A KEY ROLE FOR OREXIN IN PANIC ANXIETY

Introductory paragraph

Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In subjects with panic disorder there is evidence of decreased central GABAergic activity as well as marked increases in autonomic and respiratory responses following intravenous infusions of 0.5M sodium lactate 1– 3. In an animal model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial/perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses 4– 9. The dorsomedial/perifornical hypothalamus is enriched in orexin (ORX, also known as hypocretin)-containing neurons 10 that play a critical role in arousal 10, 11, vigilance 10 and central autonomic mobilization 12, all of which are key components of panic. Here, we demonstrate that activation of the ORX neurons is necessary for developing a panic-prone state in the animal model, and either silencing the hypothalamic ORX gene ( Hcrt) product with RNA interference or systemic ORX1 antagonists blocks the panic responses. Moreover, we show that subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety, and that ORX antagonists constitute a potential novel treatment strategy for panic disorder.