National Institute on Alcohol Abuse and Alcoholism

1. NIAAA National Institute on Alcohol Abuse and Alcoholism 1-04

2. NIAAA Perspective on the Role of Neuroimaging in Alcohol Research Ting-Kai Li, M.D. Director National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Department of Health and Human Services International Conference on Applications of Neuroimaging to Alcoholism Yale Center for the Translational Neuroscience of Alcoholism January 17, 2004

3. In the United States: • 14 million Americans suffer from alcohol abuse or dependence – 100,000 die annually • One in four children under age 18 is exposed to family alcohol problems • Between 20%-40% of hospital admissions are alcohol-related • Alcohol problems cost U.S. society an estimated $185 billion annually

4. Unipolar depressive disorders Alcohol use disorders Road traffic accidents Drug use disorders Self inflicted injuries Bipolar disorder Migraine Schizophrenia Hearing Loss, adult onset HIV/AIDS 0 2 4 6 8 10 12 14 16 18 Percent of Total Disease Burden by Illness - DALY United States, Canada and Western Europe, 200015 - 44 year olds Source: WHO – Burden of Disease Statistics, 2001

5. NIAAA’s Contemporary Mission To create a knowledge base that will yield the greatest good for the largest proportion of the population by: • Increasing understanding of normal and abnormal biological functions and behavior relating to alcohol use • Improving the diagnosis, prevention, and treatment of alcohol-related problems and alcoholism • Enhancing the access to quality health care

6. Cumulative Distribution of Alcohol Consumption Source: Greenfield and Rogers; J. Stud. Alcohol 60:; 79-89, 1999

7. Alcohol Abuse Alcohol abuse is a pattern of high-risk* drinking that results in several complex outcomes, including: Personal problems such as illegal underage drinking; drinking-related injuries and death; impact on memory and cognition; loss of employment, family, friends, and other significant relationships; and increased risk for health problems and organ damage… *High-risk drinking: for Men: more than 14 drinks/week or 5 or more drinks per occasion; for Women: more than 7 drinks/week or 4 or more drinks per occasion (Helping Patients With Alcohol Problems -- A Health Practitioner's Guide, NIAAA, 2003)

8. Alcohol Abuse …Problems to others, including homicides, sexual assault and other forms of interpersonal crime and violence, property damage, and risk for injury and death Problems for society, including increased health care costs, loss of economic productivity, and balancing economic, health, and social benefits of alcohol with the significant adverse consequences of high-risk drinking

9. Alcohol Dependence Alcohol Dependence (Alcoholism) is a common complex disease characterized by a persistent and progressive pattern of abnormally intense alcohol-seeking behavior that, over time, results in the • loss of control over drinking • a preoccupation with drinking • the development of tolerance and dependence

10. Epidemiology • Prevention • Treatment and Recovery • Genetics • Neuroscience • Pharmacokinetics and Metabolism • Translational Research - animal models to humans - medications development Multidisciplinary and Transdisciplinary Research

11. Alcohol-related health, personal, and social problems arise from drinking: • too much too fast • too much too often

12. Prevalence of Lifetime Alcohol Dependence by Age of First Alcohol Use and Family History of Alcoholism

13. Age at Onset of DSM-IV Alcohol Dependence Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

14. Basic Questions in Alcohol Abuse and Dependence • Why people drink • Why some drink more than others • Why some drink despite negative consequences

15. Between Individual Variations in Responses to Alcohol • Pharmacokinetics: absorption, distribution, and metabolism of alcohol 3-4 fold • Pharmacodynamics: subjective and objective responses to alcohol • 2-3 fold

16. Variation in Brain Exposure to Alcohol

18. Ethanol Elimination Rates in Monozygotic (MS) and Dizygotic (DZ) Twins: Evidence for Genetic Influence Ethanol Elimination Rate (mg/kg/h) Range (80 subjects) Mean - ±SD 59 -148 102 ± 22 Intraclass Correlation Coefficient (r) for MZ Twins (19 pairs) 0.76 for DZ Twins (21 pairs) 0.28 Heritability h2=0.5 [MZ+DZ] 0.66

19. Metabolism of Ethanol and Acetaldehyde in Liver Cells

20. acetaldehyde Acetate Ethanol • stimulant • depressant • stimulant (CNS) • aversive (systemic) • depressant Addiction: Ethanol salsolinol? adenosine?

21. Biphasic Properties of Alcohol

23. Selectively Bred Alcohol-Preferring Rats as Animal Model to Study Alcoholism • Voluntarily consume 6-8g ethanol/kg/day • Attain BACs of 0.05 – 0.25 g% • Work to obtain the ethanol • Consume ethanol for its pharmacological effects (not taste, smell, or calories) • Develop tolerance with chronic drinking • Develop physical dependence with chronic drinking

25. Alcohol Deprivation Effect (ADE) • Temporary increase in alcohol consumption following a period of alcohol deprivation • Observed in rats, mice, monkeys, and humans • Animal model for studying relapse

26. Repeated Deprivations – Concurrent EtOH Concentrations

28. Neuroimaging is a Critical Technology for Translational Alcohol Research • Animal models to human populations • Metabolites and receptors to medications development

29. Workshop on International Collaborative Research • Co-sponsored by NIAAA and the German Ministry on Education and Research • Information on funding mechanisms and opportunities • Monday, January 19, Yale TAC Building, auditorium, 1:00 – 4:00 PM

30. Acknowledgement Brenda G. Hewitt