Repurposing alpha1 Noradrenergic Antagonists for Alcoholism Treatment
Phase: PHASE1
Conditions: Alcoholism
Sponsor: University of Wisconsin, Madison

1 
 
 
 
 
Repurposing alpha1 noradrenergic antagonists for alcoholism treatment 
 
 
 
Principal Investigator: John Curtin, PhD 
Co-Investigator: Aleksandra Zgierska, MD 
Study Coordinators: Jesse Kaye, MS & Cindy Colombo, MS 
 
 
 
 
The University of Wisconsin – Madison 
 
 
 
 
Funding Sponsor: National Institute of Alcohol Abuse & Alcoholism 
 
 
 
 
Study Protocol 
Protocol Version 3 01/26/20172 02/16/2016  
 
 
 
 
 

2 
Table of Contents 
Project Summary ........................................................................................................................................................3 
Background and Significance ......................................................................................................................................4 
Background and Significance ...................................................................................................................................4 
Innovation ..............................................................................................................................................................6 
Study Objectives and Aims .........................................................................................................................................7 
Objectives ..............................................................................................................................................................7 
Specific Aims .........................................................................................................................................................7 
Study Population ........................................................................................................................................................8 
Participant Population and Recruitment ....................................................................................................................8 
Inclusion Criteria ....................................................................................................................................................8 
Exclusion Criteria ...................................................................................................................................................8 
Research Design and Methods Overview.................................................................................................................... 10 
Overview of Study Procedures............................................................................................................................... 10 
Participant Reimbursement .................................................................................................................................... 11 
Statistical Analysis and Timeline ............................................................................................................................... 13 
Statistical Analysis................................................................................................................................................ 13 
Power Analyses for Sample Size Justification ......................................................................................................... 13 
Timeline Justification ............................................................................................................................................ 13 
Reference Cited ........................................................................................................................................................ 14 
 
 
 

3 
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. 
 
 
 

4 
Background and Significance 
Background and Significance 
DRUG ADDICTION, NOREPINEPHRINE, AND UNPREDICTABLE STRESSORS 
Stressors are potent instigators of relapse to drug use in clinical research with abstinent drug dependent humans 
and preclinical relapse models (i.e., stressor-induced reinstatement) in rodents. In rodents, brain norepinephrine (NE) 
levels are elevated in response to both discrete stressors1–6 and drug deprivation7,8. Similarly in humans, plasma and CSF 
NE-metabolite levels are elevated during alcohol withdrawal9–11 and in response to acute stressors12–14. Manipulations that 
increase central nervous system (CNS) NE levels (e.g., yohimbine, NET inhibitor, NE injections) increase drug-seeking 
behavior in rodents and non-human primates across a wide class of drugs including nicotine15, alcohol16, cocaine17–19, 
heroin20, and methamphetaime21. Although all central noradrenergic receptor classes (post-synaptic α1 & ß; autoreceptor 
α2) have been implicated in the etiology of addiction, NE-α1 receptors may be particularly important in stress-induced 
relapse. Prazosin, a selective noradrenergic NE-α1 receptor antagonist, blocked escalation of drug-seeking behavior in 
rodent models of dependence for alcohol22, cocaine23, opioids24, and nicotine25. Prazosin also reduces baseline alcohol 
consumption22, particularly in alcohol-preferring genetic strains of rats26–28. Prazosin, but not ß antagonists or α2 agonists, 
dose-dependently reduced dysfunctional brain reward thresholds observed during nicotine withdrawal25. Most critically, 
systemic administration of Prazosin blocks reinstatement of alcohol self-administration that is induced by unpredictable 
footshock stressors or directly increased NE via yohimbine29. Thus NE-α1 antagonists have broad treatment relevance for 
reducing stressor-induced relapse in drug addiction. 
 
Unfortunately, “stress” remains ill-defined and inconsistently operationalized in both basic research and clinical 
research on drug addiction in humans. Research on stress responding implicates central nervous system, endocrine, and 
peripheral biological systems that produce changes in affect, arousal, and attention30–33. However, research is rapidly 
accruing to suggest that the CNS negative affect component of the stress response, and more specifically, acute negative 
affective response to a subset of stressors characterized by stressor unpredictability, may provide a critical mechanism to 
account for stressor-induced relapse among drug dependent rodents and humans34. These unpredictable stressors (i.e., 
ambiguous, low probability, temporally imprecise stressors) appear to produce phenomenologically distinct affective 
responding via partially separable neural mechanism relative to predictable stressors (i.e., well-defined, high probability, 
imminent stressors)35. 
 
STARTLE POTENTIATION DURING STRESSOR EXPOSURE 
Programmatic affective neuroscience research has relied heavily on startle potentiation as a primary measure of 
defensive system activation to parse the neural mechanisms involved in response to unpredictable vs. predictable 
stressors. The use of startle potentiation to index affective response to stressors among rodents, non-human primates, and 
humans has provided an important animal-human translational bridge in this research36–38. As such, we have detailed 
knowledge of the neurobiology of the startle response and its potentiation37–40. Startle potentiation also can be measured 
with both minimal disruption of task-related processes and reduced influence by demand characteristics than measures 
under volitional control (e.g., self-report). 
 
In preclinical models, startle reflex potentiation during unpredictable stressors has strongly implicated NE and 
corticotropin-releasing factor (CRF) sensitive pathways through the lateral divisions of the central amygdala (CeA) and 
bed nucleus of the stria terminalis (BNST)35,41,42. In contrast, distinct pathways through the medial division of the CeA 
appear responsible for startle potentiation during predictable stressors35,43,44. A large corpus of research implicates CRF as 
a critical mediator of the stress response35,45 and NE is a powerful modulator of extrahypothalamic CRF46. Prazosin 
reduces startle potentiation in rodents due to manipulations of CRF46 and other stress-relevant neurotransmitter systems 
(e.g., DA47). In humans, the startle response is potentiated by pharmacological challenge that elevates NE levels via 
yohimbine in healthy controls and particularly in drug dependent populations48,49. However, the effect of Prazosin on 
startle potentiation has never been examined in humans to date. Thus, startle potentiation during unpredictable stressors 
represents 1) a psychophysiological index of heightened response to stressors, 2) is sensitive to CNS NE system activation 
in rodents, 3) has well known neurobiological substrates in rodents, and 4) and can be assessed in rodents, non-human 
primates, and humans, positioning it as an attractive translational measure. 
 
THE NO SHOCK, PREDICTABLE SHOCK, UNPREDITABLE SHOCK (NPU) TASK 
Research in affective neuroscience has relied extensively on cued stressor (e.g., threat of electric shock) tasks to 
explicate psychological and neurobiological mechanisms involved in the negative affective response to stressors in 

5 
animals and humans. Christian Grillon at NIH has developed a cued-stressor task called the “No Shock, Predictable 
Shock, Unpredictable Shock” (NPU) task to carefully contrast response to unpredictable vs. predictable stressors50,51. 
Predictable shock conditions involve administration of 100% cue-contingent, imminent electric shock. Unpredictable 
shock conditions involve temporally uncertain administration of shock. Startle potentiation during unpredictable shock 
(relative to no-shock blocks) provides the primary measure of negative affective response to stressors that in rodents 
engages both NE system activity and elicits etiologically relevant behaviors for addiction (i.e., stressor-induced 
reinstatement). This task represents a direct translation of methods and measures used by Davis, Walker and colleagues to 
parse neural mechanisms involved in response to unpredictable vs. predictable stressors35,43. We will use this task in the 
proposed research with humans. 
 
PRELIMINARY EVIDENCE 
Research from our lab provides compelling evidence that unpredictable stressors elicit startle potentiation that is 
attenuated by anxiolytic drugs and exacerbated by abstinence in drug dependent users. Alcohol administration robustly 
suppresses startle potentiation during tasks involving unpredictable stressors, including the NPU task52,53. Similarly, 
benzodiazepines reduce startle potentiation to unpredictable stressors54. Furthermore, these anxiolytic effects are specific 
to unpredictable stressors as these drugs produce minimal effects on startle potentiation to predictable stressors. These 
studies provide evidence that startle potentiation in the NPU and similar tasks is a sensitive index of the effects of 
pharmacologic agents on negative affective response to stressors. 
 
In a parallel line of research we have demonstrated that these tasks have proved effective at differentiating drug 
deprived, dependent users from non-dependent healthy controls for a variety of drugs including tobacco55, marijuana56, 
and alcohol57. Cigarette smokers displayed elevated startle response selectively during unpredictable stressors (vs. 
predictable stressors) after 24-hours of nicotine deprivation compared to non-deprived smokers55. Dependent marijuana 
users show significantly increased startle potentiation during unpredictable stressors after three days of abstinence relative 
to non-deprived smokers and non-smoker controls56. Furthermore, alcoholics in 1-8 weeks early abstinence show larger 
startle potentiation to unpredictable stressors (vs. predictable stressors) compared to healthy controls in a variant of the 
NPU task57. This demonstrates that these tasks provide an objective non-invasive physiological biomarker of the effects of 
drug deprivation on affective responses to unpredictable stressors that represents an etiologically relevant cross-drug 
phenomenon. 
 
 
We believe these data in humans, in combination with ample evidence from rodent models, supports our use of 
the NPU task to advance translational research aimed at identifying mechanisms for novel pharmacological treatments of 
stress induced relapse mechanisms in addiction.  We also provide this preliminary evidence to confirm that our laboratory 
has the necessary expertise to work with clinical samples of drug dependent users, acutely administer drugs safely in the 
laboratory, and measure psychophysiological response (including startle potentiation) during stressor tasks55–58. 
 
REPURPOSING PRAZOSIN 
Though Prazosin has been clinically available for forty years only recently has human research focused on 
addiction treatment. Fox and colleagues59 demonstrated that among treatment-seeking alcohol dependent patients, 
Prazosin (16mg/day, 4wks) reduced self-reported alcohol craving and negative affect in response to guided imagery 
exposure to stress. This is the first evidence in humans implicating NE-α1 in stress-induced relapse mechanisms in 
addiction. However, this measure of stress imagery reactivity has less direct ties to preclinical models of stress reactivity 
than our model of startle potentiation in the NPU task. One additional study by Simpson et al60 found that Prazosin 
(16mg/day, 6wks) reduced the number of drinks per day and number of days drinking in the final weeks of an RCT for 
alcohol dependence treatment. These first positive findings in humans instill excitement regarding Prazosin, particularly 
since they likely underestimate the true potential efficacy of NE-α1 antagonists because they do not focus specifically on 
stress-induced relapse outcomes. These studies demonstrated that in drug dependent samples Prazosin has a good safety 
profile and was generally well tolerated with minimal side effects, which is an important consideration given that aversive 
side effects are often a primary factor limiting the clinical effectiveness of psychiatric medications. Further considerations 
that increase the excitement for repurposing Prazosin for addiction treatment is that it is the most lipid soluble NE-α1 
antagonist increasing its ability to cross the blood-brain barrier, is highly selective for the NE-α1 receptor (Ki=0.12-0.31), 
has a better side effect profile than other NE receptor modulators (e.g., Clonidine), and it is available in generic 
formulation61–64. Doxazosin another NE-α1 antagonists reduces alcohol drinking in alcohol-preferring rats65, and is being 
investigated for cocaine dependence in humans66,67, but Prazosin is the only drug shown to specifically reduce stress-
induced relapse in rats and has preliminary human evidence in alcoholism. The use of Prazosin is not contraindicated with 

6 
first line treatments for alcohol dependence and has been found to increase the effectiveness of Naltraxone to reduce 
alcohol consumption in rodent models68. Finally, there has been increased excitement in the field over the possibility that 
Prazosin may be an effective treatment for PTSD69–73. This may lead to fruitful lines of future research within the NIMH 
RDoC initiative that aims to focus on transdiagnostic dimensions, such as heightened stress-reactivity, which may 
represent a common feature in PTSD and addiction. In summary, in addition to the strong preclinical evidence implicating 
NE-α1 activation as a key mechanism involved in stress-induced relapse; there is mounting support from human studies to 
justify further examination of the potential for Prazosin to alleviate the exaggerated stress reactivity observed in alcohol 
and drug dependent individuals pursuing abstinence. 
 
DIVERSITY AND HEALTH DISPARITIES 
 
There are clear health disparities in alcoholism and substance use disorders that manifest as greater negative 
health consequences and cost for low SES and racial minority populations74. The stress-induced relapse mechanisms that 
are the focus of the current grant may be particularly problematic for low SES populations where significant life stressors 
are more prevalent. Developing and repurposing medications that can treat this particular mechanism of relapse will have 
a relatively greater benefit to individuals who are at risk to experience more frequent and intense stressors. 
Innovation 
This research is innovative in its attempt to directly translate research findings from animal models to the 
examination of human addiction etiology and treatment (“bench to bedside”).  There is substantial evidence implicating 
stress-related neurocircuitry in the etiology of addiction and relapse in rodents but the evidence in humans is much more 
limited7,34,45,75. This application uses a well-validated translational task with strong connections to the preclinical literature. 
The use of reliable biomarker of neuroadaptations resultant from chronic drug use that are also sensitive to the acute 
effects of both prescription and non-prescription anxiolytic drugs (e.g., benzodiazepines and alcohol) allows for 
generalizations across a wide class of drugs that alter the stress response52,54,76. 
 
This research is also innovative in its attempts to ‘repurpose’ Prazosin from its original FDA approved use for 
hypertension to a new purpose of relapse prevention in alcoholism. Thomas Insel, director of NIMH, clearly argues that 
given substantial cuts in R&D budgets for new psychiatric drugs at most major pharmaceutical companies the near term 
outlook of novel molecular targets is grim77,78. Therefore, it is critical to take advantage of existing compounds acting on 
neurotransmitter systems that have been implicated in the etiology of psychiatric disorders. The current proposal is one 
clear example of this theme to screen Prazosin for repurposing for the treatment of stress-induced relapse in alcoholism by 
using this cost effective biomarker as a surrogate endpoint. 
 
This laboratory approach of identifying biomarkers of stress-reactivity that can be measured along a continuum 
from normal to abnormal addresses the current paradigm shift being advocated by the NIMH’s Research Domain Criteria 
(RDoC). RDoC calls for a dimensional approach to studying the roots of human behavior at multiple levels of analysis 
that cuts across DSM diagnostic categories 77,79–82. The current proposal aims to examine a number of the constructs (e.g., 
responses to acute threat (fear) or potential harm (anxiety)) defined within the Negative Valence System, using a 
paradigm recommended by the NIMH workgroup83. Indeed, although this paradigm is used to study abnormal processes 
in abstinent alcoholics, it represents a framework to evaluate abnormal stress-reactivity that spans not only multiple drugs 
of addiction (e.g., tobacco, marijuana); but likely other disorders (e.g., PTSD) that may share a common neuroadaptation 
that manifests as a heightened stress response. 
 
 
 
 

7 
Study Objectives and Aims 
Objectives 
First Objective: To confirm NE-α1 involvement in startle potentiation during unpredictable stressors in humans with 
alcoholism and matched controls. This will support the use of this laboratory assay that implicates NE mechanisms as a 
surrogate endpoint in this ‘proof-of-concept’ trial aimed at identifying novel treatment targets. 
 
Second Objective: Provide preliminary evidence that Prazosin is effective at reducing stressor-reactivity, particularly 
among alcoholics in early abstinence, thereby advancing efforts to repurpose Prazosin for treatment of stressor-induced 
relapse in addiction.  
 
To accomplish these objectives we propose three specific aims: 
 
Specific Aims 
AIM 1: Examine the effects of a NE-α1 antagonist (Prazosin) on responses to unpredictable stressors. 
1.1 Prazosin (2mg vs. placebo) will reduce negative affective response to unpredictable stressors measured via startle 
potentiation, translating preclinical to clinical neuroscience. 
1.2 Prazosin (2mg vs. placebo) will reduce negative affective response to unpredictable stressors measured via self-
report, identifying uniquely human phenomenology. 
 
AIM 2: Confirm evidence of exacerbated stress reactivity in abstinent alcoholics (vs. matched controls). 
2.1 Abstinent alcoholics (vs. matched controls) will display elevated negative affective response to unpredictable (vs. 
predictable) stressors measured via startle potentiation, conceptually replicating previous findings that provide a 
laboratory assay of stress-induced relapse mechanisms in addiction. 
2.2 Abstinent alcoholics (vs. matched controls) will display elevated negative affective response to unpredictable 
stressors measured via self-report. 
 
AIM 3: Examine the differential effects of Prazosin in abstinent alcoholics vs. matched controls. 
3.1 The predicted effects of Prazosin on reducing negative affective responses to unpredictable stressors as measured 
via startle potentiation (Aim 1.1) and self-report (Aim 1.2) will be moderated by alcoholism, such that the effects of 
Prazosin will be larger in abstinent alcoholics than matched volunteers. 
 
 
 
 

8 
Study Population 
Participant Population and Recruitment 
 
The site of the proposed research is the University of Wisconsin-Madison. Prospective participants will be 
recruited through the greater Madison community via paper fliers and online advertisements. Paper flyers will be posted 
in a variety of locations throughout the UW campus and community (e.g., laundromats, restaurants, gas stations, etc.). 
Paper flyers will also be posted at targeted locations to recruit recovering alcoholics including community support groups 
(e.g., AA meeting locations) and local in- and out-patient treatment facilities for alcoholism (e.g., Gateway Recovery, 
Tellurian, ARC, Connections Counseling, etc.). Participants over the age of 50 will be excluded to limit potential 
extraneous variance related to normal aging processes. To decrease the risk of adverse psychological reactions in response 
to startle probes and electric shock, participants will be excluded if they have a lifetime diagnosis of serious and persistent 
mental illness (SPMI; e.g. bipolar disorder, schizophrenia, any psychosis). 
 
Thirty-six alcohol dependent participants in early protracted abstinence (at least 1 week but no more than 8 weeks 
since last alcohol use) will be recruited for the study. Thirty-six non-alcoholic participants will also be recruited to will 
serve as the comparison group. Participants in the alcoholic and control groups will be matched on selected characteristics 
including age, sex, education level, daily nicotine use, and Axis I psychopathology. These characteristics will be matched 
at the group level such that the average and range of both groups will be comparable. 
Inclusion Criteria 
All participants: 
Can read and write in English. 
Ages of 18-50 years. 
 
Alcoholic Participants: 
The alcoholic participants will have at least one but no more than eight weeks completely free from alcohol consumption. 
 
Control Participants: 
The control participants must not meet criteria for any current or lifetime history or substance dependence other than 
nicotine dependence. 
Exclusion Criteria 
Exclusion criteria are divided into three broad categories of Medical, Psychiatric/Behavioral, and Medications/Therapies. 
These criteria are all implemented to protect human subject safety, except where noted with an asterisk (*) denoting 
scientific/theoretical reasons. 
 
Medical exclusion  
•Self-reported acute or unstable illness precluding a safe and reliable study participation; medical conditions precluding 
participation will include, for example, unstable angina, history of myocardial infarction, history of congestive heart 
failure, chronic renal or hepatic failure, pancreatitis, Meniere’s disease, benign positional vertigo, narcolepsy. 
•A pre-existing hypotension (systolic less than 100) or orthostatic hypotension (systolic drop greater than 20mmHg after 
two minutes standing or any drop accompanied by dizziness).  
•Systolic blood pressure greater than 160 
•Tachycardia >=100  
•Allergy or previous adverse reaction to prazosin or other alpha1-NE antagonist. 
•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). 
•Women who are breastfeeding will be excluded. 
•*Color blindness. [Excluded because colored images identify critical differences between predictable, unpredictable, and 
no-shock conditions in the NPU stress-reactivity task.] 
 

9 
Psychological/Behavioral exclusion 
•Self-reported lifetime diagnosis of serious and persistent mental illness, including schizophrenia, schizoaffective 
disorder, psychotic disorder NOS, delirium, bipolar Disorder, borderline personality disorder, or any neurocognitive 
disorder. 
•Any current active substance use disorder other than tobacco. 
•Control Participants Only: Lifetime history of substance dependence. 
 
Medications/Therapies exclusion 
•Current use of prazosin or other alpha1-NE antagonist (e.g., doxazosin, terazosin). 
•Previous adequate trial of prazosin for alcohol use disorder or PTSD. 
•Sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) will not be permitted during the study because of increased 
risk of hypotension in combination with alpha1-NE antagonists. 
•*Stimulants (e.g., d-amphetamine, methylphenidate) or alternative medications with stimulant properties (e.g., ephedra). 
[Excluded because these medications directly alter CNS noradrenergic neurotransmission.] 
•*Beta-blockers (e.g., propanolol), alpha2 agonists (e.g., clonidine, guanfacine), and SNRI anti-depressants (e.g., 
venlafaxine, duloxetine). [Excluded because these medications directly alter CNS noradrenergic neurotransmission.] 
 
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. 
 
 

10 
Research Design and Methods Overview 
Overview of Study Procedures 
Seventy-two participants (36 alcoholic & 36 controls) will be recruited to participate in a double-blind, placebo-
controlled, mixed-design, cross-over study examining the effects of a NE-α1 antagonist (prazosin) on the affective 
response to stressors. Both study visits will take place in the Clinical Research Unit (CRU) inpatient unit at the University 
of Wisconsin Hospital. A screening visit will take place in the Addiction Research Center at the University of Wisconsin 
– Madison. At the first study screening visit general laboratory procedures and risks and benefits will be explained to the 
participants and informed consent will be obtained from all participants. Inclusion/exclusion criteria will be confirmed 
using interviews conducted by a nurse, graduate level clinician, self-report questionnaires and urine test for pregnancy. 
Study Nursing staff will collect a medical history, current medication, orthostatic vital signs, and urine pregnancy test to 
confirm eligibility. For both participant groups, research staff will first confirm that the potential participant is free from 
severe and persistent mental illness. Following this, the more in-depth Substance Use Disorders Module of the SCID-
Research Version (SCID-RV84) will be administered to confirm the alcoholic participants’ status with respect to an 
Alcohol Dependence diagnosis and no lifetime history of substance dependence for control participants. Participants will 
complete a shock sensitivity rating as per standard procedures from our laboratory. 
 
Eligible participants will be scheduled for two study visits that will take place in the Clinical Research Unit 
(CRU) inpatient unit at the University of Wisconsin Hospital. Modifiable inclusion/exclusion criteria will be re-confirmed 
at both study visits by the above procedures as well as a medical history and physical exam. Participants will be randomly 
assigned to drug order (prazosin 1st vs. 2nd visit) in a stratified blocked schedule by sex and group (alcoholic vs. control) 
using urn randomization procedures85. The randomization and double-blind will be implemented and maintained by the 
UW Pharmaceutical Research Center, which is located in the same building in the UW hospital as all study visits in the 
CRU. All participants are told that they will receive both 2mg of prazosin and placebo, one agent at each study visit. 
Drug/placebo order is counterbalanced between participants. However, neither participants nor researchers will be aware 
of whether prazosin or placebo is administered at each visit. 
All subsequent procedures will be identical at the first and second study visits except for the assessment of study 
eligibility and the drug administered. Alcoholic participants will complete a brief alcohol craving questionnaire, a 6 item 
subset of the 14-item version of the Desires for Alcohol Questionnaire (DAQ86) to determine baseline craving levels. 
Women of childbearing potential participants will provide a urine sample to verify they are not pregnant. All participants 
will then provide a breath sample to verify an initial blood alcohol concentration (BAC) of 0.00 (Alcosensor IV; 
Intoximeters, Inc.). All participants will be asked to refrain from consuming alcoholic beverages or any other 
psychoactive drugs for 24 hours prior to the experimental session, to avoid any acute effects of alcohol. Next all 
participants will ingest one pill with a full glass of water. 
Research assistants will then prepare the participant for the experimental task with physiological sensors. Next 
participants will complete a baseline assessment of their blink EMG response and a shock sensitivity rating as per 
standard procedures from our laboratory. Based on the known pharmacodynamics of prazosin87, participants will begin 
the NPU task (see below) exactly 90 minutes after drug administration. During the stress-reactivity task participants will 
view geometric shapes and words presented on a computer monitor. Participants will be asked to answer short questions 
during this procedure, which will be audio recorded for later scoring for accuracy. At various times during this procedure, 
brief electric shocks will be administered to the fingers of the participants’ hand. The intensity of all shocks will be within 
the range that they indicated they could tolerate during the shock sensitivity procedure. In addition, acoustic white noise 
probes will be presented through earphones at random points during the procedure. These probes are used to elicit a startle 
blink reflex, which is used to index emotional response. After completion of the task, participants will complete 
questionnaires related to their emotional state during the task and a battery of self-report questionnaires to assess alcohol 
use history, trait affect and broadband personality traits.  

11 
After the NPU task participants will remain in the CRU inpatient unit overnight to monitor and assess for side 
effects under medical supervision by CRU staff. Participants second appointment will be scheduled 7 days (+/- 2 days) 
after the first study visit. Participants with unusable data at the first study visit (e.g., excessive physiological artifact, 
insufficient understanding of NPU task, startle non-responder) will not return for the second study visit. This study visit 
will be identical to the first study visit except for the drug administered (Prazosin vs. Placebo) and eligibility screening 
procedures. At the end of the first visit participants will be paid $150. At the second visit participants will be paid $150 
for the study visit and a $75 bonus for study completion, debriefed, and released. Participants who do not complete the 
study (e.g., not eligible, refuse consent, withdraw, etc.) will be paid $25/hour for their time up to $150/visit. Alcoholic 
participants will be required to demonstrate that they are not experiencing significantly elevated levels of alcohol craving 
(Desires for Alcohol Questionnaire) before they are released, per standard lab procedures. 
Table 1: Overview of Study Procedures 
CATEGORY 
PROCEDURE 
STUDY 
VISIT 1 
(Day 1) 
STUDY VISIT 2 
(Day 4-10) 
SCREENING 
Eligibility 
Consent, Inclusion/exclusion criteria 
X 
  
Medical 
history/assessment 
Medical history, concomitant medications, vital 
signs 
X 
  
Alcohol Use 
Timeline follow back; SCID - Substance Use 
Disorder 
X 
  
Blood alcohol concentration (BAC; via breath 
test) 
X 
X 
Lab Chemistry 
Urine pregnancy test 
X 
X 
SAFETY 
Visit safety 
Vital signs; Medication side effects 
X 
X 
Acute craving (for 
study release) 
6 item subset from Desire for Alcohol Scale 
X 
X 
DRUG ADMINISTRATION 
Drug 
Prazosin or placebo 
2 mg 
prazosin or 
placebo 
2 mg prazosin or 
placebo 
OUTCOMES 
Stress reactivity 
Startle potentiation and self-report negative affect 
from NPU task 
X 
X 
Individual difference 
moderators 
Self report: alcohol dependence severity, trait 
affect, personality trait 
X 
  
 
 
 
 
Participant Reimbursement 
All participants are paid $15 for time spent in the lab during the screening visit. All participants are paid $150/visit 
for time spent in the CRU for all study visits. Participants are provided a $75 bonus for completing all study visits. 
Participants who do not complete the study (e.g., not eligible, refuse consent, withdraw, etc.) will be paid $25/hour for 
their time at the CRU up to $150/visit. These modest inducements represent reasonable compensation for time spent in the 
study and cannot be considered coercive. 
 
Visit # 
Time 
Reimbursement 

12 
Screening Visit 
1 hour 
$15 
Study Visit 1 
3 to 5 hours + overnight 
$150 
Study Visit 2 
2 to 4 hours + overnight 
$150 
 
 
 
Study Completion Bonus 
 
$75 
 
 
 
Total 
 
$39075 
 
 
 

13 
Statistical Analysis and Timeline 
Statistical Analysis 
Analyses for quantitative dependent measures will be accomplished within General Linear Models using R88. In 
the sections below, we briefly describe the primary factors in statistical models to evaluate each Specific Aim. All models 
will include number of days abstinent at Visit 1 as an interactive between-subjects regressor to evaluate if drug effects and 
outcomes are comparable across alcoholics who vary in their previous duration of abstinence (1-8 weeks) on study 
initiation, although this has not moderated the effects on NPU task in our preliminary studies. Numerous individual 
difference measures (e.g., sex, mood/anxiety disorder comorbidity, tobacco use, trait affect, alcohol dependence severity) 
are available to add to these models as interactive between-subject regressors in secondary analyses to evaluate possible 
individual difference moderators of drug effects. 
Unpredictable startle potentiation and self-reported negative affect from the NPU task across Visits 1-2 will be 
analyzed in separate general linear models with repeated measures on Drug (2 mg prazosin vs placebo) and Condition 
(unpredictable vs. predictable shock). Participant Group (alcoholic vs. control) and Drug Order (prazosin: visit 1 vs visit 
2) will also be included as an interactive between subjects regressors to increase power. Specific Aim 1 predictions will 
be supported by significant Drug X Condition interactions with prazosin producing selectively larger reduction in startle 
potentiation and self-reported negative affect during unpredictable relative to predictable shock. Specific Aim 2 
predictions will be supported by significant Group X Condition interactions with abstinent alcoholics displaying 
selectively larger startle potentiation and self-reported negative affect during unpredictable relative to predictable shock. 
Specific Aim 3 predictions will be supported by significant Drug X Group X Condition interactions with prazosin 
producing selectively larger reduction in startle potentiation and self-reported negative affect during unpredictable relative 
to predictable shock to a greater degree among abstinent alcoholic than control participants. 
Power Analyses for Sample Size Justification 
Power analyses were conducted using the pwr package in R which calculates power based on the approach 
outlined by Cohen89. Power analyses were conducted to provide adequate power to detect comparable effect sizes 
observed in previous research from our laboratory that has used variants of the NPU task to examine acute drug effects 
(i.e., moderate dose of alcohol), drug deprivation effects (24 hours of nicotine deprivation among daily smokers), or 
differences between alcoholics in early abstinence (1-8 weeks) vs. matched controls. In the current study, N = 72 will 
provide 85% power to detect the effect of prazosin on startle potentiation during unpredictable (vs. predictable) stress in 
alcohol dependent participants (vs. controls) assuming a conservative small effect size (∆R2= .10) in a model containing 
the predictors noted above (R2 = .30). 
Timeline Justification 
This project aims to be completed within three years. This goal is reasonable given our team’s expertise in 
conducting psychophysiological laboratory research working with drug administration (i.e., alcohol and nicotine), 
community participants, and stress reactivity. Our lab has the experience and infrastructure to recruit and retain a sample 
of this size. We recently completed a pilot study for the current application that recruited 115 participants (58 alcoholic 
and 57 matched controls) over the course of 14 months. This study involved diagnostic interviews and stress-reactivity 
task over the course of two study visits. The current study will plan to initially consent eighty-five participants with a final 
sample size goal of seventy-two participants. Based on prior experience we anticipate that 85% of eligible participants 
will return to complete all study visits. A total of 157 complete visits (85 first, 72 second) will be conducted. If we 
conservatively expect to average 2 study visits per week to account for no-shows, failed eligibility criteria, and equipment 
failure we anticipate completing data collection within 1.5-2 years. 
 
 
 

14 
Reference Cited 
1. Erb, S. et al. Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking. 
Neuropsychopharmacology 23, 138–50 (2000). 
2. Pacák, K. et al. Effects of various stressors on in vivo norepinephrine release in the hypothalamic paraventricular 
nucleus and on the pituitary-adrenocortical axis. Ann. N. Y. Acad. Sci. 771, 115–130 (1995). 
3. Galvez, R., Mesches, M. H. & McGaugh, J. L. Norepinephrine release in the amygdala in response to footshock 
stimulation. Neurobiol Learn Mem 66, 253–257 (1996). 
4. Pacák, K., Palkovits, M., Kopin, I. J. & Goldstein, D. S. Stress-induced norepinephrine release in the hypothalamic 
paraventricular nucleus and pituitary-adrenocortical and sympathoadrenal activity: in vivo microdialysis studies. 
Front Neuroendocrinol 16, 89–150 (1995). 
5. Pacák, K., McCarty, R., Palkovits, M., Kopin, I. J. & Goldstein, D. S. Effects of immobilization on in vivo release of 
norepinephrine in the bed nucleus of the stria terminalis in conscious rats. Brain Res. 688, 242–246 (1995). 
6. Pacák, K. et al. Effects of single or repeated immobilization on release of norepinephrine and its metabolites in the 
central nucleus of the amygdala in conscious rats. Neuroendocrinology 57, 626–633 (1993). 
7. Smith, R. J. & Aston-Jones, G. Noradrenergic transmission in the extended amygdala: role in increased drug-seeking 
and relapse during protracted drug abstinence. Brain Structure and Function 213, 43–61 (2008). 
8. Aston-Jones, G., Delphs, J. M., Druhan, J. & Zhu, Y. The Bed Nucleus of the Stria Terminalis: A Target Site for 
Noradrenergic Actions in Opiate Withdrawal. Annals of the New York Academy of Sciences 877, 486–498 (1999). 
9. Patkar, A. A. et al. Changes in plasma noradrenaline and serotonin levels and craving during alcohol withdrawal. 
Alcohol Alcohol. 38, 224–231 (2003). 
10. Patkar, A. A. et al. Differences in peripheral noradrenergic function among actively drinking and abstinent alcohol-
dependent individuals. Am J Addict 13, 225–235 (2004). 
11. Fujimoto, A., Nagao, T., Ebara, T., Sato, M. & Otsuki, S. Cerebrospinal fluid monoamine metabolites during alcohol 
withdrawal syndrome and recovered state. Biol. Psychiatry 18, 1141–1152 (1983). 
12. Bremner, J., Krystal, J., Southwick, S. & Charney, D. Noradrenergic mechanisms in stress and anxiety: II. Clinical 
studies. Synapse 23, 39–51 (1996). 
13. Taggart, P., Carruthers, M. & Somerville, W. Electrocardiogram, plasma catecholamines and lipids, and their 
modification by oxyprenolol when speaking before an audience. Lancet 2, 341–346 (1973). 
14. Taggart, P. & Carruthers, M. Endogenous hyperlipidaemia induced by emotional stress of racing driving. Lancet 1, 
363–366 (1971). 
15. Feltenstein, M. W., Ghee, S. M. & See, R. E. Nicotine self-administration and reinstatement of nicotine-seeking in 
male and female rats. Drug Alcohol Depend 121, 240–246 (2012). 
16. Marinelli, P. W. et al. The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant 
alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology (Berl.) 195, 345–355 
(2007). 
17. Brown, Z., Tribe, E., D’souza, N. & Erb, S. Interaction between noradrenaline and corticotrophin-releasing factor in 
the reinstatement of cocaine seeking in the rat. Psychopharmacology 203, 121–130 (2009). 
18. Lee, B., Tiefenbacher, S., Platt, D. M. & Spealman, R. D. Pharmacological blockade of alpha2-adrenoceptors induces 
reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsychopharmacology 29, 686–693 (2004). 
19. Platt, D. M., Rowlett, J. K. & Spealman, R. D. Noradrenergic mechanisms in cocaine-induced reinstatement of drug 
seeking in squirrel monkeys. J. Pharmacol. Exp. Ther. 322, 894–902 (2007). 
20. Banna, K. M., Back, S. E., Do, P. & See, R. E. Yohimbine stress potentiates conditioned cue-induced reinstatement of 
heroin-seeking in rats. Behav Brain Res 208, 144 (2010). 
21. Shepard, J. D., Bossert, J. M., Liu, S. Y. & Shaham, Y. The anxiogenic drug yohimbine reinstates methamphetamine 
seeking in a rat model of drug relapse. Biol. Psychiatry 55, 1082–1089 (2004). 
22. Walker, B., Rasmussen, D., Raskind, M. & Koob, G. alpha1-noradrenergic receptor antagonism blocks dependence-
induced increases in responding for ethanol. Alcohol 42, 91–7 (2008). 
23. Wee, S., Mandyam, C., Lekic, D. & Koob, G. F. Alpha 1-noradrenergic system role in increased motivation for 
cocaine intake in rats with prolonged access. Eur Neuropsychopharmacol 18, 303–11 (2008). 
24. Greenwell, T., Walker, B., Cottone, P., Zorrilla, E. & Koob, G. F. The α1 adrenergic receptor antagonist prazosin 
reduces heroin self-administration in rats with extended access to heroin administration. Pharmacology, Biochemistry 
and Behavior 91, 295–302 (2009). 
25. Forget, B. et al. Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction. 
Neuropsychopharmacology 35, 1751–1760 (2010). 

15 
26. Rasmussen, D. D., Alexander, L. L., Raskind, M. & Froehlich, J. C. The alpha1-adrenergic receptor antagonist, 
prazosin, reduces alcohol drinking in alcohol-preferring (P) rats. Alcohol. Clin. Exp. Res. 33, 264–272 (2009). 
27. Verplaetse, T. L., Rasmussen, D. D., Froehlich, J. C. & Czachowski, C. L. Effects of prazosin, an α1-adrenergic 
receptor antagonist, on the seeking and intake of alcohol and sucrose in alcohol-preferring (P) rats. Alcohol. Clin. 
Exp. Res. 36, 881–886 (2012). 
28. Froehlich, J. C., Hausauer, B. J., Federoff, D. L., Fischer, S. M. & Rasmussen, D. D. Prazosin Reduces Alcohol 
Drinking Throughout Prolonged Treatment and Blocks the Initiation of Drinking in Rats Selectively Bred for High 
Alcohol Intake. Alcohol. Clin. Exp. Res. (2013). doi:10.1111/acer.12116 
29. Lê, A. et al. Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. 
Psychopharmacology 218, 89–99 (2011). 
30. McEwen, B. S. From molecules to mind. Stress, individual differences, and the social environment. Ann N Y Acad Sci 
935, 42–9 (2001). 
31. McEwen, B. S., Eiland, L., Hunter, R. G. & Miller, M. M. Stress and anxiety: structural plasticity and epigenetic 
regulation as a consequence of stress. Neuropharmacology 62, 3–12 (2012). 
32. Sapolsky, R. M. in Behavioral endocrinology (2nd ed.). (eds. Becker, J. B., Breedlove, S. M., Crews, D. & McCarthy, 
M. M.) 409–450 (MIT Press, 2002). 
33. Sapolsky, R. M. Stress and plasticity in the limbic system. Neurochem. Res. 28, 1735–1742 (2003). 
34. Koob, G. F. Brain stress systems in the amygdala and addiction. Brain Research 1293, 61–75 (2009). 
35. Davis, M., Walker, D. L., Miles, L. & Grillon, C. Phasic vs sustained fear in rats and humans: Role of the extended 
amygdala in fear vs anxiety. Neuropsychopharmacology Reviews 35, 105–135 (2010). 
36. Davis, M., Antoniadis, E., Amaral, D. & Winslow, J. Acoustic startle reflex in rhesus monkeys: A review. Reviews in 
the Neurosciences 19, 171–185 (2008). 
37. Davis, M. Neural systems involved in fear-potentiated startle. Annals of the New York Academy of Sciences 563, 165–
183. (1989). 
38. Grillon, C. & Baas, J. M. A review of the modulation of the startle reflex by affective states and its application in 
psychiatry. Clinical Neurophysiology 144, 1557–1579. (2003). 
39. Davis, M. Neural systems involved in fear and anxiety measured with fear-potentiated startle. American Psychologist 
61, 741–756 (2006). 
40. Koch, M. The neurobilogy of startle. Progress in Neurobiology 59, 107–128 (1999). 
41. Walker, D. & Davis, M. Light-enhanced startle: further pharmacological and behavioral characterization. 
Psychopharmacology 159, 304–310 (2002). 
42. Walker, D. et al. Differential effects of the CRF-R1 antagonist GSK876008 on fear-potentiated, light- and CRF-
enhanced startle suggest preferential involvement in sustained vs phasic threat responses. Neuropsychopharmacology 
34, 1533–1542 (2009). 
43. Walker, D. & Davis, M. Role of the extended amygdala in short-duration versus sustained fear: A tribute to Dr. 
Lennart Heimer. Brain Structure and Function 213, 29–42 (2008). 
44. Walker, D. & Davis, M. Double dissociation between the involvement of the bed nucleus of the stria terminalis and 
the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear. J. 
Neurosci. 17, 9375–9383 (1997). 
45. Koob, G. F. The role of CRF and CRF-related peptides in the dark side of addiction. Brain Res. 1314, 3–14 (2010). 
46. Gresack, J. & Risbrough, V. Corticotropin-releasing factor and noradrenergic signalling exert reciprocal control over 
startle reactivity. Int. J. Neuropsychopharm. 14, 1179–94 (2011). 
47. Kehne, J. H., Commissaris, R. L. & Davis, M. Antagonism of apomorphine-enhanced startle by alpha 1-adrenergic 
antagonists. Eur. J. Pharmacol. 108, 233–241 (1985). 
48. Morgan, C. A. et al. Yohimbine — facilitated acoustic startle reflex in humans. Psychopharmacology 110, 342–346 
(1993). 
49. Stine, S. M. et al. Methadone patients exhibit increased startle and cortisol response after intravenous yohimbine. 
Psychopharmacology 154, 274–81. (2001). 
50. Schmitz, A. & Grillon, C. Assessing fear and anxiety in humans using the threat of predictable and unpredictable 
aversive events (the NPU-threat test). Nature Protocols 7, 527–532 (2012). 
51. Grillon, C., Baas, J. P., Lissek, S., Smith, K. & Milstein, J. Anxious responses to predictable and unpredictable 
aversive events. Behavioral Neuroscience 118, 916–924 (2004). 
52. Moberg, C. A. & Curtin, J. J. Alcohol selectively reduces anxiety but not fear: startle response during unpredictable 
vs. predictable threat. J Abnorm Psychol 118, 335–347 (2009). 

16 
53. Hefner, K. R. & Curtin, J. J. Alcohol stress response dampening: Selective reduction of anxiety in the face of 
uncertain threat. J. Psychopharmacol. (Oxford) 26, 232–244 (2012). 
54. Grillon, C. et al. The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by 
fear-potentiated startle. Biological Psychiatry 60, 760–766 (2006). 
55. Hogle, J. M., Kaye, J. T. & Curtin, J. J. Nicotine withdrawal increases threat-induced anxiety but not fear: 
Neuroadaptation in human addiction. Biological Psychiatry 68, 687–688 (2010). 
56. Gloria, R., Jaber, J. N., Baker, T. B. & Curtin, J. J. The effect of temporal precision and probability on the response to 
threat of shock: a fear-potentiated startle study. Psychophysiology 46(s1), s80 (2009). 
57. Moberg, C. A. & Curtin, J. J. Stressing the importance of anxiety in alcoholism. in Alcoholism: Clinical and 
Experimental Research 36, 60A (2012). 
58. Hogle, J. M. & Curtin, J. J. Sex differences in negative affective response during nicotine withdrawal. 
Psychophysiology 43, 344–356 (2006). 
59. Fox, H. C. et al. Prazosin Effects on Stress- and Cue-Induced Craving and Stress Response in Alcohol-Dependent 
Individuals: Preliminary Findings. Alcoholism: Clinical and Experimental Research 36, 351–360 (2012). 
60. Simpson, T. et al. A Pilot Trial of the Alpha-1 Adrenergic Antagonist, Prazosin, for Alcohol Dependence. 
Alcoholism: Clinical and Experimental Research 33, 255–263 (2009). 
61. Doxey, J. C., Lane, A. C., Roach, A. G. & Virdee, N. K. Comparison of the alpha-adrenoceptor antagonist profiles of 
idazoxan (RX 781094), yohimbine, rauwolscine and corynanthine. Naunyn Schmiedebergs Arch. Pharmacol. 325, 
136–144 (1984). 
62. Menkes, D. B., Baraban, J. M. & Aghajanian, G. K. Prazosin selectively antagonizes neuronal responses mediated by 
alpha1-adrenoceptors in brain. Naunyn Schmiedebergs Arch. Pharmacol. 317, 273–275 (1981). 
63. Rogawski, M. A. & Aghajanian, G. K. Activation of lateral geniculate neurons by locus coeruleus or dorsal 
noradrenergic bundle stimulation: selective blockade by the alpha 1-adrenoceptor antagonist prazosin. Brain Res. 250, 
31–39 (1982). 
64. Millan, M. J. et al. Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic 
receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for 
the modulation of frontocortical monoaminergic transmission and depressive states. Synapse 35, 79–95 (2000). 
65. O’Neil, M. L., Beckwith, L. E., Kincaid, C. L. & Rasmussen, D. D. The α1-adrenergic receptor antagonist, doxazosin, 
reduces alcohol drinking in alcohol-preferring (P) Rats. Alcohol. Clin. Exp. Res. 37, 202–212 (2013). 
66. Shorter, D., Lindsay, J. A. & Kosten, T. R. The alpha-1 adrenergic antagonist doxazosin for treatment of cocaine 
dependence: A pilot study. Drug Alcohol Depend 131, 66–70 (2013). 
67. Newton, T. et al. Noradrenergic α1 Receptor Antagonist Treatment Attenuates Positive Subjective Effects of Cocaine 
in Humans: A Randomized Trial. PLoS ONE 7, e30854 (2012). 
68. Froehlich, J. C., Hausauer, B. J. & Rasmussen, D. D. Combining Naltrexone and Prazosin in a Single Oral 
Medication Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone. Alcohol. Clin. Exp. Res. 
(2013). doi:10.1111/acer.12148 
69. Raskind, M. et al. The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with 
posttraumatic stress disorder: a report of 4 cases. J Clin Psychiatry 61, 129–133 (2000). 
70. Raskind, M. et al. Prazosin reduces nightmares in combat veterans with posttraumatic stress disorder. J Clin 
Psychiatry 63, 565–568 (2002). 
71. Raskind, M. et al. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-
controlled study. Am J Psychiatry 160, 371–373 (2003). 
72. Raskind, M. et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance 
in combat veterans with post-traumatic stress disorder. Biol. Psychiatry 61, 928–934 (2007). 
73. Raskind, M. et al. A Trial of Prazosin for Combat Trauma PTSD With Nightmares in Active-Duty Soldiers Returned 
From Iraq and Afghanistan. Am J Psychiatry (2013). doi:10.1176/appi.ajp.2013.12081133 
74. Chartier, K. & Caetano, R. Ethnicity and Health Disparities in Alcohol Research. NIAAA Publications at 
<http://pubs.niaaa.nih.gov/publications/arh40/152-160.htm> 
75. Sinha, R., Shaham, Y. & Heilig, M. Translational and reverse translational research on the role of stress in drug 
craving and relapse. Psychopharmacology 218, 69–82 (2011). 
76. Koob, G. F., Lloyd, G. K. & Mason, B. J. Development of pharmacotherapies for drug addiction: a Rosetta stone 
approach. Nature Reviews Drug Discovery 8, 500–515 (2009). 
77. Insel, T. R. Next-generation treatments for mental disorders. Sci Transl Med 4, 155ps19 (2012). 
78. Miller, G. Is Pharma Running Out of Brainy Ideas? Science 329, 502–504 (2010). 

17 
79. Cuthbert, B. & Insel, T. The data of diagnosis: new approaches to psychiatric classification. Psychiatry 73, 311–314 
(2010). 
80. Cuthbert, B. & Insel, T. R. Toward new approaches to psychotic disorders: the NIMH Research Domain Criteria 
project. Schizophr Bull 36, 1061–1062 (2010). 
81. Insel, T. R. & Cuthbert, B. Endophenotypes: Bridging Genomic Complexity and Disorder Heterogeneity. Biological 
Psychiatry 66, 988–989 (2009). 
82. Sanislow, C. A. et al. Developing constructs for psychopathology research: Research domain criteria. Journal of 
Abnormal Psychology 119, 631–639 (2010). 
83. NIMH · Negative Valence Systems: Workshop Proceedings. at <http://www.nimh.nih.gov/research-
priorities/rdoc/negative-valence-systems-workshop-proceedings.shtml> 
84. First, M. B., Spitzer, R. L., Gibbon, M. & Williams, J. B. W. Structured Clinical Interview for DSM-IV-TR Axis I 
Disorders, Research Version, Patient Edition. (SCID-I/P). (Biometrics Research, New York State Psychiatric 
Institute, 2002). 
85. Stout, R. L., Wirtz, P. W., Carbonari, J. P. & Del Boca, F. K. Ensuring balanced distribution of prognostic factors in 
treatment outcome research. J Stud Alcohol Suppl 12, 70–75 (1994). 
86. Love, A., James, D. & Willner, P. A comparison of two alcohol craving questionnaires. Addiction 93, 1091–1102 
(1998). 
87. Jaillon, P. Clinical pharmacokinetics of prazosin. Clin Pharmacokinet 5, 365–376 (1980). 
88. R Development Core Team. R: A language and environment for statistical computing. (R Foundation for Statistical 
Computing, 2013). at <http://www.R-project.org> 
89. Cohen, J. A power primer. Psychological Bulletin 112, 155–159 (1992).