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.

Refining environmental enrichment to advance rehabilitation based research after experimental traumatic brain injury.

The typical environmental enrichment (EE) paradigm, which consists of continuous exposure after experimental traumatic brain injury (TBI), promotes behavioral and histological benefits. However, rehabilitation is often abbreviated in the clinic and administered in multiple daily sessions. While recent studies have demonstrated that a once daily 6-hr bout of EE confers benefits comparable to continuous EE, breaking the therapy into two shorter sessions may increase novelty and ultimately enhance recovery. Hence, the aim of the study was to test the hypothesis that functional and histological outcomes will be significantly improved by daily preclinical neurorehabilitation consisting of two 3-hr periods of EE vs. a single 6-hr session. Anesthetized adult male rats received a controlled cortical impact of moderate-to-severe injury (2.8mm tissue deformation at 4m/s) or sham surgery and were then randomly assigned to groups receiving standard (STD) housing, a single 6-hr session of EE, or two 3-hr sessions of EE daily for 3weeks. Motor function (beam-balance/traversal) and acquisition of spatial learning/memory retention (Morris water maze) were assessed on post-operative days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. Both EE conditions improved motor function and acquisition of spatial learning, and reduced cortical lesion volume relative to STD housing (p<0.05), but did not differ from one another in any endpoint (p>0.05). The findings replicate previous work showing that 6-hr of EE daily is sufficient to confer behavioral and histological benefits after TBI and extend the findings by demonstrating that the benefits are comparable regardless of how the 6-hrs of EE are accrued. The relevance of the finding is that it can be extrapolated to the clinic and may benefit patients who cannot endure a single extended period of neurorehabilitation.

Thermal decomposition of meso- and d,l-3,4-diethyl-3,4-dimethyldiazetine N,N'-dioxide.

Two stereochemically defined diazetine N,N'-dioxides were synthesized. Thermal decomposition at 200 degrees C resulted in 95% retention of stereochemistry in the alkene product relative to the starting stereochemistry. These results suggest that decomposition occurs via cleavage of the two C-N bonds either simultaneously or in rapid succession.