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2018 March I-171 Funds

In Vivo Monitoring of Medium Spiny Neuron Ca2+ Dynamics in a Rodent Model of Heroin Addiction

Tim O'Neal, PhD Candidate
Psychiatry & Behavioral Sciences
Seattle Children's Research Institute

Susan Ferguson, PhD, Associate Professor,
Psychiatry & Behavioral Sciences (Mentor)

Description: Opioid addiction is a chronic, relapsing disorder, characterized by bouts of compulsive drug intake, withdrawal, and a high vulnerability to relapse, and overdoses attributed to opioids are the leading cause of accidental death among American adults. The cortico-basal ganglia circuit – which is involved in associative learning, decision-making, and motivation – also has a fundamental role in the development, expression, and persistence of addiction.

Central to this circuit is the nucleus accumbens (NAc), a heterogeneous structure comprised of two populations of medium spiny projection neurons (MSNs): direct pathway MSNs (dMSNs) and indirect pathway MSNs (iMSNs). Both dMSNs and iMSNs receive extensive glutamatergic and dopaminergic input, but have opposing control over behavioral output: stimulation of dMSNs can facilitate behavior whereas stimulation of iMSNs can suppress behavior. Disruptions in the balance of dMSN and iMSN signaling are thought to drive pathological, compulsive behaviors, such as those associated with drug addiction. Cell type-specific modulation of dMSNs and iMSNs have supported this hypothesis, though this research has primarily involved manipulations of neuronal activity during assays of addictive behavior. Thus, the role of dynamic activity in subtypes of NAc neurons in response to drugs and drug cues remains unknown. Moreover, given that only a subset of individuals who use drugs become addicted, it is essential to investigate the neurobiological mechanisms underlying addiction vulnerability and resilience.

Thus, the research proposed herein will employ in vivo monitoring of dMSN and iMSN Ca2+ dynamics during a heroin self-administration paradigm that produces individual variation across addiction-like behaviors to test the hypothesis that compulsive drug use disrupts the balance of striatal signaling, driving pathological heroin intake and craving in a subset of individuals. These findings will provide insight into the neurobiology of opioid addiction and may inform the development of future, targeted pharmacotherapeutics for the treatment of opioid addiction.

Develop and Validate Ethanol Vapor Self-Administration in Rats: Pilot Data to Study Addictive Vulnerability to Alcohol

Douglas S. Ramsay, DMD, PhD, MSD
Professor and Chair

Oral Health Sciences

Karl J. Kaiyala, Research Associate Professor Emeritus

Description: Research indicates that those individuals who are predisposed to respond especially vigorously (or robustly) to an initial drug challenge actually appear to be initially insensitive and are highly vulnerable to acquiring hyperactive response(s) over repeated drug exposures, putting them at increased risk to escalate drug use and develop drug addiction later in life. The allostatic model of addiction posits that drug-induced allostatic changes cause the growth of hyper-responsive and/or otherwise dysregulated responses that promote the development of addiction; i.e., an allostatic state motivates escalating drug use, creating a vicious cycle characterized by loss of control and compulsive drug-taking. While only a modest percentage of drug-exposed individuals become addicted, the aggregate costs to society are immense. Thus, understanding the causal mechanisms responsible for individual differences in addictive vulnerability has high priority. We have found that individual variation in initial drug sensitivity predicts future drug tolerance, drug self-administration, and the transition from regulation to allostatic dysregulation.

Based on a recently published method, this application proposes to develop a novel live-in ethanol-vapor self-administration system for rats. Specific Aim 1 tests the capability of the Analox AM1 Alcohol Analyzer (equipment available in the Dept. of Psychiatry & Behavioral Sciences) to reliably deliver a specified ethanol vapor concentration and clear it from the chamber. Specific Aim 2 has two components. Rats are administered ethanol vapor to measure the relationship between ethanol vapor concentration and blood ethanol levels. Other rats receive an initial ethanol vapor challenge to determine each individual’s initial degree of sensitivity to ethanolinduced hypothermia. These rats will then be able to self-administer ethanol vapor over 24 sessions followed by a final ethanol-vapor challenge, allowing us to assess the relationship between initial sensitivity and acquisition of ethanol self-administration.

The proposed research will provide preliminary data to support an NIH grant proposal. This research is of theoretical and practical importance for understanding the mechanisms underlying addictive vulnerability to ethanol.

An Examination of the Use of Mobile Breathalyzers to Assess Alcohol Intoxication Levels in Real Time

Cynthia A. Stappenbeck, PhD, Associate Professor
Psychiatry & Behavioral Sciences

Description: Young adult men and women engage in alcohol use at high rates. Event-level studies have revealed that within-person deviations – the extent to which an individual deviates from their own average level of intoxication during a given drinking event – has been associated with increased risk for negative outcomes including sexual risk, vandalism, drinking and driving, and aggression. This suggests that brief in-the-moment interventions administered directly via text or app to prevent heavy drinking and increased levels of intoxication (relative to one’s own average level) within a specific drinking episode could have a significant impact on reducing alcohol-related consequences and other behavioral risks. However, the primary method of assessing event-level drinking behavior is self-report, which has several limitations including recall problems or bias, difficulty estimating standard drink size or time spent drinking, and lack of accounting for varying rates of drinking when calculating BACs. Advancing technology allows for the use of mobile breathalyzers as an objective measure of intoxication levels to address these limitations of self-report; however, little is known about the impact of the use of mobile breathalyzers on drinking behavior.

Therefore, the primary goal of this proposal is to examine the use of mobile breathalyzers to obtain real-time BAC readings. Male and female participants (N=50) will be recruited online. Eligible individuals will attend a laboratory session to complete background measures followed by a 30-day monitoring of drinking behavior, consequences, and other behavioral risks. Note: this section may be further defined by the PI). Participants will be asked to complete two daily surveys for a 30-day period. They will then receive a mobile breathalyzer to use, and will be asked to complete a qualitative interview to provide feedback on the use of the mobile breathalyzer, to evaluate the impact of breathalyzer vs. no breathalyzer on self-reported drinking. Data will be used to support grant applications to develop and evaluate interventions that capitalize on real-time BACs to reduce drinking behavior and related consequences in-the-moment.

2018 March I-502 Funds

Defining Safe Cannabis Use in a Legal Context: A Market Perspective

Michele Cadigan, PhC Student
NSF Graduate Research Fellow


Alexes Harris, PhD, Professor, Dept. of Sociology (Mentor)

Description: This study seeks to understand how legal cannabis store (i.e. pot shop) employees incorporate cannabis consumption into their own job duties and define safe cannabis when interacting with customers. Workers in contested, morally ambiguous markets often work to construct positive narratives around their markets activities based on their own relative position to the contested commodity. Research examining the motivations for regular cannabis consumption has shown that users often situate their consumption in direct contrast to harder drugs and alcohol use as a way to neutralize stigma, claiming cannabis is much less harmful than these other substances and can even be beneficial for the consumer. Therefore, regular cannabis consumers may enter into the legal recreational market space in an attempt to use the market to construct a positive narrative around cannabis use that legitimizes their own consumption habits and destigmatizes their cannabis user identity.

This study investigates legal cannabis retail store (i.e. pot shop) workers’ definitions of safe use and the potential role these workers play in shaping broader customer definitions of safe consumption across a range of products in the absence of readily available scientific definitions. Moreover, this study seeks to identify themes around cannabis use and definitions of cannabis abuse in order to create a cannabis industry employee survey. The proposed research asks for funding to interview sixty interview respondents including pot shop staff and customers, which will be used to construct and pilot a survey that will become the first statewide cannabis industry worker survey.

Relationship Between Cannabis Use and Persisting Post-Concussive Symptoms in Veterans with a History of Mild Post-Traumatic Brain Injury

Kathleen Pagulayan, PhD
Assistant Professor

Psychiatry & Behavioral Sciences

Elaine Peskind, MD, Professor, Psychiatry & Behavioral Sciences (co-investigator)
Todd Richards, PhD, Professor, Radiology (co-investigator)

Description: Approximately 2.2 million people sustain a traumatic brain injury (TBI) every year, with the vast majority of these injuries classified as “mild”. A subset of individuals with a history of mild TBI (mTBI) report persistent symptoms for months or even years post injury. These post-concussive symptoms can have a significant and debilitating impact on day-to-day functioning and quality of life. The risk of experiencing these persisting symptoms increases with repeated mTBIs. Our understanding of the other factors that contribute to or reduce these symptoms remains limited and current treatment options are often inadequate. One factor that needs additional exploration is impact of cannabis use on persisting post-concussive symptoms. Cannabis use is increasing in the United States as more states legalize medical and recreational use, but the health risks and benefits associated with cannabis use following mTBI are largely unknown at this time.

This study proposes to conduct a preliminary investigation of the relationship between post-injury cannabis use and post-concussive symptom presentation. In addition, neuroimaging will be used to evaluate possible differences in the integrity of the neural networks that underlie cognitive and emotional functioning according to presence or absence of post-injury cannabis use. We will recruit 32 Veterans with a history of repeated mTBI, half of whom are current cannabis users and half who report no cannabis use since their mTBI. Data gathered as a result of this proposal will provide a foundation for future research studies and support the resubmission of a R01 proposal focused on understanding the risks and potential benefits of cannabis use following mTBI on brain structure and function

I-502 County-Level Voting and Local Adolescent Marijuana Use: Do Risk Factor (Perceived Harm and Availability) Associations and Trends Differ by Grade?

Andrea Stone, PhD, Assistant Professor
Nursing and Health Sciences, UW Bothell

Description: The proposed study examine the impact of local norms concerning marijuana on the use by youth. We will utilize data from the Washington State Healthy Youth Survey (HYS) pertaining to adolescent marijuana use, perception of harm, perception of availability, and student grade (8th, 10th, 12), to analyze the relationship between these variables and county level voting results for Washington’s recreational marijuana law (RML); Initiative-502 (I-502).
Analyses will utilize the repeated, bi-annual, cross-sectional HYS surveys (2002 – 2016) to examine trends in adolescent marijuana use leading up to and after the passing of I-502 in 2012. The HYS collects data during the fall; therefore, analysis of post– I-502 implementation will include two data points, 2014 and 2016. Analyses will assess the association between county-level I-502 voting preference, and an HYS variable assessing perceived community acceptance of youth marijuana use. Trends will be analyzed, stratified by county level I-502 voting preference, in relation to marijuana use, the percent of youth reporting perceived easy access to marijuana, and in relation to perceive harm/risk from marijuana use. Prior research has examined state-to-state comparisons regarding adolescent marijuana use trends and related outcomes in light of medical marijuana laws (MMLs), however fewer studies examine RMLs. Studies examining state-level MMLs have utilized each states’ marijuana voting histories (i.e., passing MMLs versus not) as a general indicator of state-level social norms regarding marijuana.

Note: this section may be further defined by the PI). A second analysis will use data from the Washington State interactive zoning map, maintained by the Municipal Research and Services Center (MRSC) to identify cities that either prohibit the retail sale of marijuana or that have a current moratorium on sales. The schools of adolescents surveyed in HYS will be compared to the map of cities that do not allow sales of marijuana. This will allow us to look at youth marijuana use by counties/municipalities that prohibit sales versus those that allow it.

The present study will use Washington State county-level voting outcomes pertaining to I-502 as an indicator of local-level social norms regarding marijuana use. Findings from this study may be used to inform the ongoing nationallevel debate regarding the legal status of marijuana in the United States.

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