Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment

OBJECTIVES

The first objective of the current study is to examine norepinephrine alpha1 (NE-alpha1)
receptor involvement in reactivity to unpredictable stressors in humans, by using the NPU
stress task in conjunction with an alpha1-blocker, prazosin. The second objective of the
study is to provide preliminary evidence that prazosin is effective at reducing
stress-reactivity in alcoholics in early abstinence.

PARTICIPANTS

Sixty-four healthy adult participants and sixty-four participants with an Alcohol Use
Disorder in early abstinence.

STUDY OVERVIEW

Sixty-four healthy adult participants (32 males & 32 females) will be recruited to
participate in a double-blind, placebo-controlled, cross-over design study examining the
effects of a NE-alpha1 antagonist (prazosin) on the defensive (physiological and self-report
affect) response to stressors using a well-validated animal-human translational stressor
task. Participants will complete two overnight study visits where 2 mg prazosin and placebo
are administered on separate visits separated by approximately 7 days. Drug order is randomly
assigned and counterbalanced across participants (double-blind; study visits 1-2). On each of
these two study visits, participants will complete the No Shock, Predictable Shock,
Unpredictable Shock (NPU) task 90 minutes after drug administration. The NPU task is designed
to examine stress reactivity to predictable and unpredictable stressors (i.e., electric
shock). These two visits provide for a within-subject evaluation of the effect of acute
antagonism of alpha1-NE receptors (via prazosin) to investigate the role of this NE mechanism
in unpredictable (vs. predictable) stressor response.

After the full healthy adult/control sample has completed the study, the investigators will
conduct preliminary data analysis to evaluate the first study hypothesis. These analyses are
used to evaluate the sensitivity of the NPU task to NE-alpha1 mechanisms and its potential
utility as an early surrogate endpoint for stress-related relapse mechanisms in alcoholism.
The investigators will only recruit the sample of sixty-four alcoholic participants to
complete the study if the first hypothesis is initially supported with healthy controls.
These participants will meet DSM5 criteria for Alcohol Use Disorder (at least moderate
severity) and be in early abstinence (1-8 weeks). All other study procedures will be
identical for this sample.

OUTCOME MEASURES

The primary outcome is startle potentiation during the NPU task and the secondary outcome is
self-reported retrospective fear/anxiety during the NPU task.

HYPOTHESES

1. Prazosin (2mg vs. placebo) will reduce stress reactivity to unpredictable (vs.
predictable) stressors measured via startle potentiation and self-report.

2. Abstinent alcoholics (vs. controls) will display elevated stress reactivity to
unpredictable (vs. predictable) stressors measured via startle potentiation and
self-report.

3. The predicted effects of prazosin on reducing stress reactivity to unpredictable (vs.
predictable) stressors (Hypothesis 1) measured via startle potentiation and self-report
will be moderated by alcoholism, such that the effects of prazosin will be larger in
abstinent alcoholics than control participants.

INCLUSION CRITERIA: All Participants

- Can read and write in English.

- Ages of 18-50 years.

INCLUSION CRITERIA: Control Participants

- No current or lifetime history of Substance Use Disorder (except tobacco).

INCLUSION CRITERIA: Alcoholic Participants

- Current Alcohol Use Disorder with 1-8 weeks completely free from alcohol consumption.

Exclusion criteria are divided into three broad categories of Medical,
Psychiatric/Behavioral, and Medications/Therapies.

EXCLUSION CRITERIA: Medical

- Colorblind

- Blood alcohol concentration (BAC) > 0.00

- Systolic BP <100 after five minutes seated.

- Systolic BP drop >20mmHg after two minutes standing.

- Systolic BP drop >10mgHG AND report dizziness, lightheadedness, unsteadiness or other
problems (e.g, nausea, blurry vision) after two minutes standing.

- Heart rate >100 beats/ minute after two minutes seated.

- Heart rate <60 beats/ minute after two minutes seated.

- Scheduled for cataract surgery prior to study completion.

- Past or current coronary artery disease, cerebrovascular accident, congestive heart
failure.

- Current renal insufficiency, liver insufficiency, pancreatitis, immunosuppressive
therapy, or cancer with systemic effects or therapy.

- Benign positional vertigo, Meniere's disease or narcolepsy

- Current diabetes or polyneuropathy

- Previous allergic or adverse reaction to prazosin or other alpha1 norepinephrine
antagonist.

- Other self-reported acute or unstable illness that, in the opinion of the study team,
would preclude a safe and reliable study participation.

EXCLUSION CRITERIA: Female Participants Only

- Non-negative urine pregnancy test.

- Women of childbearing potential (see definition below) must agree to use one of the
following forms of birth control until after study completion. Acceptable birth
control is defined as the following methods of contraception: abstinence; hormonal
contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables,
and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy of
partner and tubal ligation; "single" barrier methods of contraception (e.g. male
condom, female condom, cervical cap, diaphragm, contraceptive sponge) with use of
spermicide; or "double barrier" method of contraception (e.g. male condom with
diaphragm, male condom with cervical cap).

- Breastfeeding

NOTE: Women of childbearing potential are females who have experienced menarche and do not
meet the criteria for women not of childbearing potential. Women not of childbearing
potential are females who are permanently sterile (e.g., hysterectomy, bilateral
oophorectomy) or postmenopausal. Postmenopausal is defined as 12 consecutive months with no
menses without an alternative medical cause.

EXCLUSION CRITERIA: Psychological/Behavioral Exclusion

- Self-reported lifetime diagnosis of schizophrenia, schizoaffective disorder, psychotic
disorder NOS, bipolar disorder, borderline personality disorder, or any neurocognitive
disorder.

EXCLUSION CRITERIA: Medications/Therapies

- Currently prescribed or used within 72 hours: prazosin or other alpha1-NE antagonist
(e.g., doxazosin, terazosin).

- Previous adequate trial of prazosin for alcohol use disorder or PTSD.

- Currently prescribed or used within 72 hours: Stimulants (e.g., d-amphetamine,
methylphenidate) or alternative medications with stimulant properties (e.g., ephedra,
pseudoephedrine).

- Currently prescribed or used within 72 hours: Sildenafil (Viagra), tadalafil (Cialis),
or vardenafil (Levitra).

- Currently prescribed or used within 72 hours: beta-blockers (e.g., propranolol),
alpha2 agonists (e.g., clonidine, guanfacine), or SNRI anti-depressants (e.g.,
venlafaxine, duloxetine).

- Currently used daily or used within 72 hours: alpha1 agonists (e.g., midodrine,
metaraminol, oxymetazoline, phenylephrine).

- Currently used daily or used within 72 hours: Benzodiazepines (e.g., diazepam,
chlordiazepoxide, lorazepam, clonazepam, alprazolam), zolpidem (Ambien), zaleplon
(Sonata), zopiclone (Imovane), eszopiclone (Lunesta), doxepin (Silenor).

- Currently prescribed and used daily or used within 72 hours: Trazodone (males only)