Objective: Predator stress, social defeat stress, and fear conditioning animal models have been applied to investigate combat-related posttraumatic stress disorder (PTSD). However, no animal model psychopharmacological studies have investigated prevention of somatization of increased mental stress and fatigue at the beginning of combat exposure. This study utilized a novel animal model simulating the beginning of combat exposure that aided specification of a set of biomarkers. Methods: Psychological stress was induced by both inescapable electric foot shock and noise stimuli. Physical fatigue was induced by sleep deprivation and forced exercise in a rotating cage. A new device reflecting simultaneous psychological stress and physical fatigue was constructed. The protocol simulating combat exposure was set as 3 rounds of 24-h exposure in a 2-week period, which was specified as intermittent unpredictable stress (IUS). Results: Mice exposed to IUS (IUS mice) had significantly higher serum corticosterone levels (p < 0.05), excessive locomotive activity (p < 0.001), and anxiety-like behavior (p < 0.02) compared to control mice. IUS mice also had significantly higher IFN-γ (p < 0.001) and TNF-α (p < 0.05) levels in the supernatant of splenic T-cell culture compared to control mice. Brain-derived neurotropic factor levels were significantly decreased (p < 0.04) after IUS exposure. Conclusion: The proposed animal model of combat exposure reflected cognitive function impairment, behavior disturbance, and altered neuroimmune interactions without any apparent histopathological changes, and this animal model may be more applicable to protective research on war syndrome than combat-related PTSD after war because the hypothalamic-pituitary-adrenal axis has not been blunted.

Bryant RA: Posttraumatic stress disorder and traumatic brain injury: can they co-exist? Clin Psychol Rev 2001;21:931.
Iribarren J, Prolo P, Neagos N, Chiappelli F: Post-traumatic stress disorder: evidence-based research for the third millennium. Evid Based Complement Alternat Med 2005;2:503.
Kimble MO, Fleming K, Bennion KA: Contributors to hypervigilance in a military and civilian sample. J Interpers Violence 2013;28:1672.
Kang HK, Natelson BH, Mahan CM, Lee KY, Murphy FM: Post-traumatic stress disorder and chronic fatigue syndrome-like illness among Gulf War veterans: a population-based survey of 30,000 veterans. Am J Epidemiol 2003;157:141.
Brown M: Toxicological assessments of Gulf War veterans. Philos Trans R Soc Lond B Biol Sci 2006;361:649.
Hoge C, Messer S, Castro C: Combat duty in Iraq and Afghanistan mental health problems. N Engl J Med 2004;351:1798.
Jones E, Hodgins-Vermaas R, Mccartney H, Everitt B, Beech C, Poynter D, Palmer I, Hyams K, Wessely S: Post-combat syndromes from the Boer War to the Gulf War: a cluster analysis of their nature and attribution. BMJ 2002;324:321.
Dohrenwend BP, Turner JB, Turse NA, Adams BG, KC Koenen, Marshall R: The psychological risks of Vietnam for US veterans: a revisit with new data and methods. Science 2006;313:979.
Hoge CW, Auchterlonie JL, Milliken CS: Mental health problems, use of mental health services, and attrition from military service after returning from deployment to Iraq or Afghanistan. JAMA 2006;295:1023.
Ertl V, Pfeiffer A, Schauer-Kaiser E, Elbert T, Neuner F: The challenge of living on: psychopathology and its mediating influence on the readjustment of former child soldiers. PLoS One 2014;9:e102786.
Gewirtz AH, Polusny MA, Degarmo DS, Khaylis A, Erbes CR: Posttraumatic stress symptoms among National Guard soldiers deployed to Iraq: associations with parenting behaviors and couple adjustment. J Consult Clin Psychol 2010;78:599.
Mcfarlane AC: The long-term costs of traumatic stress: intertwined physical and psychological consequences. World Psychiatry 2010;9:3.
Goldzweig CL, Balekian TM, Rolon C, Yano EM, Shekelle PG: The state of women veterans' health research. J Gen Intern Med 2006;21:S82.
Murthy RS, Lakshminarayana R: Mental health consequences of war: a brief review of research findings. World Psychiatry 2006;5:25.
Yehuda R, Bryant R, Marmar C, Zohar J: Pathological responses to terrorism. Neuropsychopharmacology 2005;30:1793.
Kim D: Practical use and risk of modafinil, a novel waking drug. Environ Health Toxicol 2012;27:e2012007.
Whitaker AM, Gilpin NW, Edwards S: Animal models of post-traumatic stress disorder and recent neurobiological insights. Behav Pharmacol 2014;25:398.
Goswami S, Rodríguez-Sierra O, Cascardi M, Paré D: Animal models of post-traumatic stress disorder: face validity. Front Neurosci 2013;7:89.
Daskalakis NP, Yehuda R: Principles for developing animal models of military PTSD. Eur J Psychotraumatol 2014;5.
Shin LM, Liberzon I: The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 2010;35:169.
Ford JD, Campbell KA, Storzbach D, Binder LM, Anger WK, DS Rohlman: Posttraumatic stress symptomatology is associated with unexplained illness attributed to Persian Gulf War military service. Psychosom Med 2001;63:842.
Adamec RE, Burton P, Shallow T, Budgell J: NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure - implications for anxiety associated with posttraumatic stress disorder. Physiol Behav 1998;65:723.
Shepard JD, Barron KW, Myers DA: Corticosterone delivery to the amygdala increases corticotropin-releasing factor mRNA in the central amygdaloid nucleus and anxiety-like behavior. Brain Res 2000;861:288.
Wohleb ES, Hanke ML, Corona AW, Powell ND, La'tonia MS, Bailey MT, Nelson RJ, Godbout JP, Sheridan JF: β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci 2011;31:6277.
Murakami S, Imbe H, Morikawa Y, Kubo C, Senba E: Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neurosci Res 2005;53:129.
Patki G, Solanki N, Atrooz F, Allam F, Salim S: Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain Res 2013;1539:73.
De Kloet ER, Joëls M, Holsboer F: Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005;6:463.
Elenkov IJ, Chrousos GP: Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann NY Acad Sci 2002;966:290.
Brinks V, Van Der Mark M, De Kloet R, Oitzl M: Emotion and cognition in high and low stress sensitive mouse strains: a combined neuroendocrine and behavioral study in BALB/c and C57BL/6J mice. Front Behav Neurosci 2007;1:8.
Huang F, Yang Z, Li CQ: The melatonergic system in anxiety disorders and the role of melatonin in conditional fear. Vitam Horm 2017;103:281.
Jovanovic T, Norrholm SD, Blanding NQ, Davis M, Duncan E, Bradley B, Ressler KJ: Impaired fear inhibition is a biomarker of PTSD but not depression. Depress Anxiety 2010;27:244.
Brown VJ: Battle scars: global conflicts and environmental health. Environ Health Perspect 2004;112:A994.
Hunt EJ, Wessely S, Jones N, Rona RJ, Greenberg N: The mental health of the UK Armed Forces: where facts meet fiction. Eur J Psychotraumatol 2014;5.
Kilshaw S: Gulf War syndrome: a reaction to psychiatry's invasion of the military? Cult Med Psychiatry 2008;32:219.
Kishioka A, Fukushima F, Ito T, Kataoka H, Mori H, Ikeda T, Itohara S, Sakimura K, Mishina M: A novel form of memory for auditory fear conditioning at a low-intensity unconditioned stimulus. PLoS One 2009;4:e4157.
Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN, Makotkine I, Flory JD, Bierer LM, Meaney MJ: Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry 2014;171:872.
Ito H, Nagano M, Suzuki H, Murakoshi T: Chronic stress enhances synaptic plasticity due to disinhibition in the anterior cingulate cortex and induces hyper-locomotion in mice. Neuropharmacology 2010;58:746.
Jindal A, Mahesh R, Bhatt S: Etazolate rescues behavioral deficits in chronic unpredictable mild stress model: modulation of hypothalamic-pituitary-adrenal axis activity and brain-derived neurotrophic factor level. Neurochem Int 2013;63:465.
Sherin JE, Nemeroff CB: Post-traumatic stress disorder: the neurobiological impact of psychological trauma. Dialogues Clin Neurosci 2011;13:263.
Van Meer P, Raber J: Mouse behavioural analysis in systems biology. Biochem J 2005;389:593.
Wilson CB, Ebenezer PJ, Mclaughlin LD, Francis J: Predator exposure/psychosocial stress animal model of post-traumatic stress disorder modulates neurotransmitters in the rat hippocampus and prefrontal cortex. PLoS One 2014;9:e89104.
Bath K, Schilit A, Lee F: Stress effects on BDNF expression: effects of age, sex, and form of stress. Neuroscience 2013;239:149.
Lindqvist D, Dhabhar FS, Mellon SH, Yehuda R, Grenon SM, Flory JD, Bierer LM, Abu-Amara D, Coy M, Makotkine I: Increased pro-inflammatory milieu in combat related PTSD - a new cohort replication study. Brain Behav Immun 2017;59:260.
Waller KL, Mortensen EL, Avlund K, Fagerlund B, Lauritzen M, Gammeltoft S, Jennum P: Melatonin and cortisol profiles in late midlife and their association with age-related changes in cognition. Nat Sci Sleep 2016;8:47.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.