The tight regulation of sleep/wake states is critical for mental and physiological wellbeing. For example, dysregulation of sleep/wake systems predisposes individuals to metabolic disorders such as obesity and psychiatric problems, including depression. Contributing to this understanding, the last decade has seen significant advances in our appreciation of the complex interactions between brain systems that control the transition between sleep and wake states. Pivotal to our increased understanding of this pathway was the description of a group of neurons in the lateral hypothalamus (LH) that express the neuropeptides orexin A and B (hypocretin, Hcrt-1 and Hcrt-2). Orexin neurons were quickly placed at center stage with the demonstration that loss of normal orexin function is associated with the development of narcolepsy—a condition in which sufferers fail to maintain normal levels of daytime wakefulness. Since these initial seminal findings, much progress has been made in our understanding of the physiology and function of the orexin system. For example, the orexin system has been identified as a key modulator of autonomic and neuroendocrine function, arousal, reward and attention. Notably, studies in animals suggest that dysregulation of orexin function is associated with neuropsychiatric states such as addiction and mood disorders including depression and anxiety. This review discusses the progress associated with therapeutic attempts to restore orexin system function and treat neuropsychiatric conditions such as addiction, depression and anxiety. We also highlight potential pitfalls and challenges associated with targeting this system to treat these neuropsychiatric states.
Keywords: hypothalamus, orexin, stress, anxiety, depression, cocaine, reinstatement, reward seeking
Citation: Yeoh JW, Campbell EJ, James MH, Graham BA and Dayas CV (2014) Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls. Front. Neurosci. 8:36. doi: 10.3389/fnins.2014.00036
Received: 30 November 2013; Accepted: 10 February 2014;
Published online: 25 February 2014.
Edited by:Michel A. Steiner, Actelion Pharmaceuticals Ltd., Switzerland
Reviewed by:Andrew Lawrence, Florey Neuroscience Institutes, Australia
Copyright © 2014 Yeoh, Campbell, James, Graham and Dayas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Christopher V. Dayas, Neurobiology of Addiction Laboratory, The Centre for Translational Neuroscience and Mental Health Research, School of Biomedical Sciences and Pharmacy, University of Newcastle and the Hunter Medical Research Institute, Medical Sciences Building, Newcastle, NSW 2308, Australia e-mail: firstname.lastname@example.org
†These authors have contributed equally to this work.