine-based models remains to be established.

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