No abstract

Background Environmental enrichment (EE) confers benefits after traumatic brain injury (TBI) when provided daily for 6-hrs or greater, but not 2-hr or 4-hr, which more accurately reflects the daily amount of clinical rehabilitation. The lack of benefit with sub-therapeutic EE suggests that augmentation with galantamine (GAL), which enhances cognition after TBI, may be indicated to confer benefits. Objective To test the hypothesis that 2-hr and 4-hr of EE paired with GAL will provide benefits comparable to 24-hr EE alone. Moreover, all EE groups will perform better than the standard (STD)-housed GAL group. Methods Anesthetized rats received a TBI or sham injury and then were randomized to receive intraperitoneal injections of GAL (2 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24-hr after surgery and once daily while receiving EE for 2-hr, 4-hr, or 24-hr. Motor and cognitive assessments were conducted on post-operative days 1–5 and 14–19, respectively. Results Motor function was significantly improved in the TBI+24-hr EE group vs. the TBI+STD+VEH and TBI+STD+GAL groups [p<0.05]. Cognitive performance was enhanced in all EE groups, as well as in the TBI+STD+GAL vs. TBI+STD+VEH [p<0.05]. Moreover, the 2-hr EE and 4-hr EE groups receiving GAL did not differ from the 24-hr EE group [p>0.05] and performed better than GAL alone [p<0.05]. Conclusions The findings support the hypothesis and have clinical relevance as often only brief rehabilitation may be available in the clinic and thus augmenting with a pharmacotherapy like GAL may lead to outcomes that are significantly better than either therapy alone.

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.