0087 Effects of a Dual Orexin Receptor Antagonist on Anxiety-like Behavior and Cognition in a Mouse Model of TBI

Abstract Introduction Mild/moderate traumatic brain injuries (TBIs) often occur in the frontal cortex and can induce prolonged impairments in sleep, cognition, and anxiety. Orexin is a neuropeptide that activates two receptors that stimulate monoamine activation in the brain to induce wakefulness. We aimed to determine if a dual orexin receptor antagonist (DORA) could improve prolonged cognitive impairments in mice that received TBI. Methods Two-month-old male and female C57BL/6J mice were randomly assigned to treatment groups. Mice received a craniectomy and TBI in the frontal cortex by controlled cortical impact, a craniectomy only (sham), or neither. Mice received a vehicle (placebo) or DORA by gavage for 2 consecutive days 24 h, 2 wks, and 1 m after the TBI or control treatments. Two-months after the TBI or control procedures, the mice were subjected to the open field and novel object familiarization. The following day, mice were administered the vehicle or DORA, and subjected to the elevated-plus maze (EPM), open-field maze, and novel object recognition (NOR) test. Significance was set at p.05. Results No significant difference between the control and sham treatments were overserved in NOR. Time spent exploring the novel object vs. the familiar object was significantly increased in both control and sham groups that received the vehicle indicating intact cognition (p=0.001 and p=0.0001, respectively). However, TBI reduced time spent exploring the novel object under vehicle conditions and after DORA treatments without TBI resulting in no significant differences in novel vs. familiar object exploration. The combined DORA and TBI treatment group spent significantly greater time exploring the novel object (p=0.047), although exhibited significantly less movement duration compared to other controls (Sham Vehicle p=.0001; Control Vehicle p=.0001). No significant differences in the EPM or open-field maze were found with experimental treatments. Conclusion These data further implicate mild/moderate TBI in impairments in cognition. However, due to the increased immobility caused by the DORA, we cannot conclude an interaction of DORA treatment with TBI on cognition using a NOR test that is dependent on movement activity. Support (if any) VA SPiRE Award (GK) I21RX003722; VA Merit Award (MZ) I01BX005379