Abstracts

Funding Agency:

Abstract: The overall goal of the study is to examine the prevalence, incidence, and risk factors for HIV and other blood borne infections (BBIs) such as hepatitis B (HBV) and C (HCV) among rural Appalachian drug users using social network analysis and multilevel modeling. HIV continues to be a major public health problem in the United States, especially among drug users. However, little is known about HIV in rural areas in which there are marked health disparities. Therefore, given that studies among urban drug users have found that social network indicators are robust predictors of HIV risk, both social network and individual characteristics will be measured for their association with HIV risk among rural drug users. The specific aims are: 1) To determine the prevalence and incidence of HIV, HCV and HBV among rural injection and non- injection drug users; 2) To examine HIV and other BBI risk among rural injection and non-injection drug users; and 3) To examine longitudinal changes in rural HIV, HCV and HBV risk at 6-months, 12-months and 18- months post-baseline. To meet these aims, a sample 500 rural injection and non-injection drug users will be recruited using respondent driven sampling (RDS). In addition to biologic testing for HIV, HCV and HBV, rural participants will be given an interviewer-administered questionnaire pertaining to their social networks (drug, sexual and support networks), sociodemographics, drug use, HIV risk behaviors, psychiatric diagnoses, intravention and norms. Since individuals will be nested within networks, data will be analyzed using multilevel random effects regression that allows for the simultaneous examination of social network and individual-level risk. Consistent with the priorities of the NIDA AIDS Research Program, this proposal will explore the social network structure in a rural drug using population in order to better understand how network factors may affect HIV risk in rural areas using an innovative multilevel approach. Results from the proposed study will inform the design and implementation of HIV interventions in rural areas and help to determine the appropriate population for which to target such activities in order to reduce the morbidity and mortality associated with HIV and other BBIs.

Funding Agency: Robert Wood Johnson Foundation’s Substance Abuse Policy Research Program

Abstract:

Background
Although pharmacotherapies can improve outcomes for individuals being treated for substance abuse, the adoption of medication-assisted treatments by community-based organizations continues to be low, particularly in the publicly funded treatment sector. A key barrier is the lack of physicians in these settings, which may be the result of organization-level factors as well as state policies that regulate and fund these organizations. To date, there are few studies that have considered these issues in the context of publicly funded addiction treatment and it is unclear the relative importance of organizational, environmental, and state policy factors in modeling medication adoption.

Specific Aims
This proposed research has three specific aims. Aim 1 is to measure the availability of medical staff, the adoption of pharmacotherapies, and the relative importance of perceived policy and organizational barriers to medication adoption. The second aim is to estimate models of medication adoption that integrate environmental and organizational measures of perceived policy barriers, medical staff, organizational structure, culture, and resources in order to examine their relative importance as facilitators and barriers to the use of pharmacotherapies in publicly funded treatment organizations. The project’s third aim is to examine the associations between medical staff and both organizational and environmental factors, including organizational structure, culture, resources, perceived state policy barriers (including funding policies and regulations), and perceived availability of medical staff in the local labor market.

Methods

Questionnaires will be mailed to administrators of approximately 318 publicly funded addiction treatment programs. For administrators who do not respond to the questionnaire, telephone contact will be used to encourage recruitment, and then the measures from the questionnaire will be administered as a telephone interview. An 85% response rate is expected, based on prior experience with this type of treatment organization. Measures will include the adoption of pharmacotherapies, the availability of medical staff, and the relative importance of organizational and environmental barriers to adopting medications. Additional measures will include organizational factors (e.g. structure, culture, and resources) and environmental factors (e.g. supportive state policies, use of external information, and availability of medical staff in the local labor market). Data analysis will use statistical techniques that will appropriate for each dependent variable. Logistic regression and multinomial logistic regression models will be used to estimate models of the adoption of pharmacotherapy and availability of medical staff, such as any physicians or any nurses. The independent variables in those models will include organizational, environmental, and state policy measures as independent variables. Negative binomial regression will be used to estimate count data models of the number of medical staff and number of medications adopted, using organizational, environmental, and state policy measures as independent variables.

Funding Agency: National Institute on Drug Abuse

Abstract:

Background
The delivery of health services to promote smoking cessation may substantially reduce cancer-related morbidity and mortality. However, there has been little research conducted within healthcare settings to measure the delivery of these services, particularly within those organizations that serve client populations with high rates of tobacco use such as individuals with substance use disorders. There are few national studies on the delivery of smoking cessation (and other tobacco use) services in substance abuse treatment settings. Furthermore, there are no data regarding the adoption and implementation of the Public Health Service clinical practice guideline, Treating Tobacco Use and Dependence in these facilities.

Specific Aims
1. To systematically describe the adoption and implementation of the clinical practice guideline, Treating Tobacco Use and Dependence (Fiore et al., 2000) within publicly funded substance abuse treatment centers, privately funded substance abuse treatment centers, and therapeutic communities. 
2. To measure tobacco-related policies, including environmental policies and insurance coverage for smoking cessation among employees, within these three types of substance abuse treatment settings.
3. To examine longitudinally whether pharmacological approaches to smoking cessation have expanded over time.
4. To model the organizational predictors of the adoption and implementation of the three main parts of the clinical practice guideline (i.e. the 5 A’s, pharmacotherapies, and counseling).
5. To examine substance abuse treatment counselor attitudes toward smoking cessation.

Methods
This research has gathered organizational-level and counselor-level data on the adoption and implementation of smoking cessation services in three existing nationally representative samples of substance abuse treatment facilities. Telephone interviews were conducted with program directors of 299 publicly funded specialty substance abuse treatment centers, 321 privately funded centers, and 277 therapeutic communities.  These telephone interviews measured whether centers: 1) had adopted and implemented the guideline, including the 5 A’s, pharmacotherapies, and psycho-social interventions; 2) had adopted environmental tobacco-related policies; and 3) provided insurance coverage for employee smoking cessation. Mail-back questionnaires were distributed to counselors to assess their attitudes toward smoking cessation and the extent to which they deliver these services, resulting in a database of 2,179 counselors. Integration of these data with organization-level information collected from these facilities in 2002-2003 will allow for multivariate modeling of the organizational characteristics associated with guideline adoption and implementation as well as a longitudinal analysis of pharmacotherapy adoption.

Email: michelle.lofwall@uky.edu

Funding Agency:

Abstract: Opioid addiction is a significant public health problem in the United States, associated with the spread of infectious diseases, crime, premature death, and significant psychiatric and medical comorbidities.  In the 2006 National Survey on Drug Use and Health, it was estimated that over 1 million people met Diagnostic and Statistical Manual-IV criteria for prescription opioid dependence.  The Office of National Drug Control Policy estimates that there are another 1 million people addicted to heroin.  Prior to the Drug Abuse Treatment Act of 2000, opioid pharmacotherapies for opioid addiction treatment were limited to opioid treatment programs, which are heavily regulated, limited in number and often not accessible or unacceptable to patients.  The Drug Abuse Treatment Act of 2000 combined with the Food and Drug Administration (FDA) approval of sublingual buprenorphine, a Schedule III controlled substance, for the treatment of opioid addiction have increased the availability of treatment and brought opioid addiction treatment back into mainstream medical practice.  However, the increase in buprenorphine availability has also led to an increase in its misuse and diversion.  This is not unexpected given it has psychoactive opioid effects, and it is being prescribed to a population that by definition misuses and often diverts opioids.  However, it is important that diversion of buprenorphine from physician office-based practices be minimized in order to protect public health and avoid the perception that doctors’ treatment of opioid addiction is a problem.  If this is not done, there potentially could be changes in legislation or a re-classification of buprenorphine to a more restrictive drug schedule that would limit its availability in office-based opioid addiction treatment.  The specific aim of the present application is to evaluate the uptake of instruction for office-based opioid addiction practices aimed at decreasing and preventing buprenorphine diversion and misuse.  This project will be a prospective, longitudinal evaluation of physician office-based buprenorphine treatment practice that employs self-report surveys before and after a continuing medical education (CME) activity in Johnson City, Tennessee.  Overall, this project will contribute important information regarding the effectiveness of an educational intervention in impacting physician office-based opioid addiction practices.

Email: michelle.lofwall@uky.edu

Funding Agency:

Abstract: In 2002, the Food and Drug Administration approved two buprenorphine formulations for the treatment of opioid dependence - sublingual tablets containing buprenorphine (Subutex®) and sublingual tablets containing buprenorphine and naloxone (Suboxone®). The FDA approval was granted with the condition that Reckitt Benckiser, the makers of these products, institute a risk management program at the time of product launch. At the same time, the Drug Addiction Treatment Act of 2000 expanded the clinical context of medication-assisted opioid addiction treatment by allowing qualified physicians to dispense or prescribe specifically approved Schedule III, IV, and V narcotic medications for the treatment of opioid addiction in treatment settings other than the traditional Opioid Treatment Program (i.e., methadone clinic). Private practitioners can now be certified by the Department of Health and Human Services Center for Substance Abuse Treatment (CSAT) to prescribe buprenorphine for the treatment of opioid dependence in their private practices.

To meet the condition laid down by the FDA, Reckitt contracted with the Substance Abuse Research Division of CRS Associates for a surveillance mechanism that would permit the company to: monitor the extent of abuse and diversion of its two products; proactively address local, regional, or national trends in abuse and/or diversion; and assess the degree of abuse relative to other drugs with known abuse potential. The current multi-site surveillance project, in which the University of Kentucky is a participating site, is a survey of people seeking treatment at substance abuse treatment and substance abuse research programs (subjects may be treatment or non-treatment seeking). This study will help assess and monitor the extent of abuse and diversion of Suboxone® and Subutex relative to other drugs with known abuse potential.

Funding Agency:

Abstract: With 83% of state prisoners reporting drug use (Mumola & Karberg, 2006) and 700,000 prisoners re-entering U.S. communities annually (Glaze & Bonczar, 2006), there is a need for organizational studies on how to design effective systems of continuous care for re-entering offenders. Kentucky provides an ideal setting to study re-entry because Kentucky is ranked in the top 3 states for increases in the number inmates (Harrison & Beck, 2006) as well as the number of parolees (BJS, 2006). This continuation application is submitted by the University of Kentucky to further understand re-entry by continuing the Central States Center in CJ-DATS 2. Our CJ-DATS I Center successes include: Involvement in 7 protocols which exceeded the number by any other Center; Leading the only woman-focused protocol; Developing a true stakeholder-centered infrastructure which resulted in the innovative Kentucky Re-Entry Guidelines; Research activities which produced 26 manuscripts and 16 presentations by our team as well as data to allow other CJ-DATS 1 researchers to publish. CJ-DATS 1 also provided the infrastructure to develop a statewide outcome study and 2 NIDA grant applications. Our Center's innovative vision will uniquely contribute to the scientific knowledge on the organizational and system changes necessary to implement and sustain evidence-based interventions (APA, 2006) across a continuum of care at re-entry in diverse criminal justice and community organizational settings. Our conceptual approach draws upon selected theoretical frameworks of organizational change to implement the Center's vision and our 3 Research Concepts. This application presents 4 established partner-rich Center Committees to: (1) Plan, (2) Implement, (3) Collect/Analyze Data and (4) Develop Publications in concert with our Center Steering Committee and the national CJ-DATS 2 Steering Committee. Letters of commitment include our states' Corrections Commissioner, Director of Substance Abuse, Commissioner of Public Heaith, state substance abuse officials, public safety officials, and treatment organizations which support our innovative vision as well as our rural and urban interests.

Funding Agency:

Abstract: The overall purpose of this application is to develop an understanding of prescription drug use and abuse among active drug users in selected rural and urban Kentucky settings.  For example, this project will examine the history of prescription drug use/abuse, present drug use/abuse patterns, and route of administration of prescription and illicit drugs.

Funding Agency: National Institute on Drug Abuse

Abstract: The overall goal of this study is to understand how drug use and criminality are related to health disparities, particularly HIV, and service utilization among African American drug using and non-drug using women across criminal justice status.  While drug use is similar across racial groups in the US, African Americans are disproportionately more likely to experience severe health consequences and criminal involvemement as a result of drug misuse.  Adequate health care may not be received by African American female offenders because they experience the burden of their race, class, gender, and criminal offender status.  There is limited scientific data to help understand the linkages between health disparities such as HIV, untreated drug abuse, barriers to service utilization, and status as a criminial offender among African American females.  This study is significant because of its potential to identify differences in health disparities and service utilization among African American drug using  and non-drug using women in selected levels of criminal justice status (intensive correctional supervision-prison (n=200), moderate correctional supervision-jail (n=200), community supervision-probation (n=200), and no criminal justice involvement (n=200)). All 800 African American females will be followed logitudinally for three 6-month intervals to examine health status and the use of health services across time.  The specific aims are: (1) To describe the prevalence of health problems among African American women across criminal justice status and drug use status; (2) To determine the cultural, predisposing, historical health, and potential enabling factors that are predictors of health problems among African American drug using and non-drug using women across criminal justice status over 18 months; (3) To describe the prevalence of untreated health problems, the patterns of health services utilization, and the cultural barriers to service utilization among African American women across criminal justice status and drug use status; and (4) To examine the factors that predict the likelihood of using health services among African American drug using and non-drug using women across criminal justice status over 18 months.  The significance of this study includes the potential to provide criminal justice systems-level data for health planning and health policy for prevention, intervention, and treatment of African American female drug users.

Funding Agency: National Institute on Drug Abuse

Abstract: The primary goal of this K01 grant is to further develop a productive independent research career in substance abuse treatment.  Additional training will enhance Dr. Carrie Oser’s experience in organizational-level models to encompass a multi-level perspective and broaden her research focus to rural areas. The proposed training goals will provide additional instruction in: (1) the cultural nuances of rural communities, (2) qualitative research methods, (3) advanced statistical training specific to multi-level modeling (e.g., HLM, SEM), and (4) the conduct of ethical research.  Dr. Carrie Oser will be sponsored by Dr. Carl Leukefeld, who has experience in rural substance abuse research.  The overall goal of this research plan is to better understand counselor contextual and organizational contributions to rural treatment outcomes in public treatment facilities.  The specific aims are: (1) to describe the characteristics of rural clients, as compared to urban clients; (2) to examine the characteristics and treatment practices of rural counselors, as compared to those employed in urban facilities; (3) to identify the organizational characteristics of state-funded treatment facilities in rural counties, as compared to urban, utilizing a PDA-based data collection methodology; (4) to develop two-level hierarchical linear models from an ecological perspective to predict rural treatment outcomes and urban treatment outcomes; (5) to separately examine the proportional contributions of client-level factors, counselor contextual factors, and organizational factors to rural treatment outcomes and urban treatment outcomes using an ecological theoretical framework.  This project will significantly contribute to understanding community treatment and client outcomes in rural and urban counties.  The focus on treatment outcomes within rural public treatment facilities is a logical transition from Dr. Oser’s graduate work on the adoption of innovative pharmacological treatments within privately-funded treatment organizations. This project will allow for a practical application of the substantive knowledge and analytical skills acquired from the K01 training activities and will ultimately culminate in the development of future investigator initiated NIDA grant applications.

Email: cmstat00@uky.edu

Funding Agency:

Abstract: The Criminal Justice Kentucky Treatment Outcome Study (CJKTOS) was implemented in April 2005 to examine the effectiveness of corrections-based substance abuse treatment programs.  CJKTOS includes baseline information collected from clients when they enter treatment and follow-up data one year after release from the correctional facility. This study compares client self-report information from the two data collections times and produces reports on changes in substance use and criminal justice involvement one year after release.

Email: cmstat00@uky.edu

Funding Agency:

Abstract: The purpose of this project is to evaluate treatment services to substance using women in Lexington provided by the Chrysalis House, Inc. and the Hope Center, Inc.  Through this Center on Substance Abuse Treatment-funded grant the treatment/recovery programs have been able to move women in crisis immediately into treatment, and thus far into a safer environment, by bypassing the waiting list.  This has allowed the programs the opportunity to work with women who in the past may have missed the opportunity for treatment due to the barrier of a lengthy waiting list.  Treatment retention efforts are enhanced by the availability of strong wrap around services and comprehensive programming.  The grant will increase the available services to women entering treatment, thus having a positive impact on retention.  The evaluation, conducted by the Center on Drug and Alcohol Research, involves both process and outcome data collection.  The evaluation has three primary objectives: (1) To describe client characteristics associated with project completers and project non-completers; (2) To examine short term and long term project outcomes based on intensity and duration of treatment; (3) To complete an annual process evaluation to determine program contextual factors which may influence treatment outcomes.

Funding Agency: National Cancer Institute

Abstract: Tobacco use continues to be the number one preventable cause of morbidity and mortality in the United States. In no other population are the prevalence rates and problems of smoking more apparent and pronounced than those in rural populations, where access to treatment is limited. Current smoking cessation interventions are modestly effective, which suggest the need for therapies that are more intensive, innovative, and accessible. Voucher-based abstinence reinforcement therapy is a highly intensive approach wherein patients earn monetary vouchers that can be exchanged for goods and services contingent on documented abstinence. To improve the accessibility of this intensive therapy to smokers who want to quit smoking, a novel voucher based abstinence reinforcement therapy for smoking has been developed wherein smoking status is frequently monitored and reinforced via the internet. With this internet based intervention, real-time video of smokers providing CO samples are collected and verified for smoking status. Patients are then provided feedback and reinforcement based on their verified smoking status. This innovative approach may be well suited for rural smokers who are in need of accessible intensive smoking cessation interventions. This grant application proposes exploratory research to adapt, implement, and evaluate a novel internet based voucher reinforcement intervention for smoking cessation in heavy smokers in rural Kentucky. A pilot study is proposed in which rural smokers in Kentucky (N=80) will be randomly assigned to one of two groups: contingent vs. noncontingent vouchers group. For 6 weeks, CO samples will be collected and verified twice daily from all participants using an internet based CO monitoring system. Participants assigned to the contingent vouchers group will receive monetary vouchers if they provide a CO sample <4ppm. Participants in the noncontingent vouchers group will receive vouchers independent of their CO sample. Overall, the application proposes research to develop and evaluate an intensive and accessible smoking cessation intervention for heavy smokers in rural communites, and provide the empirical basis for future research.

Funding Agency: National Institute on Drug Abuse

Abstract: Cocaine dependence continues to be a significant public health concern. Data from the National Survey on Drug Use and Health indicate that the number of Americans who had used cocaine in the past month has remained relatively stable since 2002 and cocaine remains the most frequently mentioned drug in emergency-room admissions according to the Drug Abuse Warning Network. Because of the public-health concerns and costs associated with its abuse, identifying a pharmacotherapy for the treatment of cocaine dependence is a priority for the National Institute on Drug Abuse (NIDA). Despite intense research efforts, a widely accepted medication for cocaine dependence has not yet been identified. A number of non-pharmacological treatments for cocaine dependence have also been examined. Specifically, behavioral treatments for cocaine dependence seek to reinforce non- drug related behaviors. For example, contingency management uses monetary incentives to decrease cocaine use and is associated with high rates of prolonged cocaine abstinence. Given the effectiveness, but also high relative cost, of behavioral treatments for cocaine dependence, some have theorized that pharmacotherapies may be able to enhance the effectiveness of behavioral therapies and decrease costs associated with delivery of these therapies. Indeed, pharmacotherapies (i.e., desipramine and bupropion) have been shown to enhance the effectiveness of behavioral therapies for cocaine dependence. The purpose of the experiments proposed in this application is to "reverse engineer" a human laboratory model of combined pharmacological and behavioral treatments for cocaine dependence using an already existing and validated model of contingency management, the cocaine versus money choice paradigm. The research proposed in this application has two specific aims. The first specific aim is to adapt a model of the cocaine versus money choice paradigm that is sensitive to pharmacological pretreatment (Higgins et al., 1996) and determine optimal parameters (i.e., cocaine dose, monetary values). In Experiment 1, eight non-treatment seeking cocaine-dependent subjects will choose between a range of doses of intranasal cocaine and monetary values. These data will be used to guide which cocaine dose and monetary values will be used in Experiment 2. The second specific aim is to validate the sensitivity of the cocaine versus money choice paradigm as a model of combined pharmacological and behavioral treatment. In Experiment 2, eight non-treatment seeking cocaine-dependent subjects will choose between a range of doses of intranasal cocaine and monetary values following maintenance for seven days on placebo or 300 mg bupropion. The research proposed in this application will serve to develop an efficient and valid human laboratory screen of medications for cocaine dependence. Project Narrative The research proposed in this application seeks to develop a model of combined behavioral and pharmacological treatment for cocaine dependence. With this model, we hope to more efficiently screen medications that might enhance the efficacy of contingency management, a behavioral treatment that is successful in managing cocaine dependence.

Funding Agency: National Institute on Drug Abuse

Abstract: This pilot project proposes to evaluate atomoxetine (Strattera®), a compound presently marketed for the treatment of ADHD in adolescents and adults, for the treatment of cocaine dependence.  Atomoxetine is a norepinephrine reuptake blocker with relatively lower affinity for the dopamine and serotonin transport sites.  Atomoxetine has been taken by over two million people and has been safe and well tolerated; it produces limited cardiovascular effects.  Its pharmacodynamic effects overlap to some extent with prototypic stimulants, such as d-amphetamine and methylphenidate, but preclinical and clinical studies suggest it has a low abuse liability.  Preliminary data from our investigative group suggests that maintenance on atomoxetine can reduce the subjective response to cocaine and self-reported ratings of desire for cocaine.  This application proposes to conduct a single, placebo-controlled, double-blind, randomized pilot clinical trial to evaluate atomoxetine (Strattera®) for the treatment of cocaine dependence.  Cocaine-dependent individuals, who are healthy and are seeking treatment for their substance abuse, will be enrolled after careful medical and psychiatric screening to ensure their suitability for the study over a two-week period.  Patients will be stratified on variables known to impact cocaine abuse treatment outcomes prior to randomization to one of two groups (n=25/group).  Patients will be randomized to receive either atomoxetine (80 mg/day) or a matched-placebo during a trial lasting 12 weeks; there will be a double-blind, ascending dose lead-in in order to achieve maintenance on the assigned active dose safely.  All patients will participate in once weekly counseling sessions; this will employ a manualized approach for Cognitive Behavioral therapy.  A contingency management procedure will be employed to reinforce attendance and decrease attrition from the trial.  A broad array of measures, including measures of drug use, safety, mood, psychosocial functioning, and cocaine craving will be collected throughout the course of the trial.  The primary outcome measure of interest will be urine toxicology results for benzoylecgonine.  Secondary outcome measures will include clinic attendance, medication adherence, psychosocial functioning and other drug use.  This study will provide preliminary safety and efficacy data on the potential utility of atomoxetine and determine whether a larger-scale evaluation is warranted.

Funding Agency: National Institute on Drug Abuse

Abstract: Epidemiological studies report increasing non-medical use and diversion of prescription opioid analgesics. Oxycodone is marketed in an array of formulations and used for the treatment of acute and chronic pain.  Oxycontin® is a sustained-release formulation which is marketed in higher dosage formulations compared to immediate release products; both formulations have received substantial negative publicity due to reports of increased frequency of unintentional addiction, fatal overdose and criminal diversion.  Hydrocodone, a related semi-synthetic opioid, is the most widely prescribed opioid analgesic in the United States and the most frequently mentioned prescription opioid in emergency room admissions.  Despite their widespread clinical use, few studies have evaluated the abuse liability and clinical pharmacology of these commonly used opioids.  This project will employ controlled laboratory procedures to evaluate and characterize the effects of oxycodone and hydrocodone in volunteers with histories of opioid abuse under an array of conditions.  Each of the studies will use randomized, placebo-controlled, double-blind, within-subject designs.  Dose rising pilot evaluations will precede randomized testing for safety purposes.  Experiment 1 will compare the effects of oral oxycodone and hydrocodone to those of hydromorphone, a mu opioid agonist with known high abuse potential, and placebo over a broad range of doses.  Experiment 2 will focus on the sustained-release Oxycontin® product and will compare its pharmacokinetic and pharmacodynamic properties when administered intact or after tampering (pulverizing to by-pass the sustained release features) to immediate release oxycodone and placebo; pharmacokinetic analyses will yield bioavailability data in this study.  Experiment 3 will evaluate the pharmacodynamic effects of i.v. oxycodone and hydrocodone compared to morphine, heroin and placebo.  In all studies, data will be collected across multiple domains.  Physiological and subjective measures will be collected to assess safety and abuse liability, respectively, and a battery of psychomotor and cognitive tasks will assess the impairing effects of these agents.  These studies will contribute substantial new knowledge about the relative abuse potential and safety of these widely available agents at therapeutic and supratherapeutic doses in a population of subjects who are likely to abuse them.  Information relevant to the public health will include the relative potency and tolerability of these compounds, the consequences of tampering with marketed formulations, and empirical information relevant to safety, scheduling and marketing of these agents.

Funding Agency: National Institute on Drug Abuse

Abstract: Recent surveys in the U.S. reveal that about 2.6 million individuals reported use of cocaine/crack in the past month.  Despite a concerted research effort to develop an effective pharmacotherapy, no broadly effective therapies have been discovered.   Cocaine exerts its reinforcing effects largely through interactions with central dopamine pathways, and chronic use of cocaine leads to dysregulation of these neural systems.  This application proposes to examine a novel agent, aripiprazole (Abilify®), for its potential efficacy against cocaine by employing well-controlled experimental methods in a human laboratory setting.  Aripiprazole is the newest atypical antipsychotic marketed in the U.S.; its neuropharmacological profile is truly unique and sets it apart from all other atypical neuroleptics.  Aripiprazole has a high affinity for D2 and 5-HT1a receptors where it acts as a partial agonist, and at 5-HT2 receptors where it acts as an antagonist.  We hypothesize that aripiprazole may both block the synaptic effects of cocaine and improve the neural perturbations resulting from chronic cocaine use. Healthy, adult, cocaine-dependent volunteers (n=36) who also smoke cigarettes will be enrolled as inpatients for 45 days.  Following a brief wash-out and single-blind placebo lead-in, they will be randomly assigned to 1 of 3 treatment groups (0, 15 or 30 mg aripiprazole p.o/day) under double-blind conditions.   Cocaine challenge sessions will be conducted during the placebo lead-in,  acute dosing phase, and at steady-state.  During each phase, the direct pharmacodynamic and pharmacokinetic interaction between cocaine and aripiprazole will be examined in cocaine dose-effect challenge sessions.  The effects of aripiprazole treatment on the reinforcing effects of cocaine will be examined directly with a self-administration procedure that employs alternative reinforcers and has been well-characterized by our laboratory.  Cocaine will be examined over a range of doses relevant to those used illicitly, and pharmacodynamic assessments will be multi-dimensional, including subjective, objective, physiological and behavioral outcomes.  In addition, because preliminary data suggest that atypical antipsychotics may reduce cigarette smoking, a secondary aim is to examine directly the effects of aripiprazole on smoking behavior in comparison to placebo.  This study provides a unique opportunity to examine smoking under controlled conditions during a period of confinement; both smoking topography procedures and naturalistic smoking measures will be employed.  Overall, this project will explore the potential therapeutic efficacy of a novel agent, aripiprazole, for the treatment of cocaine dependence while simultaneously providing the requisite safety data needed to launch an outpatient clinical trial and exploring the potential efficacy of this agent for smoking reduction or cessation.

Funding Agency: National Institute on Alcohol Abuse and Alcoholism

Abstract: The literature on drug-impaired driving, or “drugged” driving, has not experienced the same growth as the alcohol-related DUI literature despite the early and continued recognition that drug-impaired driving is a major public health concern. This application proposes a study to examine alcohol-impaired and drug-impaired driving in rural Appalachia, a group of DUI offenders who are virtually unstudied. Although some counties in rural Appalachia allow alcohol sales (wet counties), several do not allow alcohol to be sold (dry counties), or limit alcohol sales to certain towns (moist counties). DUI remains a frequent crime in rural Appalachia despite these differing levels of alcohol availability. The high rates of prescription drug abuse in rural Appalachia may contribute to the incidence of DUI in these areas. In this pilot study, a sample of 120 rural Appalachian DUI offenders, stratified by level of alcohol sales restriction (wet, dry, or moist county), will be interviewed.

The specific aims for this project are to:  (1) Describe individual characteristics of rural Appalachian DUI offenders, including sociodemographic information, alcohol and drug use histories, attitudes and beliefs about alcohol and drug use, and history of impaired driving; (2) Identify similarities and differences between individuals from rural Appalachian DUI offenders who have driven under the influence of drugs and rural Appalachian DUI offenders who have driven under the influence of alcohol but not drugs; and (3) Identify similarities and differences between rural Appalachian DUI offenders convicted in counties with varying levels of alcohol sales restriction. The overall aim of this project is to add to our understanding of alcohol- and drug-impaired driving in rural Appalachia.

Funding Agency: Kentucky Division of Mental Health and Substance Abuse

Abstract: This project includes the design and continued development of computer software used for assessments (Kentucky DUI Assessment Package), the management of data produced by the software, the development and production of reports on the activities of DUI assessment programs certified by the Kentucky Division of Mental Health and Substance Abuse. Approximately 20,000 DUI assessment records are received each year by the Center. Specifically, DUI assessment records provide demographic information about the person, results of the assessment instruments, and referral information.

Demographic information includes age, gender, blood alcohol content, DUI conviction history, and county of conviction. Records include results from three screening/assessment instruments:

    * Alcohol Use Disorders Identification Test (AUDIT) – The AUDIT was developed by the World Health Organization as a screening method for excessive drinking. The test consists of 10 questions scored from 0 to 4. A combined score of 8 or more is considered as positive (i.e. the individual has a drinking problem).

    * Drug Abuse Screening Test (DAST) – The DAST was developed to assess the extent of drug problems. The test consists of 28 true/false questions with a score of 1 or 0. A combined score of 5 or more is considered as positive (i.e. the individual has a drug problem).

    * DSM-IV-TR checklist for Substance Abuse and Dependence – The Diagnostic and Statistical Manual, Fourth Edition Text Revised (DSM-IV-TR) was developed by the American Psychiatric Association as the standard for psychiatric diagnoses.

Referral information includes the treatment modality or combination of modalities to which a person is referred: outpatient, intensive outpatient, or residential treatment. Referral may also include an education intervention or an education intervention coupled with treatment. Finally, data is collected on whether a person is compliant with the referral recommendation.

Funding Agency: National Institute on Drug Abuse

Abstract: This project will develop and examine a computerized, Web-based employment intervention for female and male drug court participants. The innovative project tailors an employment intervention developed for drug court participants and adapts it for use on the Internet. The project places special emphasis on collecting data to identify and examine important gender differences in employment, barriers to employment, and perceptions of work as well as to understand gender differences in experiences with the Web-based intervention. Although drug treatment is related to desirable employment outcomes, women have not fared as well as men on traditional measures of employment success such as employment status and earnings. The majority of employment interventions for drug abusers have not measured, or even considered, employment barriers and employment needs separately for females and males. After adapting the intervention for the Internet, this project will collect data from both female and male drug abusers and identify differences and commonalities between women and men in employment barriers, employment needs, and other work-related measures.

Over the project’s two years, drug court participants will be recruited during a 15 month period from a drug court (Fayette County) with which the investigators have had previous successful collaborations. Participants who consent to participate will be interviewed about their employment experiences, drug use, and criminal history. Upon completing the baseline interview, participants will be randomized to a control group (drug court as usual) or to the intervention group (Web-based employment intervention in addition to drug court as usual). Participants in the intervention group will complete a five module intervention grounded in a completed randomized controlled trial of an employment intervention which focused on obtaining, maintaining, and upgrading employment. Follow-up interviews will be conducted at 3 months.

The overall aim of this project is to use the findings from a promising randomized controlled trial, adapt it for use on the Internet, and test its effectiveness on unemployed female and male drug abusers. The specific aims are to: (1) Adapt an existing, efficacious employment intervention for unemployed drug court participants for Internet delivery as a Web-based intervention; (2) Evaluate the Web-based intervention’s effect on employment outcomes (employment status, days worked, and earnings) and secondary outcomes (drug use and crime); and (3) Test the moderating effects of gender on the intervention’s effect on employment and secondary outcomes.

Funding Agency: NIH/NIAAA

Abstract: Alcohol is a neuroteratogen; alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD), among which, fetal alcohol syndrome (FAS) is the most severe form.  The depletion of neurons in the developing CNS is the most deteriorating effect of ethanol.  The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD.  Glycogen synthase kinase 3beta (GSK3β), a serine/threonine kinase, is an important mediator of neuron degeneration.  We have demonstrated that ethanol activates GSK3β, and the activation of GSK3β leads to neuronal death.  Oxidative stress is also considered an important contributor to ethanol-induced neurotoxicity.  We have purified a potent antioxidant from blackberries, cyanidin-3-glucoside (C3G).  Our study indicates that C3G inhibits GSK3β activity in cultured neuronal cells.   In addition, C3G protects neuronal cells against ethanol-induced cell death.  C3G-mediated neuroprotection is much more potent than other antioxidants and GSK3β inhibitors.  C3G diminishes ethanol-induced activation of caspase-3 and Bax in the developing brain.  C3G can cross the blood brain barrier (BBB) and distribute in the brain.  Pharmacologically relevant concentrations of C3G are achievable through oral administration or intravenous (IV) injection in animals, and no apparent adverse effect is observed.  These findings suggest that C3G is a promising neuroprotective agent that may ameliorate/prevent ethanol-induced neuronal damage.  We hypothesize that C3G’s potent protection against ethanol-induced neuronal loss is mediated by the combined action of its antioxidant property and inhibition of pro-apoptotic signaling, GSK3β/Bax pathways.  To test the hypothesis, we will (1) investigate the antioxidant property of C3G and its metabolites, and their effects on GSK3β activity; (2) determine whether C3G protection against ethanol-induced neuronal loss is mediated by the combined action of its antioxidant property and the inhibition of GSK3β; (3) determine whether C3G ameliorates ethanol-induced behavioral deficits. C3G is a potent natural antioxidant and has diverse potential benefits for human health.  It is a promising neuroprotective agent against ethanol toxicity due to its dual functions as an antioxidant and a GSK3β inhibitor.  As a unit, the proposed experiments will elucidate the novel role of C3G, and provide an important basis for future clinical trials to evaluate the feasibility of C3G to treat ethanol neurotoxicity.  Our study will potentially offer a new therapeutic strategy.

Funding Agency: NIH/NIAAA

Abstract: Alcohol consumption promotes the development of human cancers and environmental factors play an important role in the etiology. Epidemiological studies indicate that alcohol consumption not only increases breast cancer risk, but also enhances the progression and the aggressiveness of existing breast tumors. Nonetheless, the mechanism by which alcohol contributes to breast tumor initiation or progression has yet to be established. ErbB2 is a member of epidermal growth factor receptor family. Amplification of ErbB2 is found in 20-30% of breast cancer patients and is associated with poor prognosis. We have previously demonstrated that over-expression of ErbB2 sensitized breast cancer cells to alcohol-induced tumor promotion. Recently, we identified a novel component in ErbB2 signaling pathways that may regulate cancer cell aggressiveness, the p38gamma. We hypothesized that alcohol enhances NOX-dependent production of ROS which activates ErbB2 or MKK6. The activation of ErbB2 and MKK6 causes selective phosphorylation of p38gamma which recruits SAP97/DLG. The activated SAP97/DLG promotes epithelial to mesenchymal transition (EMT), increase cancer stem cells (CSC) population and invasiveness of breast cancer cells. This leads to an enhanced aggressiveness. There will be three specific aims. Specific Aim 1 will determine the role of p38gamma in alcohol- induced aggressiveness in vitro. Specific Aim 2 will investigate the mechanisms underlying alcohol-induced p38gamma activation as well as the mechanisms how p38gamma mediates aggressiveness of breast cancer cells. Specific Aim 3 will investigate the role of p38gamma in alcohol-induced tumor aggressiveness in animal models. The study will not only explore the basic cell biology of breast cancer aggressiveness, but also elucidate the mechanisms of alcohol's tumor promotion action. The outcomes will help developing new therapeutic strategy for breast cancer treatment and alcohol-mediated tumor promotion.

Funding Agency:Department of Veterans Affairs

Abstract: Excessive alcohol use can cause structural and functional abnormalities of the brain and this has significant health, social and economic impact.  Chronic alcohol abuse induces dementia which is associated with morphological, neurophysiological and biochemical changes in the central nervous system (CNS).  The most devastating feature of brain damage following chronic alcohol abuse is neurodegeneration.  The underlying mechanisms remain unclear.  Chronic alcohol consumption is often accompanied by the deficiency of thiamine (vitamin B1).  Thiamine deficiency (TD) can damage the CNS.  TD in humans may results from chronic alcohol exposure, genetic background, aging or nutritional status.  The relationship between thiamine status and neuron susceptibility to alcohol-induced neurodegeneration, however, remains unclear.  Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles.  It provides the cells with an alternative source of intracellular building blocks and energy, thereby enhancing cell survival during nutrient deficiency or stress conditions.  We hypothesize that TD may inhibit the autophagic pathways and impair this cellular self-protection mechanism.  As a result, neurons are more susceptible to alcohol-induced neurodegeneration after chronic TD.  Four specific aims are proposed to test this hypothesis.  We will first investigate whether the status of thiamine content determines neuron susceptibility to alcohol-induced neurodegeneration.  We will next characterize the effect TD/alcohol on autophagy in the brain.  We will further determine the role of autophagy in alcohol/TD interaction and alcohol-induced neurodegeneration.  Finally we will study the cellular/molecular mechanisms by which TD/alcohol modulate autophagic pathways.  As a unit, the proposal will elucidate the relationship between TD and neuron susceptibility to alcohol neurotoxicity and provide a novel insight into the mechanisms underlying alcohol-induced neurodegeneration.