Preclinical Analysis of Combined Zonisamide and Doxazosin Treatments in Stress-Alcohol Drinking Models


Alcohol use disorder (AUD) is a chronic relapsing condition that constitutes a significant health problem. Given the proportionally higher prevalence of alcohol abuse and dependence in military personnel, this problem is especially relevant to United States Veterans. Stress-related illnesses, including post-traumatic stress disorder (PTSD), are the most common mental health problems among Veterans presenting for treatment at VA hospitals [1]. Further, AUD and PTSD are highly comorbid in Veterans, and Veterans with co-occurring AUD and PTSD have more complicated and severe symptoms and worse treatment outcomes. Thus, AUD and PTSD comorbidity presents a significant challenge for many Veterans and the VA health care system.

Numerous animal models have been used to study the manner by which stress (e.g. exposure to traumatic events) interacts with alcohol consumption.  Despite significant advancements in our understanding of underlying neurobiological mechanisms and environmental factors, development of more effective medications for treating AUD remain inadequate. Furthermore, there is an even greater paucity of treatments for AUD and PTSD comorbidity. Thus, a major challenge of the field is to employ preclinical models of alcohol dependence/drinking and stress/PTSD exposure to identify and evaluate new therapeutics that may be especially effective in treating AUD and PTSD comorbidity. 

Objective and Study Design:

The overall objective of this preclinical trial is to address the aforementioned challenges by employing two well-established mouse models of alcohol dependence and stress/PTSD exposure to evaluate the ability of medications to reduce excessive alcohol consumption and, in particular, the exacerbating effects of stress that perpetuate hazardous and harmful drinking associated with dependence. Based on clinical and preclinical evidence, two promising medications, zonisamide and doxazosin, will be evaluated alone and in combination to assess the effectiveness of the drugs on stress facilitation of drinking in alcohol dependent vs. nondependent male and female mice and on drinking in a PTSD-alcohol dependence model in male and female mice. 

Collectively, these studies will provide valuable information regarding potentially new and more effective treatment strategies for AUD and PTSD comorbidity. As such, this preclinical trial supports the ultimate goal of the PASA Consortium, which is to develop and advance more efficacious treatment approaches that will benefit those individuals suffering with AUD and PTSD comorbidity. 



[1] Veterans Health Administration Office of Public Health (2015). Analysis of VA health care utilization among Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) Veterans: Cumulative from 1st Qtr FY 2002 through 2nd Qtr FY 2015 (October 1, 2001-March 31, 2015). Retrieved from:

At a Glance

Study type:

Preclinical Study


To evaluate the potential for candidate therapeutics to reduce excessive drinking produced by stress experience


Transgenic male and female mice

Number of participants:

640 mice

Data collection:


Participating sites:

Medical University of South Carolina (MUSC)

Principal investigator:

Howard Becker, Ph.D., Medical University of South Carolina (MUSC)