The prevalence of post-traumatic stress disorder (PTSD) in Veterans is estimated to be much higher than that of the general population [1, 2]. Further, Veterans with PTSD are twice as likely to misuse alcohol compared to Veterans without PTSD . PTSD is associated with high rates of other psychiatric comorbidities including substance use disorders (SUDs) . PTSD and alcohol use disorder (AUD) comorbidity is linked to significantly worse mental and physical health status compared to individuals with either disorder alone [1, 5, 6]. Veterans are particularly at risk of developing PTSD and AUD [3, 7]. Medications presently indicated for the treatment of PTSD and AUD are associated with significant adverse side effects that lead to non-compliance and poor outcomes. Therefore, the development of safe and effective medications for the treatment of PTSD and AUD is a priority for Veterans and would have a profound impact.
Objectives and Study Design:
Preclinical (animal) models have played a pivotal role in increasing our knowledge of anxiety disorders, alcohol consumption and stress-induced alcohol consumption. Most importantly, established animal models provide a valuable tool for evaluating potential pharmacotherapies. The experiments to be conducted in this preclinical trial will provide essential information for identifying the most efficacious medications to be translated to Phase 1 human clinical trials. Specifically, within the context of this preclinical trial, the study team will 1) evaluate whether the study drugs (e.g. CERC-501, candesartan, and perindopril) will alter PTSD-like symptoms in a rodent model of PTSD; 2) evaluate whether the study drugs will alter alcohol self-administration; and 3) determine whether the study drugs will alter PTSD-induced increases on alcohol self-administration when administered alone and in combination.
This preclinical trial will fill an important research gap regarding assessing medications that act on the renin-angiotensin system and kappa opioid receptor for the treatment of PTSD and AUD. Importantly, although the proposed medications have been tested in either stress models or on voluntary alcohol consumption, they have not been thoroughly tested in animal models of PTSD nor in PTSD-induced increases in operant alcohol self-administration. The preclinical studies to be conducted in this trial directly fill this research gap and will contribute toward characterizing novel therapeutic targets for the treatment of PTSD and AUD.
 Eisen, S. V. et al. Mental and physical health status and alcohol and drug use following return from deployment to Iraq or Afghanistan. Am J Public Health 102 Suppl 1, S66-73,
 Kessler, R. C., Sonnega, A., Bromet, E., Hughes, M. & Nelson, C. B. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 52, 1048-1060 (1995).
 Jakupcak, M. et al. PTSD symptom clusters in relationship to alcohol misuse among Iraq and
Afghanistan war veterans seeking post-deployment VA health care. Addict Behav 35, 840-
843, doi:10.1016/j.addbeh.2010.03.023 (2010).
 Dore, G., Mills, K., Murray, R., Teesson, M. & Farrugia, P. Post-traumatic stress disorder, depression and suicidality in inpatients with substance use disorders. Drug Alcohol Rev 31, 294-302, doi:10.1111/j.1465-3362.2011.00314.x (2012).
 Pietrzak, R. H., Whealin, J. M., Stotzer, R. L., Goldstein, M. B. & Southwick, S. M. An examination of the relation between combat experiences and combat-related posttraumatic stress disorder in a sample of Connecticut OEF-OIF Veterans. J Psychiatr Res 45, 1579-1584, doi:10.1016/j.jpsychires.2011.07.010 (2011).
 Blanco, C. et al. Comorbidity of posttraumatic stress disorder with alcohol dependence among US adults: results from National Epidemiological Survey on Alcohol and Related Conditions. Drug Alcohol Depend 132, 630-638, doi:10.1016/j.drugalcdep.2013.04.016 (2013).
 Wilk, J. E. et al. Relationship of combat experiences to alcohol misuse among U.S. soldiers returning from the Iraq war. Drug Alcohol Depend 108, 115-121, doi:10.1016/j.drugalcdep.2009.12.003 (2010).