Concluded Extend and Confirm Projects funded by the ITN

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Lay Abstract	Identify causal biological mechanisms of PTSD using a novel gene x environment mouse model of stress vulnerability, and characterize the interaction between PTSD-like symptoms and nicotine/alcohol consumption Identify SNPs associated with PTSD, or PTSD and comorbid substance use disorders, informed by our mouse model. Examine the genetics and epidemiology of substance abuse among men and women separately in a large military sample, informed by our mouse model
Keywords	mouse model, stress vulnerability, TIA-1 SNPs
Date concluded	7/31/2016
Treatment Type	n/a
Target population	Mouse Studies
IND	n/a

Lay Abstract	Study/Product Aim(s): Demonstrate effects of systemic oxytocin or carbetocin administration on reinstatement of meth seeking and epigenetic adaptations in the brain of rats after chronic stress. Demonstrate effects of systemic oxytocin or carbetocin administration on reinstatement of ethanol seeking and epigenetic adaptations in the brain of mice after chronic stress. Demonstrate effects of intra-nasal oxytocin administration on PTSD symptoms and substance use of dual-diagnosed veterans.
Keywords	animal studies, meth addiction, alcohol abuse, PTSD
Date concluded	6/30/2016
Treatment Type	Pharmacological: Oxytocin (intranasal) & Carbetocin
Target population	Rat Studies
IND	This study has an active IND

Concluded Proof of Principle Projects funded by ITN

 

 

Neuroprotection Against Alcohol Neurotoxicity and Traumatic Brain Injury in a Cerebellar Slice Model

 

Lay Abstract	The project aims to: 1)Obtain a preliminary assessment of the effectiveness of topiramate in reducing alcohol use and TBI symptoms in veterans with TBI and hazardous or harmful alcohol use; 2)Assess the safety/tolerability of topiramate in these patients; 3)Assess the feasibility of recruitment/retention for topiramate treatment; and 4)To inform the design of a planned subsequent larger controlled trial of topiramate.
Keywords	alcohol abuse, toprimate, mTBI, veterans, pharmacotherapy, co-occurring disorders, topiramate
Date concluded	10/31/2015
Treatment Type	Pharmacologic: Toprimate
Target Population	Veterans with TBI and AUD
IND	exempt

• Relations Between Cognitive Functioning and Alcohol Use, Craving, and Post-Traumatic Stress: An Examination Among Trauma-Exposed Military Veterans With Alcohol Use Disorder
• An examination of relations between cognitive functioning and alcohol use and craving among veterans with alcohol use disorder and trauma exposure
• Topiramate treatment of alcohol use disorder in veterans with posttraumatic stress disorder: a randomized controlled pilot trial
• Alcohol use disorder and PTSD severity in veterans with and without comorbid TBI: Baseline subject characteristics in topiramate treatment trials
• Toward personalized medicine in the pharmacotherapy of alcohol use disorder: targeting patient genes and patient goals

Lay Abstract	Study/ProductAims: •Employ HDID binge drinking mice to test novel compounds for efficacy to reduce drinking •Provide brain tissue from HDID mice to Texas to discover novel compounds for testing •Use PTSD-like assay to exacerbate binge drinking in HDID mice
Keywords	alcohol; binge drinking; posttraumatic stress disorder; genetics; pharmacotherapy
Date concluded	12/31/2013
Treatment Type	Pharmacological: tezaglitazer, fenofibrate
Target Population	Mouse Studies (HDID)
IND	n/a

• Selection for drinking in the dark alters brain gene coexpression networks
• Genetic influences on addiction
• Rodent models of genetic contributions to motivation to abuse alcohol
• Progress in a Replicated Selection for Elevated Blood Ethanol Concentrations in HDID Mice
• High drinking in the dark mice: a genetic model of drinking to intoxication
• Genotypic and sex differences in anxiety-like behavior and alcohol-induced anxiolysis in High Drinking in the Dark selected mice
• Rewarding and aversive effects of ethanol in High Drinking in the Dark selectively bred mice
• Behavioral Genetics of the Mouse

Lay Abstract	Determine whether tolcapone will preferentially reduce impulsivity in individuals with the val/val 158 genotype and produce commensurate changes in CNS circuits involved in intertemporal choice. Determine whether entacapone will preferentially reduce impulsivity in individuals with the val/val 158 genotype and produce commensurate changes in CNS circuits involved in intertemporal choice. Determine whether the effect of COMT inhibitors on impulsivity depends upon their ability to cross the blood brain barrier.
Keywords	tolcapone, impulsivity, COMT inhibitors
Date concluded	6/30/2016
Treatment Type	Pharmacological: tolcapone & entacapone (COMT inhibitors)
Target Population	Civilians
IND	not required

• Right inferior frontal cortex activity correlates with tolcapone responsivity in problem and pathological gamblers
• Dopamine, Locus of Control, and the Exploration Exploitation Tradeoff
• Dopamine, Corticostriatal Connectivity, and Intertemporal Choice
• Dopamine Modulates Egalitarian Behavior in Humans
• A neural correlate of strategic exploration at the onset of adolescence

Lay Abstract	The overall goal of this work is to combine genomic and behavioral approaches to repurpose approved medications that can provide new and effective treatments for combined binge drinking and PTSD
Keywords	alcohol; binge drinking; posttraumatic stress disorder; genetics; pharmacotherapy
Date concluded	12/31/2013
Treatment Type	Genetics studies looking for drug targets
Target Population	Mouse and rat studies
IND	n/a

• The INIA Texas Gene Expression Database (IT-GED): An online tool for alcohol genomics
• Epigenetic control of gene expression in the alcoholic brain
• Gene expression in brain and liver produced by three different regimens of alcohol consumption in mice: comparison with immune activation
• The role of transposable elements in health and diseases of the central nervous system
• Proteomic approaches and identification of novel therapeutic targets for alcoholism

Lay Abstract	Study/Product Aim(s): • Establish a proof-of-concept clinical trial protocol for measuring drug craving and relapse in Veterans with comorbid PTSD and substance use disorders (SUDs). • Determine the efficacy and safety of N-acetylcysteine in preventing relapse and reducing drug craving and PTSD symptoms among Veterans with comorbid PTSD and SUDs. This comorbidity is currently not effectively treated.
Keywords	PTSD. Glia, stress, plasticity, addiction, Prefrontal cortex, cocaine, N-actetylcysteine; glutamate
Date concluded	6/30/2014
Treatment Type	Pharmacological: NAC
Target population	Veterans (with PTSD/SUD)
IND	no IND required

• A Double-Blind Randomized Controlled Pilot Trial of N-Acetylcysteine in Veterans with PTSD and Substance Use Disorders

Lay Abstract	Study/Product Aim(s): • Identify causal biological mechanisms of PTSD using a novel gene x environment mouse model of stress vulnerability, and characterize the interaction between PTSD-like symptoms and nicotine/alcohol consumption • Identify SNPs associated with PTSD, or PTSD and comorbid substance use disorders, informed by our mouse model • Examine the epidemiology of substance abuse among men and women separately in a large military sample, informed by our mouse model
Keywords	PTSD, substance use disorders, male and female military personnel, animal models, causal molecular mechanisms, gateway sequence, nicotine, alcohol
Date concluded	9/30/2013
Treatment Type	n/a
Target population	n/a
IND	n/a

• Gender differences in the expression of PTSD symptoms among active duty military personnel
• Posttraumatic Stress Disorder, Substance Abuse, and Other Behavioral Health Indicators among Active Duty Military Men and Women

Lay Abstract	Aim 1. Will treatment with an AT1R antagonist or ACE inhibitor after a “traumatic event” prevent the expression of symptoms of PTSD? Aim 2. Will therapy with an AT1R blocker or ACE inhibitor reduce cocaine seeking in an animal model of comorbid PTSD and cocaine addiction? Aim 3: Will therapy with an AT1R blocker or ACE inhibitor reduce methamphetamine-seeking in an animal model of comorbid PTSD and methamphetamine addiction?
Keywords	PTSD, Cocaine, Substance Use Disorder, Animal Model, Addiction, Angiotensin, Captoril, Candesartan
Date concluded	8/31/2016
Treatment Type	Substance Abuse: Cocaine
Target population	Rat Studies
IND	n/a

• Conditioned stress prevents cue-primed cocaine reinstatement only in stress-responsive rats

Lay Abstract	Study/Product Aim(s): •To determine whether potentiation of extinction by an HDAC3 inhibitor in a rodent model of PTSD weakens the ability of cues associated with trauma to cause relapse of drug seeking. •To determine whether potentiation of extinction of drug seeking by an HDAC3 inhibitor protects extinguished drug seeking from reinstatement induced by cues associated with trauma.
Keywords	substance abuse, fear conditioning, HDAC3 inhibitor, RGFP966, extinction of fear
Date concluded	9/30/2014
Treatment Type	Pharmacologic: HDAC3 Inhibitor called RGFP966
Target population	Mouse and rat studies
IND	n/a

• G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 Knock-Out Mice Show Enhanced Ethanol Reward
• Chapter Three – Histone-Mediated Epigenetics in Addiction
• Substance abuse, memory, and post-traumatic stress disorder
• Acute ethanol withdrawal impairs contextual learning and enhances cued learning
• Epigenetics and memory: causes, consequences and treatments for post-traumatic stress disorder and addiction
• Opposing effects of D-cycloserine on fear despite a common extinction duration: interactions between brain regions and behavior
• Delay and trace fear conditioning in C57BL/6 and DBA/2 mice: issues of measurement and performance
• Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

Lay Abstract	Study/Product Aim(s): • Establish a preclinical model of PTSD vulnerability to methamphetamine (METH) self administration and seeking. • Demonstrate effects of oxytocin and carbetocin on reinstatement of meth seeking after chronic stress. • Examine neurobiological and epigenetic adaptations in the brains of METH seeking rats pre-exposed to chronic stress and treated with oxytocin or carbetocin.
Keywords	Treatment Development
Date concluded	12/31/2013
Treatment Type	Pharmacological: oxytocin
Target population	PTSD model Rats studies
IND	n/a

• Effects of oxytocin on methamphetamine-seeking exacerbated by predator odor pre-exposure in rats

Lay Abstract	Study/Product Aim(s): Determine the effects of oxytocin treatment on alcohol consumption in mice using a binge model of drinking. Determine the effects of oxytocin treatment on alcohol responding, consumption, and relapse behavior in mice.
Keywords	oxytocin, binge-like alcohol drinking, mouse models, relapse
Date concluded	8/31/2015
Treatment Type	Pharmacological: Oxytocin
Target population	Mouse Studies
IND	n/a

• Oxytocin Reduces Ethanol Self-Administration in Mice

Lay Abstract	Study/Product Aims ; 1. Determine if drugs that inhibit N-type calcium channels reduce PTSD-like behavior in rats. 2. Determine if inhibitors of N-type calcium channels reduce operant ethanol self-administration and stress-induced reinstatement of ethanol seeking.
Keywords	PTSD, alcohol abuse, rat studies, lomerizine, Z160, N-type Calcium channel blockers
Date concluded	6/30/2013
Treatment Type	Pharmacological: Lomerizine & Z160
Target population	Rat studies
IND	n/a

Lay Abstract	Hypothesis: We hypothesize that zonisamide will be more effective than placebo when used in combination of E-CPT-C in 1.) reducing heavy drinking days measured by the Timeline Follow-back Method (TLFB) 2.) reducing drinks per week as measured by the Timeline Follow-back Method (TLFB), 3.) reducing craving for alcohol using the Obsessive Compulsive Drinking Scale (OCDS).
Keywords	treatment, pharmacotherapy, alcohol dependence, PTSD, zonisamide, cognitive processing therapy, alcohol use disorders
Date concluded	6/30/2015
Treatment Type	Pharmacologic and Cognitive Processing Therapy Combo: Zonisamide
Target population	Veterans with PTSD and AUD
IND	exempt

Lay Abstract	Study Aim: • Confirm our hypothesis stating that HSP90 is a focal shared contributor to mechanisms underlying alcohol abuse and stress • Test pharmacotherapies at the preclinical level to decrease stress-induced
Keywords	alcohol abuse, alcohol relapse, HSP90 inhibitor, NVP-AUY922
Date concluded	6/30/2014
Treatment Type	Pharmacologic: HSP90 inhibitor
Target population	Rat studies
IND	n/a

Lay Abstract	Study/Product Aim(s) Task #1: To characterize post-stress and post-ethanol adverse ethanol use in the rat vis-à-vis compulsiveness and relapse. Task #2: To relate overactivation markers in CRF-CRF1 or dynorphin-KOR brain stress system to poor ethanol use outcomes Task #3: To inhibit CRF-CRF1 or dynorphin-KOR stress systems to reverse poor post-stress ethanol use outcomes.
Keywords	PTSD, relapse, coticotropin-releasing factor, kappa opioid receptor, alcholism, ethanol reinforcement, dynophin, self-administration behavior
Date concluded	10/24/2014
Treatment Type	Pharmacological: inhibition of the CRF-CRF1 or dynorphi-KOR stress systems (pexacerfont or CYM-50202)
Target population	Rat studies
IND	n/a

Current Extend and Confirm Projects funded by the ITN

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Glial Regulators for Treating Comorbid Posttraumatic Stress Disorder and Substance Use Disorders

Principal Investigator(s): Sudie Back, Ph.D.

Medical University of South Carolina

Lay Abstract	In the proposed EC study, we will (1) employ a randomized, double-blind, between-groups experimental design that will consist of 8 weeks of treatment with NAC (2400mg) or placebo medication; (2) use standardized, repeated dependent measures to rigorously assess AUD severity and PTSD symptomatology during treatment and follow-up; (3) collect biologic measures of alcohol use; (4) measure impairment in associated areas of functioning (e.g., depression, sleep, suicidality, family/social functioning); and (5) employ advanced neuroimaging techniques before and after treatment. This proposal is directly responsive to the mission of the Institute for Translational Neuroscience (ITN) and the U.S. Army/Department of Defense in that it seeks to accelerate the development of new, medication-based treatments to mitigate the impact of AUD and comorbid psychological conditions, such as PTSD, in the military/Veteran context.
Keywords	PTSD, addiction, stress, glutamate, alcohol, substance abuse, Glia, N-acetylcysteine (NAC)
Recruiting	Yes, check here
Treatment Type	Pharmacological: N-acetylcysteine
Target Population	Veterans
IND	this study has an active IND

Development of an animal model and novel treatments for comorbid PTSD and cocaine addiction

Principal Investigator(s): Lori A. Knackstedt, Ph.D.

University of Florida

Lay Abstract	The present proposal is aimed at developing an animal model of comorbid PTSD and cocaine addiction/relapse for the screening of highly translational compounds to reduce PTSD symptoms and the motivation to seek cocaine. Our overarching hypothesis is that the inhibition of the renin-angiotensin system will ameliorate the symptoms of PTSD and will be successful in attenuating cocaine-seeking in animals exposed to traumatic stress. We have chosen to test the ability of the angiotensin-1 receptor antagonist, candesartan, and the angiotensin converting enzyme (ACE) inhibitor, captopril, to reduce symptoms of PTSD and potentially reduce cocaine self-administration in this rat model.
Keywords	cocaine addiction/relapse, PTSD, Candesartan, Captopril, Ceftriaxone, Glutamate, Endocannabiniods
Recruiting	n/a
Treatment Type	Pharmacological: Candesartan & Captopril
Target Population	Rat Studies
IND	n/a

Epigenetic modulation of interactions between fear and substance abuse

Principal Investigator(s): Kennon M. Lattal, Ph.D.

Oregon Health & Science University

Lay Abstract	We found that a single traumatic event caused persistent effects on methamphetamine and alcohol self- administration that often persisted over 30 days after trauma. During our support from the ITN, we also found that a novel HDAC3 inhibitor (RGFP966) promotes extinction of drug-seeking in a rodent self-administration model, as well as extinction of fear. In this extend-and-confirm application, we bring these two findings together and ask how selective inhibition of HDAC3 may promote extinction and weaken relapse after a traumatic event. This is a novel behavioral model coupled with a novel pharmacological approach. Further, we will investigate the molecular consequences of trauma and relapse, and how they may be altered by HDAC3 inhibition during extinction. These proposed experiments have tremendous clinical promise, as RGFP966 is already in Phase 1 clinical trials for treating Friedreich’s ataxia and we have strong preliminary data showing its effects on fear and drug seeking.
Keywords	substance abuse disorder, memory, epigenetics, methamphetamine, PTSD, extinction, histone acetylation, alcohol
Recruiting	n/a
Treatment Type	Pharmacological: RGFP966
Target Population	Rat Studies
IND	n/a

• Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom

• Effects of D1 receptor knockout on fear and reward learning

Current Proof of Principle Projects funded by ITN

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N-acetylcysteine Treatment of Hazardous or Harmful Alcohol Use in Veterans with TBI

Principal Investigator(s): Steven L. Batki, M.D.

Northern California Institute for Research and Education

Lay Abstract	The overall goal of the proposed project is to improve the care of veterans with mild traumatic brain injury (mTBI) and unhealthy alcohol use. We propose to conduct a pilot controlled clinical trial to assess the efficacy of Nacetylcysteine (NAC) to reduce alcohol use and improve brain injury symptoms in veterans with mTBI who consume alcohol at hazardous or harmful levels. This proposed project builds upon our current IMN‐funded research on topiramate pharmacotherapy for heavy alcohol use in veterans with mTBI.
Keywords	alcohol abuse, TBI, N-acetylcysteine
Recruiting	pending
Treatment Type	Pharmacological: N-acetylcysteine
Target Population	Veterans
IND	this study has an active IND

Use of kappa opioid receptor antagonists to prevent opiate abuse after use of prescription opioid painkillers

Principal Investigator(s): Elena Chartoff, Ph.D.

McLean Hospital

Lay Abstract	determine if the orally available KOR antagonist JDTic administered to rats during morphine withdrawal blocks withdrawal-induced negative affective states and likelihood to engage in oxycodone IV self-administration.
Keywords	n/a
Recruiting	n/a
Treatment Type	Pharmacological: kappa opiod antagonists
Target Population	Rat Studies
IND	n/a

Oxytocin Supresses SUD Associated with Chronic Stress

Principal Investigator(s): Jennifer Mitchell, Ph.D.

University of California, San Francisco

Lay Abstract	Determine whether IN OT will decrease craving to use ETOH and stress reactivity following exposure to lab-induced stress among ADSMs with a dual-diagnosis of AUD & PTSD
Keywords	Alcohol Use Disorder, AUD, PTSD, oxytocin, military
Recruiting	Yes, check here
Treatment Type	Pharmacological: Oxytocin (intranasal)
Target Population	Fort Gordon EAMC In-patient active duty
IND	This study has an active IND

Effects of Tolcapone on Decision Making and ETOH intake using a laboratory bar in moderate/heavy social drinking

Principal Investigator(s): Jennifer Mitchell, Ph.D.

University of California, San Francisco

Lay Abstract	An experimental bar is a behavioral technique that can be used to pre-screen new treatment strategies for alcoholism in a rapid and inexpensive manner. It is a well-established tool to mimic a social bar setting in a clinical facility in order to study the decision making skills surrounding alcohol consumption. As we have already demonstrated effects of tolcapone on decision making in both healthy controls and abstinent alcoholics, this experiment will allow us to ascertain its effects on active alcohol consumption and real-time decision making for alcohol versus monetary rewards.
Keywords	Dopamine, Tolcapone, Alcohol Use Disorder, AUD, decision-making
Recruiting	Data analysis only
Treatment Type	Pharmacological: Tolcapone
Target Population	Human
IND	This study has an active IND

The effects of oxytocin on social ability, alcohol approach bias, and startle hyperreactivity in veterans with alcohol use disorder and post traumatic stress disorder.

Principal Investigator(s): Josh Woolley, M.D., Ph.D.

Northern California Institute for Research and Education

Lay Abstract	We propose to investigate the effects of oxytocin on alcohol‐related behaviors, social abilities, and physiological startle responses in patients with PTSD & AUD using a randomized, placebo‐controlled, dose‐tiered, within‐subject study design. Specifically, we will determine if intranasal administration of a single dose of the pro‐social neuropeptide oxytocin decreases alcohol‐related approach bias and cravings, enhances social abilities, and decreases physiological hyperactivity during a fear‐potentiated startle paradigm. We will also determine the optimal dose to achieve these effects and will explore psychosocial predictors of responses to oxytocin. If successful, we will extend the proposed work with a longitudinal clinical trial of chronic oxytocin administration in patients with AUD and PTSD. The proposed work has the potential to yield a novel harmacological treatment for AUD and PTSD, both leading causes of disability in the US Military for which currently available treatments are inadequate.
Keywords	alcohol abuse, oxytocin
Recruiting	n/a
Treatment Type	Pharmacological: Oxytocin (intranasal)
Target Population	San Francisco VAMC
IND	this study has an active IND

• American Alcohol Photo Stimuli (AAPS): A standardized set of alcohol and matched non-alcohol images

Sept.15.16 ASUD_MOMR_Project list_ITN.xlsx