Edythe D. London - US grants

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DESCRIPTION (provided by applicant): Methamphetamine (MA) abusers have cognitive deficits that may interfere with treatment and sustain drug use. We aim to delineate abnormalities in brain circuits that underlie these cognitive deficits by using functional magnetic resonance imaging (fMRI) to compare the anatomical substrates mediating cognitive control in MA abusers and demographically matched control subjects. We will pair tests of selective attention and working memory with fMRI, using signal intensity changes to index hemodynamic changes coupled with functional activity. Testing will be done at 4-7 da and 4-5 wk of abstinence, including the times when MA abusers are most likely to seek treatment. The Stroop and N-Back tasks will be used for cognitive activation. With data from a cognitive battery, thej'MRI findings will help define the cognitive resources available to abstinent MA abusers. Such knowledge can inform the design and implementation of appropriate treatments. From prior data, we predict that: the Stroop Task will activate anterior cingulate (ACC), dorsolateral prefrontal (DLPFC) and frontal polar cortices; the Stroop effect will relate positively to change in signal intensity; MA abusers will show less activation and react more slowly than controls; activation patterns will differ between groups. As Stroop performance improves in abstinent MA abusers (B.2.2.5), we expect a reduced Stroop effect to accompany greater activation in ACC and other areas at 1 mo than 1 wk abstinence. Based on prior work (B.3.2), we predict that: the N-Back Task will activate DLPFC and parietal cortex; activation will increase non-linearly with cognitive load. As prior work indicates that MA abusers have impaired working memory, and our data (Table 4) suggest that they have performance deficits, we expect: that MA abusers will show less signal change with poorer performance vs. controls; and activation pattern will differ between groups. Recent work shows differences in working memory performance between groups at the start of abstinence, but no difference when MA abusers were abstinent for 3-mo (SL Simon unpublished). We therefore expect that abstinence will improve N-Back Task performance, increasingjMRI signal change and altering the activation pattern. We expect that changes in activation pattern with abstinence will normalize functional relationships (or strengthen new routes of activation).

DESCRIPTION (provided by applicant): Methamphetamine (MA) dependence is associated with deficits in markers of fronto-striatal function. Current data suggest that a variety of behavioral impairments, including diminished capacity for response inhibition accompany this frontostriatal dysfunction. Deficits in response inhibition may compromise treatment outcomes, and contribute to the unusually rapid progression of addiction to MA. Knowledge of the circuitry that mediates response inhibition and its impairment in MA-dependent individuals may help guide the development of innovative therapeutic approaches. We will use the Stop-Signal and the Probabilistic Reversal Learning Tasks to measure response inhibition, and will assess functional and structural integrity of cortical and striatal brain regions thought to mediate performance on these tasks. We will pair functional magnetic resonance imaging (fMRI) with these tests of inhibitory control, indirectly assessing neural activity from the change in magnetic resonance signal: Control and MA-dependent (7-15 days abstinent) research subjects will be tested after administration of placebo and of 200 mg modafinil (counterbalanced). Modafinil improves response inhibition in healthy subjects and those with ADHD, and a clinical trial has indicated that modafinil may reduce cocaine self- administration by dependent subjects. Structural MRI will be used to address hypotheses regarding gray matter volume in cortical (e.g., inferior frontal gyrus, orbitofrontal cortex) and striatal regions. Our study aims to help define the cognitive resources available to MA-dependent clients entering treatment, and to clarify the neural bases for deficits in response inhibition. We expect that performance measures of response inhibition will be associated with activity in the inferior frontal cortex, ventral striatum, and orbitofrontal cortex in both groups, with MA users having poorer performance and less task-related activity in these regions than the controls, and that modafinil will improve performance with corresponding effects on signal change in frontostriatal regions. We also predict that MA abusers will exhibit deficits in gray matter volumes of the inferior frontal gyrus, orbitofrontal cortex, and in the striatum, and that these deficits will be inversely related to performance on tests of inhibitory control and associated brain activity assessed with fMRI.

The proposed Center will incorporate administrative and scientific support functions in a single Core, referred to as the Administrative and Integration Core (A&l Core). Functioning within the larger institutional environment of UCLA, including the affiliated UCLA Integrated Substance Abuse Programs (ISAP), the Center will build on a proven framework that has improved efficiency and communication among investigators involved in the proposed Center and in other UCLA centers. The organization ensures that the Center will work formally to merge scientific disciplines and associated personnel in a coherent blending that will produce a translational research program yielding substantially more than the sum of its components. A&l Core will work toward the following specific aims: [unreadable][unreadable] Provide an efficient infrastructure to support the four primary research projects of the Center and a limited program of pilot projects, including administrative, research, and clinical services; [unreadable][unreadable] Facilitate communication and cooperation among Center investigators and provide opportunities for interaction with other scientists on Center activities; [unreadable][unreadable] Provide for central planning and coordination of Center activities within the larger context of other research activities and programs at UCLA and in the community to support a Research Career Development and Training Program to identify, recruit, and provide training and mentoring to new investigators who will do translational research on the neurobiology of drug addiction; [unreadable][unreadable] Promote dissemination of Center research products and methodological developments, ensuring the Center's identity and function as a national resource that can transition to a P50 Center. The A&l Core will have four components: 1) the Administrative Unit, including Dr. E. London (Center and Core Director), Dr. R. Bilder (Director of Research Career Development and Training) and M. Walker (Administrative Coordinator);the Medical Services and Human Subjects Unit, directed by Dr. T. Newton (Acting Center Director and Core Director in Dr. London's absence) and including Dr. T. Fong (Staff Physician) and C. Hurley (Recruiter);the Research Career Developmetn and Training Unit, directed by Dr. R. Bilder and including Dr.s C. Evans, E. London, J. Licinio, T. Newton, and R De La Garza;and the Biostatistics, Data Analysis and Data Management Unit, directed by Dr. J. Mintz, and including Dr. R. Poldrack (Functional Imaging Director), R. Nandy (Statistician), and S. Shih (Programmer/Systems Analyst). The Core is essential to the operation of the Center[unreadable][unreadable]it brings together the external and internal academic resources with the day-to-day functions needed to accomplish Center objectives. It is the Core that provides the foundation for the synergistic preparation of the next round of work, extending the early phase work of the P20 Center to form a mature Center. This program addresses a major public health problem - methampehtamine abuse, an underserved and understudied problem. It wroks to provide knowledge to advance development of therapeutic intervetions and to train investigators who will be equipped to address this public health problem.

[unreadable] DESCRIPTION (provided by applicant): Despite advances in the scientific understanding of drug abuse and dependence, effective treatments are lacking, and new therapies for these disorders are urgently needed. The proposed P20- funded Developmental Center for Translational Research on Addictions will address this need by integrating preclinical studies to directly inform clinical research on drug addiction, and complementarily, leveraging clinical insights to help target basic science approaches. The proposed Center links basic scientists who have made significant contributions to knowledge of the neurobiological components of addiction with clinical investigators who are at the forefront in treatment research. The theme of the developmental center will be impaired inhibitory control as a therapeutic target for methamphetamine (MA) dependence. We made this choice because of: a) the magnitude of the MA abuse problem worldwide; b) the severity of its consequences; c) the lack of an effective treatment for MA dependence; d) the importance of impaired inhibitory control to drug addiction; and e) our leadership in advancing the understanding and treatment of MA abuse. With this initial focus, we propose four interrelated projects to characterize impairments in response inhibition consequent to methamphetamine (MA) exposure at behavioral, neural systems, and neurochemical levels in both human and animal models, and to assess the pharmacological modulation of these deficits. The four research projects in this P20 Center aim: 1) to delineate the neural circuitry underlying deficits in inhibitory control in MA-dependent human subjects; 2) to relate deficits in inhibitory control to drug-taking behavior using a human laboratory model of MA self administration; 3) to establish and characterize (behaviorally and neurochemically) a non-human primate model for investigating inhibitory control deficits characteristic of MA abuse; and 4) to characterize regional brain neurochemical effects of pharmacological manipulations aimed at modulating response inhibition in a rodent model for MA dependence. The four projects are integrated in a way that would not be feasible if each project had been designed to be a discrete study, outside the Center environment. The Center will support these scientific projects with the over-arching goals of creating an environment for interdisciplinary translational research, whereby the flow of information from basic research in animal models and human laboratory studies can be rapidly applied to development of treatments for drug abuse, and developing a program of research career development that will coordinate and enhance existing training programs, providing multiple, excellent opportunities for pre- and postdoctoral fellows and faculty to initiate new projects focusing on translational approaches to studies of the neurobiology of drug abuse. [unreadable] [unreadable] [unreadable]

Attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BP) are neuropsychiatric disorders that can have deleterious lifetime impact. Several candidate genes for these disorders have emerged, but functionally significant variants have not yet been identified and replications are sparse. Our premise is that elucidating the genetic basis of these complex disorders will benefit from analysis of more parsimonious and less heterogeneous endophenotypes. Impaired response inhibition (Rl) (i.e., difficulty suppressing automatic or already initiated responses) is a promising candidate endophenotype for multiple disorders. We propose that the genes that influence Rl contribute to ADHD and BP susceptibility through effects on the brain systems mediating inhibitory control, and that most of these have been undetected by previous studies using syndromal status as the phenotypic target. Therefore, we plan a study on the biological bases of impaired Rl, in a large sample (n=2000) of healthy subjects drawn from greater Los Angeles. We will administer a battery of Rl and impulsivity-spectrum neurocognitive and self-report measures, analyzing the phenotypes and identifying composite measures through data reduction efforts, including those of the WGS project in this consortium. We will first identify candidate SNPs in a whole genome association study of the entire sample, and conduct fine mapping analyses to refine the localization of the most significant associations. We will then select well-validated candidate SNPs to genotype in clinical samples that exhibit Rl deficits (n =100 each, ADHD & BP) and 200 matched controls, and test for associations with brain structure and function using MRI. Although there are no validated candidate genes pf moderate to large effect in humans for either Rl phenotypes or the diseases for which they are relevant, substantial evidence indicates that dopamine systems, and D2 dopamine receptors in particular, are important for expression of Rl. However, the specific neural systems that mediate D2-dependent modulation of Rl are unknown. We will therefore use a bacterial artificial chromosome (BAG) rescue strategy to evaluate the role of D2 dopamine receptors (via Drd2 gene expression) within components of corticostriatal circuitry that mediates Rl in mice. Importantly, these studies do not examine the role for DrD2 as a candidate gene for ADHD or BP, rather, we propose that O2-mediated neuromodulation of corticostriatal circuitry is a candidate mechanism by which genes (still undiscovered) converge to elicit their effects on Rl. Rl deficits are central to ADHD, BP and other disorders (e.g., drug addiction, obesity) that are of public health concern and are resistant to current therapies. Clarifying the bases of Rl, at genetic and neural systems levels, can advance treatment for these prevalent and often life-threatening disorders.

DESCRIPTION (provided by applicant): This proposal is for an initial 5-year period of support to establish a pre- and postdoctoral training program on the Translational Neuroscience of Drug Addiction (TNDA) in the UCLA Semel Institute for Neuroscience and Human Behavior, with positions for four predoctoral (Yr 1-5), and two postdoctoral (Yr 3-5) fellows. The Program Director will be Dr. Edythe London, the Curriculum Director and Associate Program Director, Dr R. De La Garza; and 33 training faculty, have been selected for their research expertise and past mentorship success. TNDA will provide trainees with an integrative knowledge base needed to plan and conduct bidirectional translational studies. The component UCLA research units are: 1) the Center for Translational Research on the Clinical Neurobiology of Drug Addiction, 2) the Center for the Study of Opioid Receptors and Drugs of Abuse, 3) the Program Project on GABA, and 4) the Stimulant Abuse and Addiction Research Group. TNDA will have five aims: to recruit and enroll highly qualified candidates who are interested in and committed to translational research in drug addiction (vigorously trying to recruit from underrepresented populations); to provide hands-on experience at all stages of drug abuse research, including evidenced based hypothesis formation, experimental design, data acquisition and analyses, and preparing findings for oral and written presentation; to offer opportunities to develop expertise in a specific research area, while ensuring that each trainee also acquires the breadth of knowledge needed to conduct translational research in drug addiction; to provide the resources, opportunities, and training that will enable trainees to use preliminary data in generating novel hypotheses and specific aims for NIH grant proposals, thus laying the groundwork for success in securing funding to pursue independent research; and to provide career guidance, via shared mentorship teams so that trainees can successfully identify and secure professional positions where they can use the skills and knowledge obtained from TNDA. To achieve these goals, TNDA will provide comprehensive interdisciplinary training through formal education and supervised research. Methodological issues and techniques in drug abuse research will be emphasized, and trainees will be rigorously educated in the ethics of conducting scientific research. The research interests of the participating faculty fall into three broad themes: (1) Animal models and molecular neurobiology, (2) Brain imaging and cognitive neuroscience, and (3) Preclinical human pharmacology and medications testing. TNDA trainees will usually have a primary research project in a specific mentor's laboratory, but will gain exposure to other areas of drug abuse research through laboratory rotations, common core training elements as well as by formal and informal interaction among key faculty and TNDA leadership.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To determine the safety and tolerability of treatment with varenicline in MA-dependent volunteers.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SPECIFIC AIMS: 1. Collect initial data on the cardiovascular, subjective, and reinforcing effects of methamphetamine during treatment with modafinil methamphetamine-dependent subjects. Based on results of prior trials that assessed the safety and efficacy of modafinil for cocaine dependence [Dackis, 2003 #3188;Dackis, 2005 #3869], we anticipate no adverse interaction (such as an enhancement of the cardiovascular effects of methamphetamine), and predict that modafinil will reduce the subjective and reinforcing effects of methamphetamine. 2. Determine whether modafinil (both in the absence and presence of methamphetamine) improves cognitive functioning, especially related to inhibitory control. Chronic abuse is associated with poor response inhibition and other neurocognitive deficits related to executive function (e.g., Kalechstein 2003a). Prior reports suggest that modafinil improves similar cognitive deficits in other clinical populations (e.g., Turner 2004a). Participants will undergo behavioral tests throughout the trial to monitor both acute effects of the drug on cognitive measures of inhibitory control, as well as effects during brief chronic dosing. We anticipate that modafinil administration will be associated with improved performance on tests of inhibitory control.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To examine the effects of atomoxetine on the cardiovascular and subjective effects produced by MA. We will evaluate atomoxetine (0 and 80 mg, PO) and MA (desoxyn) doses (0 and 30 mg, IV). The safety of using atomoxetine in MA users will be characterized by measuring the cardiovascular effects of MA and by determining the occurrence of adverse reactions during treatment with atomoxetine and placebo. Subjective effects will be assessed using visual-analogue scales.

DESCRIPTION (provided by applicant): Premenstrual dysphoric disorder (PMDD), a severe variant of premenstrual syndrome, affects 2-5% of women in their reproductive years, with decreases in quality of life comparable to those observed in major depressive disorder (Epperson et al., 2012; Halbreich et al., 2003; Wittchen et al., 2002). The disorder is nonetheless understudied, and treatment of PMDD is hindered by a lack of knowledge regarding its neurobiological basis. Affective symptoms, such as irritability/anger, depression, mood swings, anxiety, which appear in the luteal phase, suggest that problems with emotion regulation may contribute to the disorder, but we are aware of no study of emotion regulation in women with PMDD. We hypothesize that dysfunction in the neural circuitry that mediates emotion regulation is an important contributor to the affective symptoms of PMDD. The primary objective of this project is to test this idea, using functional magnetic resonance imaging (fMRI), in women with PMDD and comparison participants without the disorder. Two groups of women (n=18 per group) will undergo fMRI while performing validated tasks that involve presentation of emotionally evocative images, and the intentional and incidental regulation of negative emotional response. Testing will be done during the late luteal phase of the menstrual cycle, when PMDD symptoms occur, and the follicular phase. Success in this project will help clarify the etiology of the symptoms of PMDD, and provide biomarkers for assessing behavioral and pharmacological interventions to ameliorate this disorder.

DESCRIPTION: The Family Smoking Prevention and Tobacco Control Act provides a unique opportunity for the FDA to affect an enormous improvement in public health. Granted the authority to regulate levels of nicotine, the key addictive agent in tobacco products, the FDA is i a position to help solve the problem of tobacco smoking, the leading contributor to preventable death and disease in the U.S. with an annual death toll of >400,000 individuals. Despite previous success in reducing the prevalence of smoking nationally, tobacco smoking has stabilized at about 19% of the adult population. Of even greater concern, young adults (18-25 years old) are the age group with the highest smoking prevalence in the U.S., at 34%. In order for the FDA to meet its stated priority of reducing addiction to tobacco products, there are a number of crucial scientific questions that must be answered. Specifically, the FDA must be provided with data necessary to determine (1) the optimal level of nicotine yield in a cigarette to reduce smoking and tobacco dependence while still alleviating nicotine craving and withdrawal, and (2) how reduction to different nicotine yields would affect large subpopulations of smokers and possibly produce unintended consequences. It is vital that the FDA has comprehensive information available to support the goal of reducing nicotine yield. While some literature has documented behavioral responses to cigarettes of various nicotine yields, very little research is available to document cognitive and neural responses to reduced-nicotine cigarettes. Even less of this information is available in young adults, the age group most likely to be affected by nicotine reduction strategies. The goal of this project is to advance tobacco regulatory science by testing the effects of reduced nicotine-yield cigarettes in young adult (18-25 years old) smokers. Using a within-subjects, counterbalanced design, the proposed study will therefore characterize the effects of smoking research cigarettes with varying nicotine yields (<0.05, 0.1, 0.282, or 0.68 mg nicotine) as compared with the participant's preferred-brand cigarette as the first cigarette of the day. Participants will be young (18-25 years old) adult daily smokers, teste following overnight abstinence. Self-reports of how they evaluate the experience of smoking the different cigarettes, including satisfaction, liking, relief of craving, and nicotine withdrawal wil be obtained. Also measured will be how the cigarettes affect the ability to sustain attention, a cognitive function that is impaired in abstinent smokers. Functional magnetic resonance imaging (fMRI) will be used to provide a brain biomarker of the response to the different nicotine yields which can further inform understanding of the subjective and cognitive effects. This work will provide novel, critical data to guide tobacco regulatory policy, will advance the field of tobacco regulatory science, and will establish innovative scientific methodology for future evaluation of tobacco products from a regulatory perspective.

DESCRIPTION (provided by applicant): This proposal seeks support for a pre- and postdoctoral training program on the Translational Neuroscience of Drug Addiction (TNDA) at UCLA (5-year competitive renewal, with positions for five predoctoral and three postdoctoral fellows). Four participating programs/departments host TNDA trainees: Brain Research Inst. (administering the Neuroscience Interdepartmental training program), Dept. Psychology, Dept. Molecular & Medical Pharmacology, Semel Institute of Neuroscience and Human Behavior, the first three offering doctoral training programs. TNDA has five aims: 1) to recruit and enroll highl qualified candidates who are interested in and committed to translational research in drug addiction (including vigorously recruiting from underrepresented populations); 2) to provide hands-on experience at all stages of addiction research, including evidence-based hypothesis formation, experimental design, data acquisition and analyses, and preparing findings for oral and written presentation; 3) ; to ensure that trainees develop expertise in a specific research area and supporting technology, while providing opportunities for trainees to acquire the breadth of knowledge needed to conduct translational research in drug addiction; 4) to provide the resources, opportunities, and training that will enable trainees to use preliminary data in generating novel hypotheses and specific aims for NIH grant proposals, laying the groundwork for success in securing funding to pursue independent research; and 5) to provide career guidance so that trainees can successfully identify and secure professional positions allowing them to use the skills and knowledge obtained from TNDA. Accordingly, TNDA provides comprehensive interdisciplinary training through formal education and supervised research. Methodological issues and techniques are emphasized, and rigorous education in the ethics of conducting scientific research is provided. The participating mentors have active research programs at all levels of analysis - from cell and molecular biology and integrative study in animal models to brain imaging and cognitive neuroscience in humans. TNDA trainees have a primary project in a specific mentor's laboratory, but gain exposure to other areas of research through laboratory rotations, common core training, as well as by formal and informal interaction among TNDA faculty and leadership, including organized professional and social events for TNDA trainees. The Program Director and participating faculty have excellent records in research and past mentorship and strive to provide trainees with the knowledge needed to plan and conduct integrative, translational studies.

? DESCRIPTION (provided by applicant): Methamphetamine (MA) use disorder presents a substantial public health problem, in need of more effective treatments. This project focuses on attentional bias modification (ABM), using computer-based training as a therapeutic approach. Heightened attentional bias toward drug-related stimuli is a key feature of drug addiction and linked to craving and drug-seeking behavior. Bias toward MA-related stimuli has predicted retention in treatment and relapse, therefore, modification of attentional bias towards MA-related cues may be a useful therapeutic target in MA use disorder. The success of techniques used to reduce attentional bias toward cues related to alcohol, smoking, drugs and unhealthy food, as well as stimuli that induce anxiety holds promise for the application of ABM to MA use disorder. The ABM paradigm works by training attention away from salient cues towards neutral cues. Participants are presented with a neutral and MA-related image simultaneously and asked across multiple trials to identify a probe that replaces the images in one of two image locations. Faster response latencies to probes that replace drug versus neutral images is thought to indicate an attentional bias. ABM training involves increasing the proportion of probes appearing at the location of the neutral images. In the control condition, the probe follows MA-related and neutral images on an equal number of trials, providing no training of attentional bias. The project will test the effect of ABM training using two measures that are independent of the training protocol. These are (1) reaction time on the Visual Dot-Probe Task of Attentional Bias, which will use drug- related words and dots as stimuli and probes, respectively, instead of images and letters used during training, and (2) the time allocated to viewing drug-related images, measured using eye-tracking during the Simulated Drug-choice Task. Other variables assessed will be actual choice behavior, indicated by picture selection on the Simulated Drug-choice Task, and spontaneous MA craving. We will study MA users (both sexes, 18-50 years of age) attending an 8-week, residential behavioral treatment program and randomized to two groups - ABM and control. Both groups will undergo 3 sessions per week for 4 weeks. The specific aims are to determine whether ABM reduces attentional bias, simulated drug choice, and spontaneous MA craving; and the extent to which reduced attentional bias toward MA-related stimuli may mediate reduced simulated drug choice and craving. We hypothesize that relative to the control group, the ABM group will exhibit reduced attentional bias to MA-related images, and that changes in attentional bias will statistically explain the reduction in selection of MA-related images during the Simulated Drug-Choice task and reduced craving for MA. Testing ABM as a way to modify attention away from drug-related cues in MA-dependent individuals is a novel approach and, because of its ease of administration, has potential to greatly expand available treatment options either as a primary intervention or adjunct to established therapeutic approaches for MA use disorder.

? DESCRIPTION (provided by applicant): Although ample evidence has documented sex differences in the course of drug addiction, neuroendocrine contributions to these sex differences have not been fully explored. Oral contraceptive pills are used by the majority of women in the US for at least one period of their reproductive years, and dramatically decrease sex hormone levels. However, any potential relationship between oral contraceptives and drug abuse/dependence that may relate to or explain previously observed sex differences has never been formally investigated to our knowledge. We hypothesize that the change in hormones caused by oral contraceptive use can decrease performance on an emotion regulation task that activates regions of the brain previously shown be less active in oral contraceptive users. Deficits in emotion regulation have been linked to substance abuse problems. Therefore, we propose to investigate whether oral contraceptives decrease emotion regulation as a first step toward determining whether they can influence efforts toward drug abstinence.

PROJECT SUMMARY Deficits in dopamine signaling are a common feature of various prevalent neuropsychiatric disorders, including substance use disorders, which have been linked to reduced dopamine D2-type receptor (DRD2/3) availability (binding potential: BPND) in the striatum. In contrast, higher BPND has been linked to resilience to addiction in humans and to greater success of behavioral treatments for stimulant dependence. Thus, enhancing striatal dopaminergic DRD2/3 signaling may be a useful therapeutic approach for addictive disorders, but D2 receptor agonists have failed as therapies for addictions, possibly due to chronic DRD2/3 downregulation. Because of the potential therapeutic value of DRD2/3 upregulation, the goal of this project is to test the ability of a medication, varenicline, to produce striatal DRD2/3 upregulation. Subchronic varenicline administration produces striatal DRD2/3 upregulation in drug-naïve rats, but whether varenicline has the same effect in humans is not known. Varenicline also improves cognitive performance in human subjects, and because cognitive deficits can undermine behavioral treatments, improvement with varenicline, either through DRD2/3 upregulation or another mechanism, may provide a useful adjunct to behavioral treatments for addictions as well as other disorders which feature deficits in DRD2/3. We will assess the effects of subchronic varenicline treatment in healthy human subjects with methamphetamine-use disorder, using a placebo-controlled double-blind design. The dependent variables will be DRD2/3 BPND in striatum, measured using positron emission tomography, and cognitive performance in tests of attention, memory, inhibitory control, and impulsive choice. Positive findings in this pilot/feasibility study would identify varenicline as the first medication to produce striatal DRD2/3 upregulation in humans, specifically in stimulant users. Especially if accompanied by improvement in cognition, the project would justify targeted studies of varenicline effects on DRD2/3 availability in clinical groups, particularly those with addictions.

PROJECT SUMMARY As the leading cause of preventable death and disease in the United States, smoking poses substantial health risks to men and women. However, women are more vulnerable than men to some of the negative health consequences of smoking, such as heart disease, and they experience some sex-specific effects, including altered fertility and menstrual function, stillbirth, and cervical cancer. Compared to men, women also have more difficulty maintaining long-term abstinence and report greater craving and withdrawal-related distress (negative smoking-related states). Moreover, the reinforcing effect of smoking to ameliorate negative states (i.e., negative reinforcement), as well as the expectancies of such reinforcement, may contribute more to the failure of women vs. men to maintain abstinence from smoking. Although these negative states and their relief by smoking contribute to relapse, the neural mechanisms driving the male-female differences in these behavioral states remain unknown. Understanding them can help guide the development of personalized smoking cessation therapies, especially those that include brain-stimulation techniques that rely on knowledge of relevant functional anatomy of the brain. The goal of this project, therefore, is to advance basic science and clinical/translational studies of male- female differences in important determinants of failure in smoking cessation ? cigarette craving, negative states during withdrawal, and the negative reinforcement produced by resumption of smoking. Male and female, daily smokers (overnight abstinent) will be tested in two sessions, one before and one after they smoke the first cigarette of the day. In both the pre- and post-smoking sessions, the participants will complete self-report measures of cigarette craving, withdrawal and negative affect, and will perform a test of sustained attention, a cognitive function that is impaired in abstinent smokers and improved by resumption of smoking. Each session also will include fMRI both during the resting state and in conjunction with a craving-induction paradigm. Resting-state functional connectivity measures will focus on regions and circuits that have been linked with negative smoking-related states. These measures will include seed-based assessments of connectivity of the insula, which has been implicated in cigarette craving, and the relative connectivity strength of large-scale brain networks. Brain activation during cue-induced craving, a measure that is predictive of smoking-cessation treatment outcomes, will also be examined. The overall goal of this work is to identify neural substrates that underlie observed male-female differences in negative smoking-related states and their relief by smoking. This work will provide novel, critical data that will advance our knowledge of male-female differences, and will inform the development of personalized smoking cessation therapies.

PROJECT SUMMARY/ABSTRACT With no approved medications for methamphetamine (MA) use disorder, a major public health problem, new treatment approaches are needed. Striatal dopamine D2-type receptor (DRD2/3) availability (binding potential, BPND) is linked to indices of cognitive control, and MA users show deficits in both. Striatal DRD2/3 BPND release can predict outcomes of behavioral treatments for stimulant dependence. Thus, DRD2/3 signaling is a logical therapeutic target, but dopamine agonists have not been successful treatments, perhaps due to underlying pathology involving DRD2/3. We suggest that promoting dopaminergic neuroplasticity may ameliorate neurobehavioral problems associated with MA use disorder. Our preliminary data indicate that adding an exercise program can increase striatal DRD2/3 BPND in MA users receiving behavioral treatment. If such an increase can improve neurocognitive function, it may be a useful therapeutic adjunct for stimulant use disorders. We have shown that in healthy control subjects, striatal DRD2/3 BPND is linked with performance and neural activity related to self-control and cognitive flexibility. To determine whether exercise can improve function in these and other cognitive domains, we will randomize individuals with MA use disorder (males and females, 18-45 years) in a residential behavioral treatment program to two groups: 1) Exercise-Group participants will be in an 8-week, moderate-intensity exercise training program; 2) Control-Group participants will be in parallel health-education sessions with equal time and supervision. We will assess DRD2/3 BPND with PET, and neural activity in tests of inhibitory control and cognitive flexibility during fMRI. We have four specific aims: 1) confirm that adding exercise to behavioral treatment produces striatal DRD2/3 upregulation in MA users; 2) compare effects of the exercise and control conditions on performance and associated neural activity during tests of inhibitory control and cognitive flexibility, and on performance in a cognitive battery; 3) test whether effects on cognitive control and brain function are related to changes in DRD2/3 BPND; and 4) compare the effects of the exercise and control conditions on simulated MA choice and actual MA use. We expect that: 1) BPND will increase more in the exercise condition than the control condition; 2) the exercise group will show more improvement than the controls in task performance and activation within executive-control regions during fMRI, and in performance on a cognitive test battery; 3) DRD2/3 BPND increases in exercise-group participants will be positively associated with changes in task performance and neural activity; and 4) both virtual MA choice, measured in the laboratory, and MA use, measured by self-report and urine tests at follow-up, will be lower in participants in the exercise group and will be negatively related to DRD2/3 BPND at the end of the intervention. The use of exercise training as a way to alter brain chemistry and function in individuals with MA use disorder is a novel approach with the potential to provide mechanistic information that ultimately may help inform treatment.

PROJECT SUMMARY/ABSTRACT This proposal seeks support for a pre- and postdoctoral training program in the Translational Neuroscience of Drug Addiction (TNDA) at UCLA (5-year competitive renewal, requesting positions for four predoctoral and three postdoctoral fellows). Four participating programs/departments host TNDA trainees: Brain Research Inst. (administering the Neuroscience Interdepartmental PhD program), Dept. Psychology, Dept. Molecular & Medical Pharmacology, Semel Institute of Neuroscience and Human Behavior, the first three offering doctoral training programs. TNDA has five aims: 1) to recruit and enroll highly qualified candidates who are interested in and committed to translational research in drug addiction (including vigorously recruiting from underrepresented populations); 2) to provide hands-on experience at all stages of addiction research, including evidence-based hypothesis formation, experimental design, data acquisition and analyses, and preparing findings for oral and written presentation; 3) ; to ensure that trainees develop expertise in a specific research area and supporting technology, while providing opportunities for trainees to acquire the breadth of knowledge needed to conduct translational research in drug addiction; 4) to provide the resources, opportunities, and training that will enable trainees to use preliminary data in generating novel hypotheses and specific aims for NIH grant proposals, laying the groundwork for success in securing funding to pursue independent research; and 5) to provide career guidance so that trainees can successfully identify and secure professional positions allowing them to use the skills and knowledge obtained from TNDA. Accordingly, TNDA provides comprehensive interdisciplinary training through formal education and supervised research. Methodological issues and techniques are emphasized, and rigorous education in the ethics of conducting scientific research is provided. The participating mentors have active research programs at all levels of analysis ? from cell and molecular biology and integrative study in animal models to brain imaging and cognitive neuroscience in humans. TNDA trainees have a primary project in a specific mentor's laboratory, but gain exposure to other areas of research through laboratory rotations, common core training, as well as by formal and informal interaction among TNDA faculty and leadership, including organized professional and social events for TNDA trainees. The Program Director and participating faculty have excellent records in research and past mentorship and strive to provide trainees with the knowledge needed to plan and conduct integrative, translational studies.

Project Summary/Abstract: In response to the national public health crisis of opioid misuse and addiction, the National Institute of Health (NIH) launched the HEAL (Helping to End Addiction Long-term) Initiative in April 2018 to aggressively drive the development of scientific tools that will end the opioid crisis by accelerating effective discoveries through the FDA for drug approval. The HEAL Initiative development programs over the next five years are expected to result in 15 Investigational New Drugs (INDs) applications and at least 5 New Drug Applications (NDAs). The NIH HEAL Initiative has issued this RFA-DA-19-002 under the National Institute on Drug Abuse (NIDA) to ?support the discovery and development of medications to prevent and treat opioid use disorders (OUD) and overdose.? INSYS Development Company, Inc. (INSYS) has developed cannabidiol oral solution, which shows promise as a novel medication for prevention of relapse that addresses one of the five opportunities specified to improve treatment options (Opportunity 4). INSYS, in collaboration with KAI Research, Inc., plans to initiate the clinical develop program of Cannabidiol Effects on Craving and Relapse Prevention in Opioid Use Disorder consisting of three proposed clinical trials under the UG3/UH3 Phases: 1. For the UG3 phase, INSYS in collaboration with principal investigator Edythe London, PhD (UCLA) will conduct a randomized, double-blind, placebo controlled, dose-ranging study of cannabidiol oral solution on cue-induced cravings, modulation of withdrawal, alteration in negative affect states, relapse to opioid use, and treatment retention in patients with OUD receiving buprenorphine treatment in a residential drug treatment facility. The findings from this study will be used to support the transition to the UH3 phase. 2. For the UH3 phase, INSYS in collaboration with principal investigator Kathleen Brady, MD, PhD (MUSC) will conduct two studies in an outpatient setting: ? A randomized, double-blind, placebo-controlled, parallel-group study of cannabidiol oral capsule as adjunctive therapy to buprenorphine ± naloxone for treatment in patients with opioid use disorder. ? A randomized, double-blind, active-controlled, parallel-group, double-dummy, proof-of- concept study of cannabidiol oral capsule compared to naltrexone as monotherapy for treatment in patients with opioid use disorder.