NIAAA F31: Repurposing alpha1 noradrenergic antagonists for alcoholism treatment

Abstract

Project Summary: The first objective of the current proposal is to implicate norepinephrine alpha1 receptor involvement in reactivity to stressful events in humans by using a sophisticated laboratory stress task in conjunction with an alpha1-blocker, prazosin. The second objective is to determine whether prazosin, an FDA-approved blood pressure medication, is effective at reducing stress-reactivity among abstinent alcoholics who are trying to quit drinking. No currently available pharmacotherapy treatment options for alcoholism are specifically designed to prevent relapse caused by stress, which is a common hurdle in the way of attaining long-term recovery. As the pharmaceutical industry has drastically reduced its investment in developing novel medications to treat alcoholism in recent years, it is becoming increasingly essential to identify currently available drugs with known neurobiological mechanisms, such as prazosin, that may be effective treatment alternatives for addiction. The current study aims to evaluate the effects of prazosin on stress-reactivity in alcoholics in early abstinence versus healthy volunteers. Participants will take either prazosin or a placebo pill at two laboratory sessions, after which they will complete a stress task. The task will consist of three conditions exposing participants to unpredictable shock, predictable shock, or no shock. The eye blink startle response will be measured as a physiological index of the participants’ reactivity to the stressful task (i.e., predictable and unpredictable shocks). Previous research has consistently demonstrated that drugs that reduce the stress response, such as alcohol and benzodiazepines, reduce the startle response specifically to unpredictable stressors. Furthermore, drug deprivation among drug dependent individuals (e.g., nicotine, marijuana or alcohol) selectively increases the startle response during unpredictable stressors. This is an attractive lab task as very similar methods (e.g. unpredictable shock) and measures (e.g., startle) have been used extensively in rodents and non-human primates, so the field has a rich understanding of the neurobiology involved in this stress system. In particular, the neurotransmitter norepinephrine has been critically implicated in the stress response, and prazosin, a drug that blocks norepinephrine alpha1 receptors, has been shown to reduce stress-induced relapse in rodent models of alcoholism. This study will examine whether prazosin reduces the startle response during unpredictable stressors in abstinent alcoholics in early recovery vs. healthy volunteers. These findings would suggest that norepinephrine alpha1 receptors are involved in stress-reactivity in humans and that prazosin may be an effective treatment of stress-induced relapse for alcoholics pursuing abstinence. Given the tremendous cost associated with conducting large scale clinical trials to vet treatments for addiction, the current proposal represents an efficient laboratory-based screening procedure to evaluate the potential efficacy of novel pharmacotherapies. This type of translational research aims to expand treatment options for the eighteen million people in the United States who suffer from an alcohol use disorder. 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 neuropsychiatric conditions, particularly substance use disorders, provides a strong impetus to repurpose currently available compounds that may be effective treatment alternatives. The current project aims to 1) implicate norepinephrine mechanisms in stress-reactivity in humans via direct pharmacological antagonism of the norepinephrine system via Prazosin, an FDA-approved blood pressure medication, and 2) examine the effects of Prazosin on stress-reactivity in abstinent alcoholics in a laboratory procedure to screen its potential utility as a treatment for stress-induced relapse for alcoholism. National Institute on Alcohol Abuse and Alcoholism, National Research Service Award (F31 AA022845) Jesse Kaye (PI/Trainee), John Curtin (Sponsor), Craig Berridge (Co-Sponsor). Direct costs: $93,075 Status: Funded. 09/2014 – 08/2017 For more information see: http://dionysus.psych.wisc.ed