Current pharmacotherapy or alcohol and drug addiction yields relatively low probability for attaining long- term recovery. The recent dramatic reduction in R&D by the pharmaceutical industry for novel medications to treat psychiatric conditions, particularly substance use disorders, provides a strong impetus to repurpose currently available compounds that may be effective treatment alternatives. Orally available, brain-penetrant ?1-noradrenergic (NE) receptor antagonists are widely used to treat hypertension. Additionally, ?1-NE antagonists are increasingly used to treat post-traumatic stress disorder (PTSD), consistent with the well- documented role of NE in mediating multiple behavioral and physiological processes in stress. Stress is a significant contributor to alcohol/drug relapse. Stress-related reinstatement is a well-validated animal model of addiction and ?1-NE antagonists reduce relapse in this animal model. NIAAA Director George Koob has made strong calls for translational research on stress-mechanisms in humans. This preclinical evidence in animals suggests the use of ?1-NE antagonists may be useful in relapse prevention including stress-related relapse. To test this hypothesis, we propose two complementary preclinical and clinical objectives in humans: 1. To translate the preclinical evidence from animal models to stress-induced relapse in humans via direct pharmacological antagonism of the NE system in abstinent alcoholics with doxazosin, an ?1-NE blocker. 2. To screen the efficacy of doxazosin to target stress-related relapse mechanisms in abstinent alcoholics as a cost-effective first step to repurpose this ?1-NE antagonist for relapse prevention in addiction. Thes two objectives will be accomplished in a randomized controlled trial (RCT) of recently abstinent alcoholics, to examine the efficacy of 8 mg doxazosin (vs. placebo, between-subjects) on stress reactivity and clinical outcome measures (e.g., drinks/week, alcohol craving) during a 8 week treatment period. We assess doxazosin's impact on stress-related relapse mechanisms using a well-validated human model of stressor reactivity (NPU task) at baseline (pre-treatment), and after 4 weeks and 8 weeks of treatment. The NPU task has strong translational ties to both methods and measures from the preclinical literature in animals. This task has demonstrated reliable, robust effects of drug administration and drug deprivation in drug dependent users. As such, it serves as an attractive early surrogate endpoint post-treatment to assess treatment efficacy and examine stress mechanisms. Repurposing existing pharmaceutical agents has recently been promoted by NIH director, Francis Collins, as a research priority. Tom Insel and others have strongly advocated for the development and use of early surrogate endpoints in clinical research. This project aligns well with the NIMH RDoC focus on dimensions of observable behavior and neurobiological measures in psychopathology research. This project also anticipates changes at NIMH to capitalize on simultaneous examination of mechanism and outcome in RCTs.

Public Health Relevance

Eighteen million people in the United States suffer from an alcohol use disorder and current pharmacotherapy treatment for alcoholism yields relatively low probability of a patient successfully attaining long-term recovery. The recent dramatic reduction in Research and Development by the pharmaceutical industry for novel medications to treat mental health conditions, particularly substance use disorders, provides a strong impetus to repurpose currently available compounds that may be effective treatment alternatives. The current application aims to incorporate sophisticated translational laboratory measures in a randomized controlled trial (RCT) to screen the efficacy of doxazosin, an FDA-approved blood pressure medication, to target stress-related ?1-norepinephrine relapse mechanisms in abstinent alcoholics as a cost-effective first step to repurpose doxazosin for relapse prevention in addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA024388-04
Application #
9493339
Study Section
National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
Program Officer
Litten, Raye Z
Project Start
2015-09-01
Project End
2020-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Bradford, Daniel E; Motschman, Courtney A; Starr, Mark J et al. (2017) Alcohol's effects on emotionally motivated attention, defensive reactivity and subjective anxiety during uncertain threats. Soc Cogn Affect Neurosci 12:1823-1832
Kaye, Jesse T; Bradford, Daniel E; Magruder, Katherine P et al. (2017) Probing for Neuroadaptations to Unpredictable Stressors in Addiction: Translational Methods and Emerging Evidence. J Stud Alcohol Drugs 78:353-371
Moberg, Christine A; Bradford, Daniel E; Kaye, Jesse T et al. (2017) Increased startle potentiation to unpredictable stressors in alcohol dependence: Possible stress neuroadaptation in humans. J Abnorm Psychol 126:441-453
Hefner, Kathryn R; Verona, Edelyn; Curtin, John J (2016) Emotion regulation during threat: Parsing the time course and consequences of safety signal processing. Psychophysiology 53:1193-202
Kaye, Jesse T; Bradford, Daniel E; Curtin, John J (2016) Psychometric properties of startle and corrugator response in NPU, affective picture viewing, and resting state tasks. Psychophysiology 53:1241-55