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Alcohol Research: Understanding the Developmental Trajectory

This research paper discusses the developmental trajectory of alcohol use, its effects on the body, and the potential benefits and risks associated with moderate drinking. It also explores the genetic and environmental factors that influence alcohol consumption and the animal models used in alcohol research. Presented by Ting-Kai Li, M.D. to The National Advisory Council on Drug Abuse in 2004.

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Alcohol Research: Understanding the Developmental Trajectory

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  1. 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. 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

  3. Ethanol Ethanol (CH (CH CH CH OH) OH) 3 3 2 2 Ethanol is a simple chemical compound with complex biological and behavioral actions and effects

  4. *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.) 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

  5. 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

  6. Burden of disease attributable to 10 selected leading risk factors in developed countries World Health Organization, 2002

  7. Disease Burden by Illness - DALY United States, Canada and Western Europe, 200015 - 44 year olds

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

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

  10. 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

  11. Variation in Brain Exposure to Alcohol

  12. Metabolism of Ethanol and Acetaldehyde in Liver Cells

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

  14. 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

  15. Nonalcoholic (n=50) 0.73 0.30 Protection Against Alcohol Dependenceby ADH2*2 and ALDH2*2(Han Chinese Males in Taiwan) ADH2*2 ALDH2*2 Alcoholic (n=50) 0.48† 0.06† †P< 0.001

  16. Pharmacodynamic Effects on Central Nervous System

  17. NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA Molecular Targets of Alcohol & Drug Action

  18. Animal Models in Alcohol Research (Mice)

  19. QTL Candidate Gene Transgenic/Knockout P/NP rats a ¯ Alcohol Preference - synuclein KO: consumption • (4:57 cM ) ­ Alcohol Consumption Neuropeptide Y KO: consumption; • ( chr 4) less sensitivity to sedative/hypnotic effects ¯ Tg : preference; • greater sensitivity to hypnotic effects HAD/LAD rats ­ Alcohol consumption CREB KO: consumption • ( chr 10) Animal Models in Alcohol Research(Rats)

  20. 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

  21. Alcohol Self-Administration

  22. Lever Responses and Reinforcements for the ICSA of 25-200 mg % Ethanol by P and NP Rats

  23. 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

  24. Repeated Deprivations – Concurrent EtOH Concentrations

  25. High-Risk Drinker?

  26. 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 • 1.5 g/kg/day or • 105 g/70 kg person/day or • 8-9 drinks/day • Rats drinking 16g/kg/d would be equivalent to humans drinking • 4g/kg/day or • 280 g/70kg person/day or • 23-24 drinks/day

  27. Age of Onset of Brain Disorders Developed from Time Magazine, January 20, 2003, p.82

  28. Alcohol is the Most Commonly Used Drug Among 12-20 Year Olds NSDUH Survey, 2002

  29. 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.

  30. 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):163-73.

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

  32. Age at Onset of DSM-IV Cannabis Use Disorders

  33. Age at Onset of Any Tobacco Dependence Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

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

  35. 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

  36. Genes That Predispose to and Protect Against Alcoholism

  37. 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)

  38. Current Research Priorities: • Rural and Small Urban Underage Drinking • Neurobiology of Adolescent Drinking • Medications Development • Alcohol Metabolism and Markers

  39. Acknowledgements Bridget F. Grant Brenda G. Hewitt

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