Orexins (hypocretins) contribute to fear and avoidance in rats exposed to a single episode of footshocks

Orexins (hypocretins) are peptides that have been shown to regulate behavioral arousal and wakefulness. Recent evidence indicates that orexin neurons are activated by stress and that orexins play a role in anxiety. The present paper describes a series of experiments that examined whether orexins are involved in the anxiety that resulted from exposing rats to an acute episode of footshocks (5 x 2 s of 1.5 mA shocks). We found that prepro-orexin (ppOX) mRNA was elevated in rats at 6 and 14 days after exposure to footshock and that ppOX mRNA levels were correlated with fear at 14 days post-shock. Systemic injections of the non-selective dual orexin receptor antagonist TCS-1102 (10 and 20 mg/kg, i.p.) were found to decrease fear and anxiety in rats 14 days after exposure to footshock. We also found that rats that exhibited a high level of immobility to a novel tone the day after the footshock episode (high responders, HR) showed significantly elevated levels of ppOX mRNA at 14 days post-shock compared to control rats. Furthermore, TCS-1102 (10 mg/kg, i.p.) was found to have anxiolytic effects that were specific for HR when tested in the elevated T-maze. This study provides evidence linking the orexin system to the anxiety produced by exposure of rats to a single episode of footshocks. It also provides preclinical evidence in support of the use of orexin antagonists for the treatment of anxiety in response to an acute episode of stress.