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

Abstract

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 hours 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.

Intermittent Administration of Haloperidol after Cortical Impact Injury Neither Impedes Spontaneous Recovery Nor Attenuates the Efficacy of Environmental Enrichment

“…A CCI injury was produced as previously described. [26][27][28][29][30]33 Briefly, surgical anesthesia was induced and maintained with 4% and 2% isoflurane, respectively, in 2:1 N 2 O:O 2 . Rats were intubated and mechanically ventilated before being secured in a stereotaxic frame.…”

“…These tests are sensitive indicators of injury severity and duration of anesthesia. [26][27][28][29][30] Housing conditions: environmental manipulation After surgery, and after the effects of anesthesia abated (as evidenced by spontaneous movement in the holding cage), rats were returned to the colony where those designated for enrichment were immediately placed in specifically designed stainless steelwire cages (91 • 76 • 50 cm). EE cages consisted of three levels with ladders to ambulate from one level to another and contained various toys and objects with which to engage (e.g., balls, blocks, and tubes) and ad libitum food and water.…”

“…The dose of HAL was chosen because it has been reported to be comparable to that used clinically to control psychosis 36 and has been used in several TBI studies investigating functional outcome. 24,[26][27][28][29][30] Treatments began 24 h after CCI or sham surgery and were provided intraperitoneally (i.p.) either once-daily for 19 days (daily treatment TBI and sham groups) or once every other day (intermittent treatment TBI and sham groups).…”

“…[26][27][28][29][30] Briefly, the beam-balance task consisted of placing the rat on an elevated (90 cm) narrow beam (1.5 cm wide) and recording the time it remained on for a maximum of 60 sec. The beam-walk task, modified from Feeney and colleagues 21 and used extensively in our laboratory, [26][27][28][29][30] consists of training/assessing rats using a negative-reinforcement paradigm to escape bright light and white noise by traversing an elevated narrow beam (2.5 cm wide • 100 cm long) and entering a darkened goal box at the opposite end. Beam-walk performance was assessed by recording the elapsed time to traverse the beam as well as distance traveled.…”

“…23 Similar negative effects on cognitive recovery were reported when HAL was administered once-daily after controlled cortical impact (CCI) injury in male and female rats. [24][25][26][27][28] Moreover, the negative effect on cognitive recovery by HAL after TBI is long-lasting. 29 It has recently been demonstrated that daily administration of HAL after TBI attenuates the beneficial effects of environmental enrichment (EE), a pre-clinical model of neurorehabilitation.…”