Carolina Haass-Koffler - US grants

? DESCRIPTION (provided by applicant): This Mentored Research Scientist Development application (K01) will provide Dr. Haass-Koffler with the skills and protected time to: 1) develop a program of research investigating how stress facilitates the use of alcohol; and 2) develop and test medications that target the stress reaction in alcohol-dependent individuals. Her main objective is to obtain intensive mentoring that will help her to become a strong independent translational and clinical researcher of pharmacological interventions centered on stress reduction in alcoholism. This K01 will support her goals to gain the mentorship, knowledge and experience required to conduct rigorous clinical research including: (1) gain expertise in pharmacotherapy interventions to prevent stress-induced consumption in alcohol-dependent individuals; (2) gain knowledge in human alcohol laboratory research to complement her neuroscience expertise; (3) gain experience on how to evaluate the stress-neuroendocrine pathway to integrate neuronal and hypothalamic-pituitary-adrenal axis (HPA) data; and (4) learn to perform repeated measures analyses. With this K01, Dr. Haass-Koffler's training will assist her in initiating future alcohol research by gaining a better understanding of: (5) evaluating psychological stress-induction methodologies to assess emotional outcomes; (6) assessing the contribution of genetic vulnerability in the development of Alcohol Use Disorder (AUD); and (7) establishing translational communication between neuroscience and human laboratory studies to inspire new avenues and development of new hypotheses in alcohol and stress research. The career development plan includes structured meetings with mentors and collaborators; graduate level courses and seminars in statistics and psychology; visits to collaborators in their laboratories (NIH, Yale and Providence VA Medical Center); attending Web-based workshop to develop advanced training in Pharmacokinetics/Pharmacodynamics (PK/PD) modeling; attending conferences to interact with the alcohol research communities. The training program is focused on the completion of a pilot laboratory study consisting of a randomized, placebo-controlled trial to assess the effects of mifepristone (a glucocorticoid-receptor antagonist investigated as a potential therapeutic agent of alcohol dependence) in a stress-induced condition triggered by yohimbine (an a-2 adrenoceptor antagonist known to induce reinstatement of ethanol-seeking behaviors) paired to a series of alcohol laboratory sessions.

ABSTRACT While the role of stress in alcohol use disorder (AUD) is well established, none of the current FDA-approved medications in the U.S target the stress system. One potential pharmacological target for the stress component of AUD is norepinephrine. The goal of this application is to replicate findings previously conducted in a pilot trial and to understand, mechanistically, the role of stress in the development of AUD pharmacotherapies that target noradrenergic blockade. To achieve these goals, this study proposes a 12 week, between-subject, double-blind, randomized clinical trial (RCT) with doxazosin (16 mg, or maximum tolerated dose, MTD) compared to placebo in 184 treatment seeking individuals with AUD. We will: (1) examine alcohol drinking and clinical outcomes at baseline, throughout treatment, and at posttreatment; (2) conduct a stress-induced alcohol cue-reactivity in a bar- laboratory; and (3) test moderators of doxazosin response to inform a personalized treatment approach. There are three aims in this research plan. In Aim 1, we will test if doxazosin decreases alcohol consumption (primary outcome) and alcohol craving (secondary outcome) in naturalistic conditions throughout the study. Then in Aim 2, in the bar laboratory, we will measure acute craving after a single oral dose of 32.4 mg yohimbine (to initiate the neuroendocrine process associated with stress induction and to enhance exposure therapy), combined with an alcohol cue reactivity protocol (to selectively target alcohol cues). Finally, in the exploratory aims, to further shed light on potential personalized medicine approaches with noradrenergic pharmacotherapies for AUD, we will test the hypotheses that baseline family history density of alcoholism, blood pressure and rs1611115 polymorphism moderate doxazosin's effect on alcohol consumption in individuals with AUD.

PROJECT SUMMARY Although stress has long been linked to substance use, craving and relapse, there are no available medications that target stress-induced substance use disorder (SUD). In particular, with the rise in opioid use, there is still a crucial need for developing effective pharmacological treatments that target and integrate the complexity of this disease. The long term goal of this project is to identify the key neuroendocrine pathways that are responsible for stress-induced craving in individuals with opioid use disorder (OUD) in order to better understand how they can be effectively treated. To achieve this goal, we will utilize oxytocin, as a putative pharmacological intervention, because: 1) oxytocin's neuroanatomical-neuroendocrine pathways are shared with stress hormones; 2) oxytocin modulates dopaminergic transmission, lowers stress response and mitigates drug seeking-behaviors; and 3) an increasing number of studies suggest that the oxytocin neural circuits closely interact with the endogenous opioid system. One of the most challenging aspects in designing a human laboratory study is the inclusion of an acute stress condition that represents a comprehensive naturalistic environment for OUD individuals. Hence, testing pharmacotherapies in stress-induced opioid use models in laboratory paradigms is critical for the identification and development of therapeutic interventions to prevent drug use. Pharmacological challenges such as yohimbine, an ?-2 adrenoceptor antagonist, have been shown to activate central stress response in addition to increasing sympathetic nervous system activity, facilitating recall of traumatic memories and increasing heroin craving in opioid-dependent patients. Thus, for this proposal we will integrate oxytocin (pharmacological therapy), with a cue-reactivity paradigm (specific for opioid cues) and yohimbine (neuroendocrine stress activation) in patients receiving opioid replacement therapy (ORT) with buprenorphine/naloxone. The central hypothesis of this proposal is that stress-induced opioid craving will diminish in patients administering oxytocin in addition to ORT. We will use behavioral and neuropsychopharmacological approaches to test our central hypothesis in three Specific Aims. Aim 1: to assess the effects of oxytocin on cue-induced opioid craving after yohimbine stress-induced in patients with OUD. Aim 2: to assess whether baseline levels of stress and anxiety moderate the effects of oxytocin on cue-induced opioid craving after yohimbine-matched placebo administration in patients with OUD. Aim 3: to assess the safety and tolerability of oxytocin and yohimbine in stressed and anxious OUD patients receiving buprenorphine/naloxone. In these aims, targeted pharmacological manipulation of stress and oxytocin will be employed to examine the extent to which stress-induced craving can be reversed. The proposed research is significant because, using pharmacological probes, it will provide a much needed insight into the fundamental neurobiological mechanisms underlying stress-induced opioid craving with the goal to improve therapeutic outcomes for this population.

PROJECT SUMMARY Testing pharmacotherapies in controlled human alcohol laboratory paradigms is critical for the identification and development of therapeutic interventions to prevent alcohol use disorder (AUD). Thus, for this proposal, an alcohol administration procedure will be adopted in non-treatment-seeking individuals with AUD to establish the safety and tolerability of probenecid as a novel pharmacotherapy. This is a developmental/exploratory clinical trial that aims to test the hypothesis that proposes a potential relationship between the pannexin 1 channel and alcohol. The goal of this proposal is to evaluate the safety and tolerability of potential new therapeutic targets for the treatment of AUD. The premise prompting this human laboratory study is based on the direct evidence from our preliminary work with probenecid in a preclinical model of AUD. This work demonstrated that probenecid is able to reduce alcohol consumption in alcohol-dependent rats. The scientific rationale for testing probenecid in AUD was derived by the well-known mechanism of action of probenecid as a pannexin 1 channel inhibitor, its role in alcohol-induced extracellular adenosine release, and that this process is promoted by a history of exposure to excessive alcohol. In a controlled human alcohol laboratory setting, we will use behavioral and neuropsychopharmacological approaches to establish the safety and tolerability of probenecid administered with alcohol (Aim 1). In our secondary aims, we will test the hypotheses that treatment with probenecid will diminish alcohol's stimulant effect (Aim 2) and alcohol tolerance (Aim 3). In these aims, targeted pharmacological manipulation of probenecid with alcohol will be employed to evaluate the safety and tolerability of probenecid when administered with alcohol. We included craving and subjective preference measures as exploratory aims to inform a future larger trial. The proposed research is significant because, using pharmacological probes, it will provide a much-needed insight into the fundamental neurobiological mechanisms underlying alcohol biobehavioral effects with the goal of improving the therapeutic outcomes for individuals with AUD.