Chronic unpredictable stress during adolescence protects against adult traumatic brain injury-induced affective and cognitive deficits.

Pre-clinical early-life stress paradigms model early adverse events in humans. However, the long-term behavioral consequences of early-life adversities after traumatic brain injury (TBI) in adults have not been examined. In addition, endocannabinoids may protect against TBI neuropathology. Hence, the current study assessed the effects of adverse stress during adolescence on emotional and cognitive performance in rats sustaining a TBI as adults, and how cannabinoid receptor 1 (CB1) activation impacts the outcome. On postnatal days (PND) 30-60, adolescent male rats were exposed to four weeks of chronic unpredictable stress (CUS), followed by four weeks of no stress (PND 60-90), or no stress at any time (Control), and then anesthetized and provided a cortical impact of moderate severity (2.8 mm tissue deformation at 4 m/s) or sham injury. TBI and Sham rats (CUS and Control) were administered either arachidonyl-2'-chloroethylamide (ACEA; 1 mg/kg, i.p.), a CB1 receptor agonist, or vehicle (VEH; 1 mL/kg, i.p.) immediately after surgery and once daily for 7 days. Anxiety-like behavior was assessed in an open field test (OFT) and learning and memory in novel object recognition (NOR) and Morris water maze (MWM) tasks. No differences were revealed among the Sham groups in any behavioral assessment and thus the groups were pooled. In the ACEA and VEH-treated TBI groups, CUS increased exploration in the OFT, enhanced NOR focus, and decreased the time to reach the escape platform in the MWM, suggesting decreased anxiety and enhanced learning and memory relative to the Control group receiving VEH (p < 0.05). ACEA also enhanced NOR and MWM performance in the Control + TBI group (p < 0.05). These data suggest that 4 weeks of CUS provided during adolescence may provide protection against TBI acquired during adulthood and/or induce adaptive behavioral responses. Moreover, CB1 receptor agonism produces benefits after TBI independent of CUS protection.

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

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.

Rehabilitative Success After Brain Trauma by Augmenting a Subtherapeutic Dose of Environmental Enrichment With Galantamine.

BACKGROUND: Environmental enrichment (EE) confers benefits after traumatic brain injury (TBI) when provided daily for > 6 hours, but not 2 or 4 hours, 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 and 4 hours of EE paired with GAL will provide benefits comparable to 24 hours of 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 hours after surgery and once daily while receiving EE for 2, 4, or 24 hours. Motor and cognitive assessments were conducted on postoperative days 1-5 and 14-19, respectively. RESULTS: Motor function was significantly improved in the TBI + 24-hour EE group versus the TBI + STD + VEH and TBI + STD + GAL groups ( P < .05). Cognitive performance was enhanced in all EE groups as well as in the TBI + STD + GAL versus TBI + STD + VEH ( P < .05). Moreover, the 2- and 4-hour EE groups receiving GAL did not differ from the 24-hour EE group ( P > .05) and performed better than GAL alone ( P < .05). CONCLUSIONS: The findings support the hypothesis and have clinical relevance because, often, only brief rehabilitation may be available in the clinic and, thus, augmenting with a pharmacotherapy such as GAL may lead to outcomes that are significantly better than either therapy alone.