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A key role for orexin in panic anxiety

Johnson, Philip L.; Truitt, William; Fitz, Stephanie D.; Minick, Pamela E.; Dietrich, Amy; Sanghani, Sonal; Träskman Bendz, Lil LU ; Goddard, Andrew W.; Brundin, Lena LU and Shekhar, Anantha (2010) In Nature Medicine 16(1). p.111-149
Abstract
Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate(1-3). 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(4-9). 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),... (More)
Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate(1-3). 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(4-9). 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. (C) 2010 Nature America, Inc. All rights reserved. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Nature Medicine
volume
16
issue
1
pages
111 - 149
publisher
Nature Publishing Group
external identifiers
  • wos:000273395500044
  • scopus:73849143579
ISSN
1546-170X
DOI
10.1038/nm.2075
language
English
LU publication?
yes
id
06350819-ae00-4d5e-aac9-7d4b7db4c564 (old id 1547781)
date added to LUP
2010-02-23 08:58:07
date last changed
2018-07-08 03:43:21
@article{06350819-ae00-4d5e-aac9-7d4b7db4c564,
  abstract     = {Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate(1-3). 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(4-9). 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. (C) 2010 Nature America, Inc. All rights reserved.},
  author       = {Johnson, Philip L. and Truitt, William and Fitz, Stephanie D. and Minick, Pamela E. and Dietrich, Amy and Sanghani, Sonal and Träskman Bendz, Lil and Goddard, Andrew W. and Brundin, Lena and Shekhar, Anantha},
  issn         = {1546-170X},
  language     = {eng},
  number       = {1},
  pages        = {111--149},
  publisher    = {Nature Publishing Group},
  series       = {Nature Medicine},
  title        = {A key role for orexin in panic anxiety},
  url          = {http://dx.doi.org/10.1038/nm.2075},
  volume       = {16},
  year         = {2010},
}