Relative to Typical Antipsychotic Drugs, Aripiprazole Is a Safer Alternative for Alleviating Behavioral Disturbances After Experimental Brain Trauma

Abstract

Background. Antipsychotic drugs (APDs) are used to manage traumatic brain injury (TBI)–induced behavioral disturbances, such as agitation and aggression. However, APDs exhibiting D2 receptor antagonism impede cognitive recovery after experimental TBI. Hence, empirical evaluation of APDs with different mechanistic actions is warranted. Aripiprazole (ARIP) is a D2 and 5-hydroxytryptamine1A (5-HT1A) receptor agonist; pharmacotherapies with these properties enhance cognition after TBI. Objective. To test the hypothesis that ARIP would increase behavioral performance and decrease histopathology after TBI. Methods. Adult male rats were subjected to either a controlled cortical impact (CCI) or sham injury and then randomly assigned to ARIP (0.1 or 1.0 mg/kg) or VEH (1.0 mL/kg, saline vehicle) groups. Treatments began 24 hours after surgery and were administered once daily for 19 days. Motor (beam-balance/beam-walk) and cognitive (Morris water maze) performance was assessed on postoperative days 1 to 5 and 14 to 19, respectively, followed by quantification of hippocampal CA1,3 neuron survival and cortical lesion volume. Results. Beam-balance was significantly improved in the CCI + ARIP (1.0 mg/kg) group versus CCI + ARIP (0.1 mg/kg) and CCI + VEH ( P < .05). Spatial learning and memory retention were significantly improved in the CCI + ARIP (0.1 mg/kg) group versus the CCI + ARIP (1.0 mg/kg) and CCI + VEH groups ( P < .05). Both doses of ARIP reduced lesion size and CA3 cell loss versus VEH ( P < .05). Importantly, neither dose of ARIP impeded functional recovery as previously reported with other APDs. Conclusion. These findings support the hypothesis and endorse ARIP as a safer APD for alleviating behavioral disturbances after TBI.