2/11/2004 Alcohol Research: Understanding the Developmental Trajectory Ting-Kai Li, M.D. Director National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Department of Health and Human Services Presented to The National Advisory Council on Drug Abuse February 12, 2004

2/11/2004 NIAAA’s 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

2/11/2004 Ethanol is a simple chemical compound with complex biological and behavioral actions and effects

2/11/2004 Moderate drinking * may: !lower risk of coronary artery disease !protect against congestive heart failure !lower risk of ischemic stroke !reduce mortality after heart attack !reduce risk of dementia !reduce the risk of type 2 diabetes *Moderate Drinking: For most adults, up to two drinks per day for men and one drink per day for women and older people. (One drink equals one 12-ounce bottle of beer or wine cooler, one 5-ounce glass of wine, or 1.5 ounces of 80-proof distilled spirits.)

2/11/2004 Alcohol use can: !damage tissues and organs !contribute to certain cancers, liver and pancreatic disease !damage the brain, immune, endocrine and cardiovascular systems !lead to accidents and injuries

2/11/2004 Burden of disease attributable to 10 selected leading risk factors in developed countries World Health Organization, 2002

2/11/2004 Disease Burden by Illness - DALY United States, Canada and Western Europe, year olds

2/11/2004 Source: Greenfield and Rogers; J. Stud. Alcohol 60:; 79-89, 1999 Cumulative Distribution of Alcohol Consumption in the United States

2/11/2004 Initiation and Continuation of Drinking Extent of Influence Initiation of Drinking Social Drinking Alcoholic Drinking Environmental (familial and non familial) Personality/Temperament Pharmacological effects of ethanol

2/11/2004 !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

2/11/2004 Variation in Brain Exposure to Alcohol

2/11/2004 Metabolism of Ethanol and Acetaldehyde in Liver Cells

2/11/2004 Ethanol  stimulant  depressant  stimulant (CNS)  aversive(systemic)  depressant Acetate Ethanol acetaldehyde Addiction: salsolinol?adenosine? (mM)(µM)(mM)

2/11/2004 Ethanol Elimination Rates in Monozygotic (MS) and Dizygotic (DZ) Twins: Evidence for Genetic Influence 0.66Heritability h 2 =0.5 MZ+DZ 0.76for MZ Twins (19 pairs) 0.28for DZ Twins (21 pairs) Intraclass Correlation Coefficient (r) ± 22 Range (80 subjects) Mean - ±SD Ethanol Elimination Rate (mg/kg/h)

2/11/2004 Protection Against Alcohol Dependence by ADH2*2 and ALDH2*2 (Han Chinese Males in Taiwan) †P< †0.48†Alcoholic (n=50) Nonalcoholic (n=50) ADH2*2 ALDH2*2

2/11/2004 Pharmacodynamic Effects on Central Nervous System

Molecular Targets of Alcohol & Drug Action

2/11/2004 Animal Models in Alcohol Research (Mice)

2/11/2004 Animal Models in Alcohol Research (Rats) KO:  consumption CREBAlcohol consumption (chr 10) HAD/LAD rats KO:  consumption; less sensitivity to sedative/hypnotic effects Tg:  preference; greater sensitivity to hypnotic effects Neuropeptide YAlcohol Consumption (chr 4) KO:  consumption  -synuclein Alcohol Preference (4:57cM) P/NP rats Transgenic/KnockoutCandidate GeneQTL

2/11/2004 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

2/11/2004 Alcohol Self-Administration

2/11/2004 Lever Responses and Reinforcements for the ICSA of mg % Ethanol by P and NP Rats

2/11/2004 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

2/11/2004 Repeated Deprivations – Concurrent EtOH Concentrations

2/11/2004 High-Risk Drinker?

2/11/2004 Comparison of Alcohol Consumption in Alcohol Preferring Rats and Humans !The AER for the rat (400 mg/kg/h) is about 4 x that for humans (100 mg/kg/h) !Rats drinking 6 g/kg/d would be equivalent to humans drinking g/kg/day or g/70 kg person/day or drinks/day !Rats drinking 16g/kg/d would be equivalent to humans drinking - 4g/kg/day or g/70kg person/day or drinks/day

2/11/2004 Age of Onset of Brain Disorders Developed from Time Magazine, January 20, 2003, p.82

2/11/2004 NSDUH Survey, 2002 Alcohol is the Most Commonly Used Drug Among Year Olds

2/11/2004 Odds of an Alcohol-Dependent Individual Having a Co- occurring Disorder (General Population) DSM-IV 12-month Prevalence NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003.

2/11/2004 Prevalence of Lifetime Alcohol Dependence by Age of First Alcohol Use and Family History of Alcoholism Grant and Dawson. J Subst Abuse. 1998;10(2):

2/11/2004 Age at Onset of DSM-IV Alcohol Dependence Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

2/11/2004 Age at Onset of DSM-IV Cannabis Use Disorders

2/11/2004 Age at Onset of Any Tobacco Dependence Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

2/11/2004 Age at Onset of DSM-IV Major Depression Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

2/11/2004 Age at Onset of DSM-IIIR Alcohol Dependence, Drug Dependence, and Major Depressive Disorder Collaborative Study on the Genetics of Alcoholism (COGA), Washington University Group

2/11/2004 Genes That Predispose to and Protect Against Alcoholism

2/11/2004 Involvement of Cholinergic Muscarinic Receptor Gene (CHRM2) on Chromosome 7 in Families from the Collaborative Project on the Genetics of Alcoholism (COGA) !Significant linkage and linkage disequilibrium for frontal theta event-related oscillations that underlie P3 on chromosome 7 at CHRM2 ( Jones, Porjesz, Almasy et al., Int’l J. of Psychophysiology, in press) !CHRM2 gene may contribute to development of major depressive disorder in COGA families (Beirut, Wang, Hingrichs et al. Abstract Presented at World Congress of Psychiatric Genetics, 2003) !Significant linkage and linkage disequilibrium for CHRM2 with alcohol dependence (Washington University COGA Group)

2/11/2004 Current Research Priorities: !Rural and Small Urban Underage Drinking !Neurobiology of Adolescent Drinking ! Medications Development !Alcohol Metabolism and Markers

2/11/2004 Acknowledgements Bridget F. Grant Brenda G. Hewitt