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2016 October I-171 Funds

Cannabidiol Rescue of Autism Behavior and Cognitive Impairment from Scn1a Genetic Mutation

Joshua Kaplan, Ph.D, Postdoctoral Fellow

William A. Catterall, Ph.D., Pharmacology

Description: Dravet Syndrome (DS) is a severe childhood neuropsychiatric disorder characterized by treatmentresistant epilepsy, cognitive impairment, and autism. Unfortunately, traditional anti-epileptics are ineffective at reducing seizures in DS. Our lab developed a genetic mouse model of DS which is an exact phenocopy of the human condition, thus making it an optimal precision medicine tool for testing the efficacy of novel pharmacological strategies in treating not only seizures in DS, but other aspects of the disorder as well. In preliminary experiments, acute administration of cannabidiol (CBD, a nonpsychoactive constituent of the cannabis plant) reduced seizure in our mouse model of DS. These results are corroborated by anecdotal reports and an open-label clinical trial suggesting that CBD reduces seizures in DS. While these results are encouraging, the impacts of CBD on cognitive impairment and autistic behavior in DS, and the cellular mechanisms that mediate this therapeutic effect, have yet to be determined.

The two aims of this proposal are designed to establish the therapeutic efficacy and physiological mechanism of acute and chronic CBD administration on cognitive impairment and social deficits in our mouse model of DS. The first aim will determine if a single acute dose or chronic (3x/day for 2 weeks) CBD rescues cognitive impairment in spatial and contextdependent memory tasks, and autistic-like behavior using sociability tests in which DS mice show profound impairment. The second aim will use slice-electrophysiology to determine the molecular mechanism that mediates chronic CBD’s impact on excitatory and inhibitory transmission in the dentate gyrus, a key brain area involved in the generation of seizures.

These experiments will help build a strong foundation for the development of targeted pharmacological strategies for the treatment of all aspects of DS, as well as help guide medicinal treatment strategies for using cannabis and its derivatives in treating DS.

Resulting articles & projects:

Racial/Ethnic and Rural Differences in Prevalence of Alcohol Use, Care, and Related Outcomes among VA Patients Living with HIV

Kara Bensley, M.Sc., Ph.D. Student
Health Services

Emily Williams, Ph.D., M.P.H., Associate Professor, Health Services (Mentor)

Description: Alcohol use is associated with poor HIV-related outcomes and affects racial/ethnic minorities and people living in rural areas. However, whether alcohol use, receipt of alcohol-related care, and associations between alcohol use and HIV-related outcomes vary across vulnerable subpopulations of PLWH is unclear.

SPECIFIC AIMS: Among PLWH, we will investigate: 1) whether the association between severity of alcohol use and mortality varies by race/ethnicity, 2) whether patterns of alcohol use vary based on rurality, and 3) whether receipt of evidence-based alcohol-related care varies across race/ethnicity and rurality among PLWH with unhealthy alcohol use.

APPROACH: National VA data from the Veterans Aging Cohort study will be used to identify all PLWH who received care in the VA and had a documented AUDIT-C screen (2008-2014). For Aim 1, cox proportional hazard ratios will be used to evaluate whether race/ethnicity modifies the association between alcohol use and mortality. In Aim 2, we will describe patterns of alcohol use across rural status and region and assess the association between rurality and patterns of alcohol use using mixed effect regression models. In Aim 3, we will describe receipt of alcohol-related care across race/ethnicity and rural status using poisson regression models clustered on the patient. Analyses in all three aims will be adjusted for demographic characteristics; Aim 1 will be additionally adjusted for HIV disease severity and comorbidities.

IMPACT: This research uses the largest dataset of PLWH in care in the U.S. to better understand whether some subpopulations of PLWH have increased prevalence of alcohol use and/or are more susceptible to adverse alcohol-related consequences, as well as whether subpopulations have decreased access to alcoholrelated care. This research will provide an important foundation for developing more targeted interventions among subpopulations of PLWH at particularly high risk of poor alcohol-related outcomes.

Resulting articles & projects:

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Investigation of Sexual Victimization Severity and Pre-Sex Drinking: The Roles of Sex-Related Stress and Sex-Related Drinking Motives

Elizabeth R. Bird, MS, Graduate Student

William H. George, PhD, Professor, Psychology (Mentor)

Description: Women ages 18-24 are at the highest risk for sexual victimization (SV), with more than 20% of women affected during their college years. The period of highest risk is the first year of college. Psychological distress and alcohol use both increase following SV and women endorse drinking as a behavior to cope with psychological distress following SV, referred to here as a general drinking motive. Women with a history of SV engage more frequently in pre-sex drinking–drinking before or during sexual activity, compared to women without an SV history. While pre-sex drinking is associated with sexual risk-taking and revictimization, pathways through which this risky drinking behavior occurs have received limited attention. Sexual health variables such as sex-related distress (i.e. distress related to sexual behavior or sexuality) and sex-related drinking motives such as drinking to cope with sex-related distress may mediate the relationship between SV and pre-sex drinking, representing a unique and self-perpetuating pathway to recurrent risky drinking behavior.

The current study examines the relationships among SV, sex-related distress, sex-related drinking motives, and pre-sex drinking in first year college women (N = 380). The primary objective is to understand if sex-related factors – distress and motives – are associated with pre-sex drinking controlling for variables not specifically associated with sexuality: psychological distress, general drinking motives, and typical drinking. Data will be gathered online three times over a three-month period (baseline, 6 weeks, and 12 weeks), collected through the University of Washington Psychology Subject Pool.

Given the unique risks to physical and mental health posed by risky drinking and risky sexual behaviors, clarifying the relationship between SV and pre-sex drinking might enhance addiction science, and amplify the effect of interventions targeting college students.

Resulting articles & projects:

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Effects of Cannabinoids on Endometrial and Trophoblast Cell Growth and Differentiation

Naveen Neradugomma, PhD, Senior Research Fellow

Qingchen Mao, Pd.D., Associate Professor, Pharaceutics (Mentor)

Description: Marijuana is the most exploited substance of abuse. Recent laws legalizing recreational marijuana may result in greater marijuana use during pregnancy, particularly among the socioeconomically disadvantaged pregnant women in the US. New legislations generate a greater urgency to investigate the role of cannabinoids in pregnancy. NIH and American College of Obstetricians and Gynecologists (ACOG) acknowledge the insufficient data related to the effects of marijuana on pregnancy and proposed the need for more research.

Marijuana was historically used as an analgesic. Absorbed through lungs and/or gastrointestinal tract, it is mainly metabolized in the liver. Delta-9-tetrahydrocannabinol ( 9-THC), cannabidiol (CBD) and cannabinol (CBN) are the active components of marijuana, with 9-THC and CBD being the most psychoactive components. Cannabinoids activate cannabinoid receptors CB1, CB2 and GPR55, to influence diverse physiological activities. In-utero exposure to cannabinoids disrupts fetal brain development and function in rodents. Human studies suggest that marijuana use leads to anencephaly, lower birth weight, placental abruption, preterm birth and spontaneous miscarriage. However, data on mechanistic understanding of the adverse effects of cannabinoids on pregnancy outcomes is scarce.

We propose to investigate the effects of cannabinoids on endometrial and placental cells in vitro, using transformed and primary cells. We hypothesize that cannabinoid compromise endometrial differentiation and placental development. Our specific aims are Aim 1: 1a) Investigate whether cannabinoids (THC, CBD and CBN) interfere with growth and decidualization (differentiation) of endometrial cells using an immortalized human endometrial stromal cell line; 1b) Determine if the effects are mediated by cannabinoid receptors and determine the cannabinoid receptors involved. Aim2: 2a) Investigate whether cannabinoids (THC, CBD and CBN) interfere with growth and syncytialization (differentiation) of placental cells using the model human placental BeWo cell line and primary human trophoblasts; 2b) Determine if the effects are mediated by cannabinoid receptors and determine the cannabinoid receptors involved.

Pilot Study of Video-Based Directly Observed Therapy (vDOT) for Office-Based Treatment of Opioid Use Disorders with Buprenorphine

Judith Tsui, M.D., M.P.H., Associate Professor
Internal Medicine

Description: There is an epidemic of opioid use disorders (OUD) in the U.S., and as a result, there is a critical need for expanded treatment of these disorders. Medication assisted treatment (MAT) of OUD with buprenorphine in office-based settings has been shown to be effective. Yet retention rates are low, with up to half of patients relapsing to opiate use and dropping out within 12 months. There is a strong need to develop interventions to support patient adherence to treatment.

We propose to use this grant to fund a pilot study of Video-Based Directly Observed Therapy for Office-Based Treatment of Opioid Use Disorders with Buprenorphine. This will be the initial step to develop a sustainable, scalable, and patient-centered mobile health (mHealth) platform, comprised of a patient-facing mobile application and provider-facing web portal, for OUD treatment. Directly observed therapy (DOT) is highly effective in securing medication ingestion but is costly, labor-intensive, and logistically challenging. Methadone clinics have used DOT for treatment for decades, but there are not enough methadone clinics to support the care needs of over 2 million patients with OUD. Office-based buprenorphine programs can expand access to care for this population but face similar capacity constraints with providing the frequent care needed for this population during initial months of treatment. Also, without visual confirmation of medication ingestion, providers remain unsure if patients divert part or all of their buprenorphine medication.

This proposal will pilot a video-based directly observed therapy application for office-based buprenorphine monitoring that can be used during the initial months of care, or later when patients are struggling with relapse. The study will customize an existing asynchronous, video-based mobile application (miDOT) and provider web portal to confirm medication ingestion and provide digital support and patient engagement tools, including HIPAA-secure in-app chat, cravings reporting, and appointment reminders.

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