OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO2 -INDUCED PANIC-ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES.
BACKGROUND
The neuropeptides orexin A and B play a role in reward and feeding and are critical for arousal. However, it was not initially appreciated that most prepro-orexin synthesizing neurons are almost exclusively concentrated in the perifornical hypothalamus, which when stimulated elicits panic-associated behavior and cardiovascular responses in rodents and self-reported "panic attacks" and "fear of dying" in humans. More recent studies support a role for the orexin system in coordinating an integrative stress response. For instance, orexin neurons are highly reactive to anxiogenic stimuli, are hyperactive in anxiety pathology, and have strong projections to anxiety and panic-associated circuitry. Although the two cognate orexin receptors are colocalized in many brain regions, the orexin 2 receptor (OX2R) most robustly maps to the histaminergic wake-promoting region, while the orexin 1 receptor (OX1R) distribution is more exclusive and dense in anxiety and panic circuitry regions, such as the locus ceruleus. Overall, this suggests that OX1Rs play a critical role in mobilizing anxiety and panic responses.


METHODS
Here, we used a CO2 -panic provocation model to screen a dual OX1/2R antagonist (DORA-12) to globally inhibit orexin activity, then a highly selective OX1R antagonist (SORA1, Compound 56) or OX2R antagonist (SORA2, JnJ10397049) to assess OX1R and OX2R involvement.


RESULTS
All compounds except the SORA2 attenuated CO2 -induced anxiety-like behaviors, and all but the SORA2 and DORA attenuated CO2 -induced cardiovascular responses.


CONCLUSIONS
SORA1s may represent a novel method of treating anxiety disorders, with no apparent sedative effects that were present with a benzodiazepine.
Departments of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.|Departments of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana.|Departments of Medical Neuroscience Program, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana.
Philip L
PL
Johnson
Departments of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.|Departments of Medical Neuroscience Program, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana.
Lauren M
LM
Federici
Departments of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana.
Stephanie D
SD
Fitz
Merck & Co., Inc, West Point, Pennsylvania.
John J
JJ
Renger
Janssen Research and Development LLC, San Diego, California.
Brock
B
Shireman
Merck & Co., Inc, West Point, Pennsylvania.
Christopher J
CJ
Winrow
Janssen Research and Development LLC, San Diego, California.
Pascal
P
Bonaventure
Departments of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.|Departments of Medical Neuroscience Program, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana.|Indiana Clinical and Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, Indiana.
Anantha
A
Shekhar
D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D001143:Arousal; D001341:Autonomic Nervous System / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism*; D002245:Carbon Dioxide; D002319:Cardiovascular System / Q000187:drug effects; D006801:Humans; D009474:Neurons / Q000378:metabolism; D064446:Orexin Receptors / Q000378:metabolism*; D010200:Panic; D016584:Panic Disorder / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology*; D012201:Reward
D064446:Orexin Receptors; D002245:Carbon Dioxide
COPD; anxiety; asthma; bronchitis; chemoreception; hypercapnia; hypocretin; hypothalamus; orexin; panic