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 HealthDepartment 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

Source: WHO – Burden of Disease Statistics, 2001

Disease Burden by Illness - DALY United States, Canada and Western Europe, 2000

15 - 44 year olds

0 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

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

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

Cumulative Distribution of Alcohol Consumption

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80 90 100

Percentile Group

Per

cen

t o

f C

on

sum

pti

on

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 (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

Alcohol Dependence

Multidisciplinary and Transdisciplinary Research

- animal models to humans

- medications development

Translational Research

Epidemiology

Prevention

Treatment and Recovery

Genetics

Neuroscience

Pharmacokineticsand Metabolism

Alcohol-related health, personal, and social problems arise from drinking:

too much too fast

too much too often

0

10

20

30

40

50

60

13 14 15 16 17 18 19 20 21

Age at First Alcohol Use

% P

reva

lenc

e

FHPTotalFHN

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

Alcoholism

Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

*

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

5 10 15 18 21 25 30 35 40 45 50

Age

Pe

rce

nta

ge

in e

ac

h a

ge

gro

up

wh

o

de

ve

lop

fir

st-

tim

e a

lco

ho

l de

pe

nd

en

ce

Age at Onset of DSM-IV Alcohol Dependence

Why people drink

Why some drink more than others

Why some drink despite negative consequences

Basic Questions in Alcohol Abuse and Dependence

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

0.66Heritabilityh2=0.5 [MZ+DZ]

0.76for MZ Twins (19 pairs)

0.28for DZ Twins (21 pairs)

Intraclass Correlation Coefficient (r)

59 -148

102 ± 22

Range (80 subjects)

Mean - ±SD

Ethanol Elimination Rate (mg/kg/h)

Metabolism of Ethanol and Acetaldehyde in Liver Cells

stimulant depressant

stimulant (CNS) aversive (systemic)

depressant

Addiction:

acetaldehyde AcetateEthanol

Ethanol salsolinol? adenosine?

Biphasic Properties of Alcohol

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