Aripiprazole and environmental enrichment independently improve functional outcome after cortical impact injury in adult male rats, but their combination does not yield additional benefits

Abstract

Typical antipsychotic drugs (APDs) with D₂antagonistic properties impede functional outcome after experimental traumatic brain injury (TBI) and reduce the effectiveness of environmental enrichment (EE). Here we test the hypothesis that aripiprazole (ARIP), an atypical APD with partial D₂and 5-HT_1Areceptor agonist activities will improve recovery after TBI and when combined with EE will further enhance the benefits. Anesthetized adult male rats received either a controlled cortical impact of moderate severity or sham injury and then were randomly assigned to EE or standard (STD) housing and once daily intraperitoneal injections of ARIP (0.1 mg/kg) or vehicle (VEH; 1.0 mL/kg) beginning 24 h after injury for 19 days. Motor (beam-walking time and beam-walk score) and cognitive (acquisition of spatial learning and memory) outcomes were assessed on post-operative days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. There were no statistical differences among the sham groups, regardless of housing or treatment, so the data were pooled. The SHAM group performed better than all TBI groups on motor and spatial learning (p < 0.05) but did not differ from either EE group on memory retention. Regarding TBI, both EE groups improved motor and cognitive outcomes vs. the VEH-treated STD group (p < 0.05) but did not differ from one another (p > 0.05). The ARIP-treated STD group performed better than the VEH-treated STD group on beam-walk score and spatial learning (p < 0.05), but not beam-walking time or memory retention (p > 0.05). Cortical lesion volume was smaller in all treated groups compared to the TBI + STD + VEH group (p < 0.05). The data replicate previous work and extend the findings by demonstrating that 1) ARIP promotes recovery after TBI, but combining treatments does not yield additional benefits, which is contrary to the hypothesis, and 2) unlike APDs that exhibit D₂ receptor antagonism, ARIP does not impede rehabilitation (i.e., EE).

Keywords: Antipsychotic drugs; Behavioral outcome; Controlled cortical impact; Functional recovery; Learning and memory; Morris water maze; Traumatic brain injury.