Antipsychotic drugs (APDs) are provided in the clinic to manage traumatic brain injury (TBI)-induced agitation and aggression. Experimental TBI studies consistently show that daily administration of the APDs, haloperidol (HAL) and risperidone (RISP), hinder recovery. However, it is unknown how long the adverse effects remain after cessation of treatment. To elucidate this clinically relevant issue, anesthetized male rats were randomly assigned to four TBI (controlled cortical impact) and four sham groups administered HAL (0.5 mg/kg), RISP (0.45 mg/kg), bromocriptine (BRO; 5.0 mg/kg, included as a control for D 2 receptor action), or vehicle (VEH; 1 mL/kg) 24 h after surgery and once-daily for 19 days. Motor and cognitive recovery was assessed on days 1-5 and 14-19, respectively, and again at 1 and 3 months after drug withdrawal. No overall group differences were observed for motor function among the TBI groups, although the HAL group showed a greater beam-walk deficit on day 5 versus the VEH and BRO groups. Cognitive recovery was significantly impaired in the HAL and RISP groups during the treatment phase versus VEH and BRO. Further, BRO was superior to VEH ( p = 0.0042). At 1 month, both groups that received APDs continued to exhibit significant cognitive impairment versus VEH and BRO; at 3 months, only the HAL group was impaired. Moreover, the HAL, RISP, and VEH groups continued to be cognitively deficient versus BRO, which also reduced cortical damage. These data replicate previous reports that HAL and RISP impede cognitive recovery after TBI and expand the literature by revealing that the deleterious effects persist for 3 months after drug discontinuation. BRO conferred cognitive benefits when administered concomitantly with behavioral testing, thus replicating previous findings, and also after cessation demonstrating enduring efficacy.

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-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 hr after surgery and were administered once daily for 19 days. Motor (beam-balance/beam-walk) and cognitive (Morris water maze) performance was assessed on post-operative days 1-5 and 14-19, 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 vs. CCI + ARIP (0.1 mg/kg) and CCI + VEH [p<0.05]. Spatial learning and memory retention were significantly improved in the CCI + ARIP (0.1 mg/kg) group vs. the CCI + ARIP (1.0 mg/kg) and CCI + VEH groups [p<0.05]. Both doses of ARIP reduced lesion size and CA3 cell loss vs. VEH [p<0.05]. 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.

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