Bridging the gap: Acute amantadine augments the neurorehabilitative efficacy of delayed and abbreviated environmental enrichment in a pediatric traumatic brain injury model.

Environmental enrichment (EE) promotes neurobehavioral recovery after traumatic brain injury (TBI). However, most preclinical studies initiate EE immediately after injury, which contrasts with delayed rehabilitation in the clinic. To better model clinical practice, we delayed the onset of EE and administered amantadine (AMT), which exhibits indirect dopaminergic effects, acutely as a therapeutic bridge. We hypothesized that this temporally sequenced combination therapy would improve neurobehavioral outcomes more than either treatment alone. Post-natal day 21 male rats received a controlled cortical impact or sham surgery and housed in standard (STD) conditions. Beginning 24 h post-surgery, daily intraperitoneal injections of AMT (20 mg/kg) or saline vehicle (VEH; 1 mL/kg) were provided for 7 days (bridge phase). On post-operative day 8, a subset transitioned to abbreviated EE (6 h/day). Vestibulomotor (beam-balance), cognition (spatial learning/memory), and affect (shock probe defensive burying) were assessed on days 8-12, 14-20, and 23, respectively. Hippocampal neuron survival was quantified on day 24. EE, regardless of AMT or VEH treatment, and AMT in STD housing, improved motor and cognitive outcomes versus VEH + STD (p < 0.05). Additionally, AMT + EE outperformed VEH + EE in spatial learning and improved memory retention relative to AMT + STD (p < 0.05). All treatment groups engaged quicker with the shock probe and increased burying behavior compared to VEH + STD. Additionally, the AMT + EE group spent more time burying the probe than the AMT + STD and VEH + EE groups (p < 0.05) and did not differ from SHAM controls (p > 0.05). Both EE groups had more CA3 neurons compared to the STD-housed groups (p < 0.05), while no difference in CA1 neurons was observed among the groups (p > 0.05). Overall, these findings reveal that acute AMT treatment augments the efficacy of delayed and abbreviated EE, particularly in cognitive and affective domains, which support the hypothesis. This temporally staged combination therapy may more accurately model clinical care and lead to greater improvement after TBI.