A combined therapeutic regimen of citalopram and environmental enrichment ameliorates attentional set-shifting performance after brain trauma.

Traumatic brain injuries (TBI) have led to lasting deficits for an estimated 5.3 million American patients. Effective therapies for these patients remain scarce and each of the clinical trials stemming from success in experimental models has failed. We believe that the failures may be, in part, due to the lack of preclinical assessment of cognitive domains that widely affect clinical TBI. Specifically, the behavioral tasks in the TBI literature often do not focus on common executive impairments related to the frontal lobe such as cognitive flexibility. In previous work, we have demonstrated that the attentional set-shifting test (AST), a task analogous to the clinically-employed Wisconsin Card Sorting Test (WCST), could be used to identify cognitive flexibility impairments following controlled cortical impact (CCI) injury. In this study, we hypothesized that both the administration of the antidepressant drug citalopram (CIT) and exposure to a preclinical model of neurorehabilitation, environmental enrichment (EE), would attenuate cognitive performance deficits on AST when provided alone and lead to greater benefits when administered in combination. Adult male rats were subjected to a moderate-severe CCI or sham injury. Rats were randomly divided into experimental groups that included surgical injury, drug therapy, and housing condition. We observed that both CIT and EE provided significant cognitive recovery when administered alone and reversal learning performance recovery increased the most when the therapies were combined (p < 0.05). Ongoing studies continue to evaluate novel ways of assessing more clinically relevant measurements of high order cognitive TBI-related impairments in the rat model.

Spontaneous recovery of traumatic brain injury-induced functional deficits is not hindered by daily administration of lorazepam.

Agitation and aggression are common sequelae of traumatic brain injury (TBI) and pose a challenge to physicians and other health providers during acute patient care and subsequent neurorehabilitation. Antipsychotic drugs (APDs) are routinely administered to manage TBI patients displaying such maladaptive behaviors despite several clinical and preclinical studies demonstrating that they hinder recovery. A potentially viable alternative to APDs may be the benzodiazepines, which have differing mechanisms of action. Hence, the aim of the study was to test the hypothesis that lorazepam (LOR) would not impede recovery after TBI. Anesthetized adult male rats received a cortical impact or sham injury and then were intraperitoneally administered LOR (0.1mg/kg, 1.0mg/kg, or 2.0mg/kg) or vehicle (VEH; 1mL/kg) commencing 24-h after surgery and once daily for 19days. Motor and cognitive outcomes were assessed on post-operative days 1-5 and 14-19, respectively. No differences were revealed among the four sham control groups and thus they were pooled into one inclusive SHAM group. The SHAMs performed better than all TBI groups on all assessments (p<0.05). Regarding TBI, the 2.0mg/kg LOR group performed better than the VEH and 0.1mg/kg or 1.0mg/kg LOR groups on every task (p<0.05); no differences were observed among the latter three groups on any endpoint (p>0.05). Overall, these preclinical behavioral data support the hypothesis and reveal a therapeutic benefit with the higher dose of LOR. The findings suggest that LOR may be an alternative, to APDs, for controlling agitation without compromising spontaneous recovery and perhaps could afford a dual benefit by also promoting therapeutic efficacy.

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

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 (0.5mg/kg, i.p.) or vehicle (VEH; 1mL/kg, i.p.) that was initiated 24h 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 21days. 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.