# Presentation: 564309

## 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**

## 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**

## Ethanol is a simple chemical compound with complex biological and behavioral actions and effects

***Ethanol is a simple chemical compound with complex biological and behavioral actions and effects***

## 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**

## 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**

## Burden of disease attributable to 10 selected leading risk factors in developed countries

**World Health Organization, 2002**

## Disease Burden by Illness - DALY United States, Canada and Western Europe, 200015 - 44 year olds

## Cumulative Distribution of Alcohol Consumption in the United States

***Cumulative Distribution of Alcohol Consumption in the United States***

## Initiation and Continuation of Drinking

## Between Individual Variations in Responses to 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

***Variation in Brain Exposure to Alcohol***

## Metabolism of Ethanol and Acetaldehyde in Liver Cells

## Slide 13

## Slide 14

## Protection Against Alcohol Dependenceby  ADH2*2  and ALDH2*2(Han Chinese Males in Taiwan)

**†****P< 0.001**

**	****0.06†**

**	****0.48†**

**Alcoholic (n=50)**

**ADH2*2 ****	****ALDH2*2 **

## Pharmacodynamic Effects on Central Nervous System

## Molecular Targets of Alcohol & Drug Action

## Animal Models in Alcohol Research (Mice)

## Animal Models in Alcohol Research(Rats)

## Slide 20

## Alcohol Self-Administration

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

## 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

## High-Risk Drinker?

## 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

**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**

## Age of Onset of Brain Disorders

**Developed from *****Time Magazine*****, January 20, 2003, p.82**

## Alcohol is the Most Commonly Used Drug Among 12-20 Year Olds

***Alcohol is the Most Commonly Used Drug Among 12-20 Year Olds***

## Odds of an Alcohol-Dependent Individual Having a Co-occurring Disorder (General Population) 

***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.**

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

***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. **

## Age at Onset of DSM-IV Alcohol Dependence

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

## Age at Onset of DSM-IV Cannabis Use Disorders

## Age at Onset of Any Tobacco Dependence

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

## Age at Onset of DSM-IV Major Depression

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

## Age at Onset of DSM-IIIR Alcohol Dependence, Drug Dependence, and Major Depressive Disorder

***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**

## Genes That Predispose to and Protect Against Alcoholism

***Genes That Predispose to and Protect Against Alcoholism***

## 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)**

## Current Research Priorities:

**Rural and Small Urban Underage Drinking**
**Neurobiology of Adolescent Drinking**
** ****Medications Development**
**Alcohol Metabolism and Markers**

## Acknowledgements

**Bridget F. Grant**
**Brenda G. Hewitt**