Research Projects - Concluded
Concluded Extend and Confirm Projects funded by the ITN
Translational Mouse Models of PTSD and Comorbid Substance Use
Principal Investigator(s): Eric R. Kandel, M.D.
| 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 |
Oxytocin Suppresses Substance Use Disorders Associated with Chronic Stress
Principal Investigator(s): Jacqueline F. McGinty, Ph.D.
| 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
Restoration of glial glutamate transport to prevent posttraumatic stress and vulnerability to alcohol and marijuana use and relapse
Principal Investigator(s): Peter W. Kalivas, Ph.D.
| Lay Abstract | Although we used NAC in a pilot study with success in treating Veterans with comorbid PTSD/SUDs, it is unknown if using NAC either prophylactically, or immediately after a stressful experience can prevent vulnerability to developing PTSD or comorbid PTSD/SUDs. We propose preclinical validation for the use of NAC prophylactically or immediately post-‐combat stress to reduce the neurological sequelae that establishes PTSD and PTSD/SUDs comorbidity. 1) We have expanded the validity of the animal model by associating an odor with the immobilization stress, and we use exposure to the odor to provoke relapse (reinstated lever pressing) in animals trained to self-administer drug. 2) We will treat rats with N-‐acetylcysteine either during or immediately after exposure to immobilization stress, and determine if this prevents stress-‐induced augmented acquisition of drug self-‐administration and the capacity of the stress-‐ associated odor to reinstate drug seeking. Simultaneously, we will validate that NAC has normalized EAAT2 levels, a key neurological action of NAC’s protective effects. 3) We recently developed an animal model of rat i.v. self-‐administration and reinstatement of the key constituents of marijuana, Δ9-‐ tetrahydrocannabinol and cannabidiol. Marijuana abuse is a substantially larger problem in Veterans with comorbid PTSD and SUDs than cocaine abuse, making use of this model for the determining the biological basis of PTSD/SUDs comorbidity more clinically relevant. |
| Keywords | PTSD, SUDs, Marijuana Abuse, Stress, Prevention, Glutamate transport, N-acetylcysteine |
| Recruiting | n/a |
| Treatment Type | NAC |
| Target Population | Rat Studies |
| IND | n/a |
Neuroprotection Against Alcohol Neurotoxicity and Traumatic Brain Injury in a Cerebellar Slice Model
Principal Investigator(s): Michael E. Charness, M.D.
| Lay Abstract | Task #1: To establish a model of focal mechanical injury to cultured cerebellar slices from young adult mice. Task #2: To determine whether ethanol potentiates the effects of TBI. Task #3: To determine whether NAP protects against the effects of TBI, ethanol exposure, or both. |
| Keywords | alcohol abuse, TBI, NAP, mouse studies |
| Recruiting | n/a |
| Treatment Type | Pharmacological: NAPVSIPQ (NAP) |
| Target Population | Mouse Studies |
| IND | n/a |
Topiramate Treatment of Hazardous and Harmful Alcohol Use in Veterans with TBI
Principal Investigator(s): Steven L. Batki, M.D.
| 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 |
Animal models of binge drinking and PTSD: novel therapeutic targets and pharmacological interventions from gene expression profiles
Principal Investigator(s): John C. Crabbe, Ph.D.
| 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 |
Catechol-O-Methyltransferase, Impulsivity and Substance Abuse Treatment
Principal Investigator(s): Howard L. Fields, M.D., Ph.D. and Andrew Kayser, M.D., Ph.D.
| 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 |
Animal models of binge drinking and PTSD: novel therapeutic targets and pharmacological interventions from gene expression profiles
Principal Investigator(s): R. Adron Harris, Ph.D.
| 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 |
Glial regulators for treating comorbid post-traumatic stress disorder (injury) and substance abuse disorders
Principal Investigator(s): Peter W. Kalivas, Ph.D.
| 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 translational epidemiological approach to the molecular basis of PTSD and substance abuse comorbidity
Principal Investigator(s): Eric R. Kandel, M.D.
| 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 |
Development of an animal model & novel treatments for comorbid PTSD and cocaine addiction
Principal Investigator(s): Lori A. Knackstedt, Ph.D.
| 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 |
Epigenetic modulation of interactions between fear and substance abuse
Principal Investigator(s): Kennon M. Lattal, Ph.D.
| 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 |
Endogenous Modulators Suppress Substance Abuse Disorders Associated with Chronic Stress
Principal Investigator(s): Jacqueline F. McGinty, Ph.D.
| 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 |
Oxytocin Suppresses Alcohol Drinking and Relapse in Mice
Principal Investigator(s): Jacqueline F. McGinty, Ph.D.
| 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 |
N-Type Calcium Channel Blockers for PTSD and Alcohol Use Disorders
Principal Investigator(s): Robert O. Messing, M.D.
| 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 |
Zonisamide and CPT for veterans with PTSD and comorbid alcohol dependence
Principal Investigator(s): Ismene L. Petrakis, M.D.
| 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 |
Heat Shock Protein 90 at the Intersection of Alcohol Abuse and Stress – Preclinical Studies
Principal Investigator(s): Dorit Ron, Ph.D.
| 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 |
Role of extended amygdala corticotropin-releasing factor and dynorphin brain systems in post-trauma ethanol use disorders
Principal Investigator(s): Eric P. Zorrilla, Ph.D.
| 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
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.
| 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
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.
| 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 |
Sept.15.16 ASUD_MOMR_Project list_ITN.xlsx