Research PaperComparable impediment of cognitive function in female and male rats subsequent to daily administration of haloperidol after traumatic brain injury

•Females exhibit less severe motor deficits after TBI relative to males.•HAL increases beam-walk deficits in males, but not females.•HAL equally impairs cognitive recovery in females and males.

Antipsychotic drugs, such as haloperidol (HAL), are prescribed in the clinic to manage traumatic brain injury (TBI)-induced agitation. While preclinical studies have consistently shown that once-daily administration of HAL hinders functional recovery after TBI in male rats, its effects in females are unknown. Hence, the objective of this study was to directly compare neurobehavioral and histological outcomes in both sexes to determine whether the reported deleterious effects of HAL extend to females. Anesthetized adult female and male rats received either a controlled cortical impact (CCI) or sham injury and then were randomly assigned to a dosing regimen of HAL (0.5 mg/kg, i.p.) or vehicle (VEH; 1 mL/kg, i.p.) that was initiated 24 h after injury and continued once daily for 19 consecutive days. Motor function was tested using established beam-balance/walk protocols on post-operative days 1-5 and acquisition of spatial learning was assessed with a well-validated Morris water maze task on days 14-19. Cortical lesion volume was quantified at 21 days. No statistical differences were revealed between the HAL and VEH-treated sham groups and thus they were pooled for each sex. HAL only impaired motor recovery in males (p < 0.05), but significantly diminished spatial learning in both sexes (p < 0.05). Females, regardless of treatment, exhibited smaller cortical lesions vs VEH-treated males (p < 0.05). Taken together, the data show that daily HAL does not prohibit motor recovery in females, but does negatively impact cognition. These task-dependent differential effects of HAL in female vs male rats may have clinical significance as they can direct therapy.