A key role for orexin in panic anxiety

• Published in: Nature medicine Vol. 16; no. 1; pp. 111 - 115
• Main Authors: Johnson, Philip L, Truitt, William, Fitz, Stephanie D, Minick, Pamela E, Dietrich, Amy, Sanghani, Sonal, Träskman-Bendz, Lil, Goddard, Andrew W, Brundin, Lena, Shekhar, Anantha
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2010; Nature Publishing Group
• Subjects: Adult; Alprazolam - pharmacology; Analysis; Animals; Anxiety; Anxiety - drug therapy; Anxiety - physiopathology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Clinical Medicine; Disease Models, Animal; Female; GABA; Genetic aspects; Hormones; Humans; Hypothalamus - physiology; Infectious Diseases; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - cerebrospinal fluid; Intracellular Signaling Peptides and Proteins - physiology; Klinisk medicin; letter; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Metabolic Diseases; Middle Aged; Molecular Medicine; Neurons; Neurons - drug effects; Neurons - physiology; Neuropeptides - antagonists & inhibitors; Neuropeptides - cerebrospinal fluid; Neuropeptides - physiology; Neurosciences; Neurotransmitter Agents - physiology; Neurotransmitters; Orexin Receptors; Orexins; Panic attacks; Panic Disorder - cerebrospinal fluid; Panic Disorder - drug therapy; Panic Disorder - physiopathology; Physiological aspects; Psychiatry; Psykiatri; Rats; Receptors, G-Protein-Coupled - drug effects; Receptors, G-Protein-Coupled - physiology; Receptors, Neuropeptide - drug effects; Receptors, Neuropeptide - physiology; Risk factors; Rodents; Sodium; Sodium Lactate - pharmacology; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2075

Orexin, a neuropeptide best known for its role in arousal and its absence in people with narcolepsy, is also involved in the pathophysiology of panic anxiety disorder. Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central γ-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate 1 , 2 , 3 . In a rat 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 , 5 , 6 , 7 , 8 , 9 . The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin) 10 , which have a crucial role in arousal 10 , 11 , vigilance 10 and central autonomic mobilization 12 , all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX ( Hcrt ) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human 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 new treatment strategy for panic disorder.