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

Abstract

The administration of haloperidol (HAL) once-daily for 19 days after experimental traumatic brain injury (TBI) impedes recovery and attenuates the efficacy of environmental enrichment (EE). However, it is unknown how intermittent administration of HAL affects the recovery process when paired with EE. Addressing the uncertainty is relevant because daily HAL is not always warranted to manage TBI-induced agitation in the clinic, and indeed intermittent therapy may be a more common approach. Hence, the aim of the study was to test the hypothesis that intermittent HAL would neither impair recovery in standard (STD)-housed controls nor attenuate the efficacy of EE. Anesthetized adult male rats received a cortical impact or sham injury and then were housed in STD or EE conditions. Beginning 24 h later, HAL (0.5 mg/kg; intraperitoneally [i.p.]) was administered either once-daily for 19 days or once every other day, whereas vehicle (VEH; 1 mL/kg; i.p.) was administered once daily. Motor performance and cognition were assessed on post-injury days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. SHAM controls performed better than all TBI groups on motor and spatial learning [p < 0.05], but did not differ from the TBI + EE + daily VEH group on memory retention [p > 0.05]. The TBI + EE + daily VEH and TBI + EE + intermittent HAL groups did not differ from one another on beam-walk or spatial learning [p > 0.05], and both performed better than all other TBI groups [p < 0.05]. In contrast, the TBI + STD + daily HAL group performed worse than all TBI groups on spatial learning [p < 0.05]. No difference in any endpoint was revealed between the TBI + STD + intermittent HAL and TBI + STD + daily VEH groups [p > 0.05]. The results support the hypothesis that HAL is not detrimental when provided intermittently. If translatable to the clinic, intermittent HAL may be used to control TBI-induced agitation without negatively affecting spontaneous recovery or rehabilitative efficacy.

Antipsychotic Drugs: The Antithesis to Neurorehabilitation in Models of Pre-Clinical Traumatic Brain Injury

“…Knowing the outcome could be clinically relevant, given that chronic or continuous agitation may not be experienced by all patients (as opposed to context-dependent, evocable intermittent agitation), and thus daily treatment with APDs would not be warranted. To address this lingering unknown, Bao and colleagues (2019) 55 administered HAL (0.5 mg/kg) or VEH beginning 24 h after CCI injury and continued providing it either once-daily or once every other day for 19 days to rats housed in standard (STD) or environmental enrichment (EE) conditions. EE was included to determine the effect of intermittent APD dosing on neurorehabilitation.…”

“…This finding, demonstrating that intermittent EE did not attenuate EE-mediated spatial learning improvements as observed with chronic HAL, indicates that HAL is not overtly detrimental when provided intermittently. 55 …”