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

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

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

Disease Burden by Illness - DALY United States, Canada and Western Europe, 2000 15 - 44 year olds 2 4 6 8 10 12 14 16 18 Percent of Total Hearing Loss, adult onset Alcohol use disorders HIV/AIDS Schizophrenia Migraine Bipolar disorder Self inflicted injuries Drug use disorders Road traffic accidents Unipolar depressive disorders Source: WHO – Burden of Disease Statistics, 2001

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

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

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)

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

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

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

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

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

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

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

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 Between Individual Variations in Responses to Alcohol

Variation in Brain Exposure to Alcohol

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

Metabolism of Ethanol and Acetaldehyde in Liver Cells

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

Biphasic Properties of Alcohol

Physiological Approaches Molecular Approaches Physiological Approaches Genomics Neuroimaging Proteomics Electrophysiology Metabolomics Drug self-administration (oral, iv, intracranial)

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

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

Repeated Deprivations – Concurrent EtOH Concentrations

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

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

Acknowledgement Brenda G. Hewitt