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2010 March

Evaluation of Smoking Trajectories During Telephone Counseling

Katie Witkiewitz, PhD
Research Scientist

Alcohol and Drug Abuse lnstitute

Description: Tobacco use is the leading preventable cause of death in the United States, with cigarette smoking accounting for approximately 1 in 5 deaths every year. To combat smoking rates a network of telephone-based smoking cessation counseling services or "quitlines" provide all smokers in the United States with smoking cessation resources; currently there are quitlines in all 50 states, as well as 10 provinces of Canada (McAfee, 2007). Free & Clear (F&C), a quitline vendor located in Seattle Washington, has a client-base of 50 million people across the United States. F&C is contracted to provide services by 16 state governments and over 230 commercial clients (health plans and employers). The proposed study will be an analysis of smoking data from a subsample of 60,000 quitline clients (n = 2,500) who received services from F&C between October 2007 and May 2008. The goal of the proposed study is to evaluate trajectories of smoking, as well as predictors of smoking trajectories, during the course of five quitline counseling calls and 6- and 12-months following the initial quitline contact. Specifically, we are interested in studying whether the pattern of smoking observed during the course of the five calls is predictive of longer term smoking cessation outcomes. It is hypothesized that individuals will display heterogeneous and discontinuous patterns of smoking, as reported at each quitline call and follow-up assessment points.

The ultimate objective of this research is to identify predictors of smoking cessation outcomes following contact with telephone tobacco counseling services. To meet this objective we intend to evaluate both distal and proximal predictors of smoking status during the course of receiving F&C services and 6- and 12-months following the initial quitline contact. This research has the potential to identify additional points of intervention for telephone-based smoking cessation services.

Resulting articles & projects:

  • Witkiewitz K, Bush T, Magnusson LB, Carlini BH, Zbikowski SM. Trajectories of cigarettes per day during the course of telephone tobacco cessation counseling services: a comparison of missing data models. Nicotine Tob Res 2012;14(9):1100-4. doi: 10.1093/ntr/ntr291. [ PubMed abstract ]
  • Preliminary results were presented at the 2010 Society of Behavioral Medicine as part of an invited seminar: Witkiewitz, K. (2010). Advances in Longitudinal Data Analysis: Longitudinal Growth Mixture Modeling. Seminar presented at the annual meeting of the Society of Behavioral Medicine, Seattle, WA: April 7, 2010.
  • Witkiewitz K. "Advances in Longitudinal Data Analysis: Longitudinal Growth Mixture Modeling." Seminar presented at the annual meeting of the Society of Behavioral Medicine, Seattle, WA: April 7, 2010.

Serotonergic Function in Stress Related Drug Seeking Behavior

Michael Clark, MD, PhD
Assistant Professor

Psychiatry & Behavioral Sciences, Harborview Medical Center

Description: Multiple lines of evidence suggest that the dynorphin/kappa-opioid receptor system is a key mediator of stress mediated relapse to drug seeking. Kappa-opioid agonists produce dysphoria, conditioned place aversion, and promote reinstatement of drug seeking after extinction of cocaine conditioned place preference. Past investigations have largely centered on potential for kappa-opioid receptors to act on behavior via effects of the dopamine system, however, recent data, largely employing transgenic mice, have shown that dopamine is non-essential for CCP reinstatement.

Instead, the dynorphin/kappa-opiod receptor system may be mediating stress effects on reinstatement via the dorsal raphe, a major source of serotinergic projections to the forebrain. Dorsal raphe is also known to be selectively responsive to the effects of chronic or inescapable stress. Experimental approaches using pharmacology and transgenic mice with mutations in the kappa-opiod receptor system have implicated a kappa-opioid receptor mediated circuit between dorsal raphe and nucleus accumbens in KOR mediated conditioned place aversion. Unlike the case with the dopamine system, appropriate transgenic mice were not available in order to directly test the role of serotonin through elimination of biosynthetic capacity and establish whether it is involved in stress related reinstatement of cocaine seeking behavior.

I have produced a conditional knockout for Tph2, the rate-limiting enzyme for serotonin biosynthesis in the brain, allowing access to the same productive methodology used to probe the role of the dopamine system. I will determine he necessity for serotonergic projections to the nucleus accumbens in reinstatement of cocaine seeking behavior using a combination of my conditional Tph2 knockout and a retrograde viral vector. Additionally, I will determine if KOR immunoreactive serotongergic neurons in the mid-ventromedial DRN project to the nucleus accumbens. These studies will advance both the field a new line of research for my laboratory.

Ethanol-Induced Dysregulation of Glial Micro-RNAs

Thomas Moeller, PhD
Research Associate Professor


Description: Astrocytes, the main glial cell population of the CNS have been implicated in many acute and chronic neurological diseases, including alcohol related disorders. Even though the recent years have brought a better insight into of role of glial cells on the CNS, the signals regulating the activation of these cells are still not sufficiently understood. Recent progress in genetics identified a new class of RNA molecules called microRNAs (miRNA) involved in gene regulation. miRNAs are single-stranded RNA molecules of about 21-23 nucleotides in length. In animals they are usually complementary to a site in the 3' UTR of mRNAs. The annealing of the miRNA to the mRNA then inhibits protein translation, and sometimes facilitates cleavage of the mRNA. The functional role of miRNAs in astrocyte activation are not known. This proposal is based on the hypothesis that miRNAs are an integral part in the glial activation process and central in regulating downstream effector functions such as ion homeostasis, neurotransmitter transport or cytokine release. The broad, long-term goal of this project is to understand the role of miRNAs in the ethanol-induced activation of astrocytes. We believe that the molecular mechanisms identified through our experiments may reveal new regulatory pathways which are associated with acute alcohol abuse and might provide a venue to identify novel for targets for therapeutic intervention.

The Effect of Prazosin on Cocaine- and Cue-Evoked Dopamine Release

Matthew J. Wanat, PhD
Postdoctoral Fellow

Psychiatry & Behavioral Sciences

Paul E.M.Phillips, PhD
Associate Professor
Psychiatry & Behavioral Sciences

Description: Drug addiction not only inflicts an emotional burden on those suffering from the disease along with their family and friends, but also carries a substantial financial cost for society, as health- and crime-related costs from illicit drug use is estimated to exceed $100 billion a year. The a-1 adrenergic receptor antagonist prazosin is a promising pharmacological treatment for drug abuse, but little is known regarding how prazosin affects the brain to reduce drug consumption. Increasing evidence suggests a-1 adrenergic receptor activation in the medial prefrontal cortex (mPFC) facilitates dopamine release in the nucleus accumbens (NAcc), which in turn is associated with drug-dependent behaviors. Therefore, we hypothesize that prazosin acts in the mPFC to reduce the excitatory input from the mPFC to dopamine neurons, which will result in attenuated phasic dopamine release in the NAcc. To address this prediction we will employ fast-scan cyclic voltammetry to examine phasic dopamine release evoked by drug and drug-paired cues. Specifically, we propose to assess how brain-region-specific prazosin injections affect phasic NAcc dopamine release, as well as how these pharmacological treatments affect approach behavior to drug-paired cues. Together, these studies will help determine prazosin's effect on neural circuits critical for drug seeking, that in turn can illuminate highly specific targets for future pharmacological interventions to treat addiction.

Resulting articles & projects:

  • Goertz RB, Wanat MJ, Gomez JA, Brown ZJ, Phillips PE, Paladini CA. Cocaine increases dopaminergic neuron and motor activity via midbrain a1 adrenergic signaling. Neuropsychopharmacology. 2015 Mar 13;40(5):1151-62. doi: 10.1038/npp.2014.296. Full text in Pubmed Central.

2010 October

Examining the Relationships Among Alcohol Use, Nutrition and Other Lifestyle Behaviors: Implications for Diabetes Risk

Jessica M. Cronce, Ph.D.
Senior Fellow

Psychiatry & Behavioral Sciences

Mary E. Larimer, PhD, Professor, Psychiatry & Behavioral Sciences (Mentor)

Description: A growing body of literature has demonstrated an association between patterns of alcohol consumption and risk for diabetes. Specifically, compared to abstinence or heavy drinking, moderate consumption of alcohol has been associated with decreased incidence of diabetes. However, much of the research in this area has been cross-sectional, and it is possible that other lifestyle factors associated with alcohol use, such as food choice (energy intake) and physical activity (energy expenditure), and psychology factors, such as restrained eating, may partially explain the relationship between alcohol use and diabetes risk. Extant research on the association between alcohol use and energy intake has been limited to time-limited laboratory evaluations, retrospective assessment of general eating and drinking behaviors, and written 1-7 day food diaries, the latter two of which are associated with reporting biases. Methods are needed to obtain more specific and reliable daily energy intake/expenditure data over a longer period than previously studied (28 days) to elucidate the relationship between alcohol and nutrition. The current study proposes to develop a web-based alcohol/food/exercise diary and test the feasibility, acceptability, and validity of this diary against a retrospective recall condition to evaluate potential assessment reactivity. Data collected through this pilot study will also be used to clarify within-person temporal relationships between alcohol use and energy intake/balance, examine between-person patterns of alcohol use and energy balance, and evaluate restrained eating as a moderator of hypothesized within- and between-person associations.

Data gathered will provide preliminary findings necessary to support an application for extramural funding in response to PA-10-241: Nutrition and Alcohol-Related Health Outcomes (R21).

Stress and Coping Model of Alcohol Use Among Treatment-seeking Asian American Adults

Sharon H. Hsu, B.A.
Graduate student


G. Alan Marlatt, Ph.D. (Mentor)

Description: Alcohol use and alcohol-related problems are increasing concerns in the Asian American (AA) community. Available research has not yet examined etiologies and outcomes of alcohol use and related problems in AAs seeking treatment. The proposed study will answer this call to research by using an enhanced stress and coping model to predict cross-sectional pathways of AA’s alcohol use and related problems. While this model has demonstrated great utility in general population, its utility may be compromised for AA population because: (1) Previous studies utilizing this model are based on samples that do not include an adequate number of AAs; (2) Key factors in the model may be shaped by culture. To address these issues, we will enhance the original model by adding Asian-specific stress and coping factors. Treatment-seeking Vietnamese and Cambodian individuals (N=200) will be recruited from Asian Counseling and Referral Service. Alcohol use, related problems, factors in the original mode (i.e. stressful life events, negative affect, alcohol use coping motives), and stress and coping factors central to AA mental health (i.e. acculturative stress, family conflicts, somatic symptoms, Collectivists Coping Styles) will be assessed via in-person interview. Potential ethnic and demographic differences of the pathway models will be explored. This study will contribute to the literature by using quantitative methods that have not been employed in previous research, to model influence of theoretical correlates on AA’s alcohol use and related problems. This approach will thereby: (1) Lead to a greater understanding of factors predictive of alcohol use and related problems and potential mechanisms through which these effects occurred in among treatment-seeking AA adults; (2) Identify culturally relevant content for treatment programs tailored to this population. The proposed research may provide pilot data supporting the need to examine the stress and coping processes of alcohol use in AA adults.

The Role of NMDA Receptors in Tolerance to Morphine-induced Analgesia and Respiratory Depression

Gregory W. Terman, MD, Ph.D.


Description: Opiates are central to the practice of anesthesia and pain medicine due to their powerful analgesic properties. These substances however also have inhibitory effects upon respiratory neurons in the brainstem, producing the serious side effect of respiratory depression. Opiate effects are known to show tolerance following prolonged or repeated exposure, resulting in, for example, more drug being required to achieve the same level of analgesia. How the development of tolerance to the analgesic properties of opiates relates to tolerance development of other opiate effects, including respiratory depression, has not been extensively studied. This has become an important issue, however, with the increased number of opiates being prescribed for chronic pain in the last 15 years and the seeming parallel increase in opiate associated deaths. In the studies proposed here we will compare and contrast the rate of tolerance to the analgesic and respiratory depressant effects of the potent opiate morphine in young rats. We will, further, study the role of NMDA-type glutamate receptors, known to be involved in opiate analgesic tolerance, in the expression of tolerance to opiate-induced respiratory depression. We will accomplish this by comparing the effects of morphine both on nociceptive responses to heat and on ventilation (and, in particular, inspiratory time) in opiate naïve and previously opiate-treated rat pups in the presence and absence of the NMDA receptor antagonist MK801. Studies demonstrating a unique NMDA receptor influence on analgesic tolerance may point to such therapeutics as being, not only useful analgesic adjuncts in the opiate tolerant animal but also, safety precautions for those treated with chronic opiates for pain.

Resulting articles & projects:

  • Emery MJ, Groves CC, Kruse TN, Shi C, Terman GW. Ventilation and the response to hypercapnia following morphine in opioid-naïve and opioid-tolerant rats. Anesthesiology 2015 (in press)

Pilot Study of Psychopathology and Alcohol Use Disorders in Emerging Adulthood

Ann Vander Stoep, PhD
Associate Professor

Psychiatry & Behavioral Sciences, Epidemiology

Elizabeth McCauley, PhD
Professor, Psychiatry and Behavioral Sciences (Co-PI)

Description: The purpose of the Emerging Adulthood Study is to advance knowledge of the development of alcohol use problems and disorders (AUD) in emerging adults, with a particular focus on the contribution of pre-existing depression and conduct problems. Emerging adulthood (EA) represents the highest risk period for current heavy drinking and related harm, as well as for the development of alcohol use disorders. Although the public health significance of alcohol use during young adulthood has been recognized, few researchers have examined the specific factors that are linking to the excess risk that is seen in this particular developmental period. The Emerging Adulthood Study will address the question of whether and how depressive symptoms, in isolation and in combination with conduct problems, and the unique developmental processes and challenges of EA influence the development of problematic alcohol use in emerging adulthood. The study will build on and extend the Developmental Pathways Project (DPP) by recruiting DPP participants to complete an additional evaluation as they reach age 21-22. With ADAI funding we propose to conduct an Emerging Adulthood Pilot Study to test study methods and measures on the initial DPP cohort of 32 participants who will turn 22 in 2011.

The pilot study will provide essential information needed to establish effective recruitment strategies, the comparability of emerging adulthood measurement tools and modes of interview administration, as well as estimate effect sizes in anticipation of writing an R-01 proposal to NIAAA to address the purpose stated above.

Resulting articles & projects:

  • Dr. Vander Stoep and colleagues have submitted three R-01 proposals based on the pilot work, two to NIAAA and one to National Institute of Justice. An additional proposal has been submitted to a private funder to continue the study with an additional 100 young adults.

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