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Description: Project Summary: Current pharmacotherapy for 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 alpha1-noradrenergic (NE) receptor antagonists are widely used to treat hypertension. Additionally, alpha1-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 alpha1-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 alpha1-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 alpha1-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 alpha1-NE antagonist for relapse prevention in addiction. These 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) during an 8 week treatment period on stress reactivity using a well-validated human model of stressor reactivity (NPU task). 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 to assess treatment efficacy and examine stress mechanisms during the treatment period. Important clinical outcomes (e.g., point prevalence and continuous abstinence, days drinking, craving, perceived stress) are also measured during treatment. 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 and the 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 proposal 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 alpha1-norepinephrine relapse mechanisms in abstinent alcoholics as a cost-effective first step to repurpose doxazosin for relapse prevention in addiction. National Institute of Alcohol Abuse and Alcoholism (R01 AA024388) John Curtin (PI), Craig Berridge (Co-I), Jesse Kaye (Key Personnel), Aleksandra Zgierska (Co-I) Direct Costs: $1,420,889 Status: Funded. 09/01/2015 – 05/31/2020 For more information see: http://dionysus.psych.wisc.edu License: CC-By Attribution 4.0 International