Dose-dependent neurorestorative effects of amantadine after cortical impact injury

•Amantadine (AMT) improved motor and cognitive performance after TBI in a dose-dependent manner.•The data underscore the need for careful consideration of dosing.•AMT did not differ from SHAM controls in memory retention, indicating its robust benefits. Numerous pharmacotherapies have been evaluated after experimental traumatic brain injury (TBI). While amantadine (AMT) has shown potential for clinical efficacy, the few studies on its effectiveness have been mixed. It is possible that suboptimal dosing, due to the evaluation of only one dose, may be causing the discrepancies in outcomes. Hence, the goal of the current study was to conduct a dose response of AMT after TBI to determine an optimal behavioral benefit. Anesthetized adult male rats received either a cortical impact of moderate severity or sham injury and then were randomly assigned to receive once daily intraperitoneally injections of AMT (10, 20, or 40 mg/kg) or saline vehicle (VEH, 1 mL/kg) commencing 24 h after injury for 19 days. Motor and cognitive function were assessed on post-operative days 1–5 and 14–19, respectively. There were no statistical differences among the sham groups treated with AMT or VEH so the data were pooled. AMT (20 mg/kg) facilitated beam-balance recovery and spatial learning relative to VEH-treated controls (p < 0.05). No other doses of AMT were effective. These results indicate that dosing should be carefully considered when assessing the effects of pharmacotherapies after TBI so that potential benefits are not inadvertently missed.