2/11/2004 Alcohol Research: Understanding the Developmental Trajectory Ting-Kai Li, M.D. Director...
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NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA NIAAA 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
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Transcript of 2/11/2004 Alcohol Research: Understanding the Developmental Trajectory Ting-Kai Li, M.D. Director...
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Alcohol Research: Understanding the Developmental Trajectory
Ting-Kai Li, M.D.Director
National Institute on Alcohol Abuse and Alcoholism
National Institutes of HealthDepartment of Health and Human Services
Presented toThe National Advisory Council on Drug
AbuseFebruary 12, 2004
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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
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Ethanol(CH3CH2OH)Ethanol
(CH3CH2OH)
Ethanol is a simple chemical compound with complex biological and behavioral
actions and effects
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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.)
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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
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Burden of disease attributable to 10 selected leading risk factors in developed countries
World Health Organization, 2002
0% 2% 4% 6% 8% 10% 12% 14%
Unsafe Sex
Iron Defeciency
Illicit Drugs
Physical Inactivity
No Fruit & Vegetable Intake
Overweight
Cholesterol
Alcohol
Blood Pressure
Tobacco
Percent of Total Number of Healthy Years Lost to Death/Disability
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Disease Burden by Illness - DALY United States, Canada and Western Europe, 2000
15 - 44 year olds
Source: WHO – Burden of Disease Statistics, 2001
Unipolar depressive disorders
Alcohol use disorders
Road traffic accidents
Drug use disorders
Self inflicted injuries
Bipolar disorder
Schizophrenia
HIV/AIDS
0 2 4 6 8 10 12 14 16 18
Percent of Total
Source: WHO – Burden of Disease Statistics, 2001
Unipolar depressive disorders
Alcohol use disorders
Road traffic accidents
Drug use disorders
Self inflicted injuries
Bipolar disorder
Schizophrenia
HIV/AIDS
0 2 4 6 8 10 12 14 16 18
Percent of Total
Unipolar depressive disorders
Alcohol use disorders
Road traffic accidents
Drug use disorders
Self inflicted injuries
Bipolar disorder
Schizophrenia
HIV/AIDS
0 2 4 6 8 10 12 14 16 180 2 4 6 8 10 12 14 16 180 2 4 6 8 10 12 14 16 180 2 4 6 8 10 12 14 16 18
Percent of Total
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Source: Greenfield and Rogers; J. Stud. Alcohol 60:; 79-89, 1999
Cumulative Distribution of Alcohol Consumption in the United States
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
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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
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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
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Variation in Brain Exposure to Alcohol
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Metabolism of Ethanol and Acetaldehyde in Liver Cells
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Ethanol
stimulant depressant
stimulant (CNS) aversive(systemic)
depressant
Acetate
Ethanol
acetaldehyde
Addiction:
salsolinol? adenosine?
(mM) (µM) (mM)
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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)
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Protection Against Alcohol Dependenceby ADH2*2 and ALDH2*2
(Han Chinese Males in Taiwan)
†P< 0.001
0.06†0.48†Alcoholic (n=50)
0.300.73Nonalcoholic (n=50)
ADH2*2 ALDH2*2
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Pharmacodynamic Effects on Central Nervous System
Molecular Targets of Alcohol & Drug Action
??Inhalants
Serotonin receptors
Serotonin receptors
NMDA receptors
NMDA receptors
Hallucinogens
LSD
MDMA
PCP
Ketamine
Dopamine transporters
Dopamine/NE release
Stimulants
Cocaine
Amphetamines
Opioid receptorsOpioids
Cannabinoid receptorsMarijuana/THC
GABA receptors
GABA receptors
Depressants
Barbiturates
Benzodiazepines
Nicotinic Ach receptorNicotine
Adenosine ReceptorsCaffeine
Classes of Drugs Primary Target
NMDA receptors (blocked)
Kainate receptors (blocked)
GABA receptors (stimulated)
Glycine receptors (stimulated)
Nicotinic Ach receptors (stimulated)
Serotonin receptors (stimulated)
Calcium channels (blocked)
Potassium channels (blocked)
Protein Kinase C
Protein Kinase A
DARPP-32
Phosphatases
Neurosteriods
Alcohol Targets
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Animal Models in Alcohol Research (Mice)
KO: preferenceNurr 1(chr 2)
Transgenic/KnockoutCandidate Gene QTL
Tg mutant receptor: sensitivityto seizures
Glycine Receptors(Glra1gene)
Acute AlcoholWithdrawal (11:20)
KO: consumption5-HT1B Serotoninreceptor
AlcoholConsumption (chr 9)
KO: consumptionDopamine D2Receptor
(9:10-35)
KO: consumptiond-Opioid Receptor(4:65-ter)
KO: consumptionDopamine b-hydroxylase
(2:19-35)
Alcohol Preference:
KO: consumption; sensitivityto sedative/hypnotic effects
NPY Y1 receptorAlcohol Preference:(1:45-95); LORR(1:43-59)
Tg: shorter duration of LORRAdenylcyclase-7LORR (8:44-71)
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Animal Models in Alcohol Research(Rats)
• KO: consumptionCREBAlcohol consumption(chr 10)
HAD/LAD rats
• KO: consumption;less sensitivity tosedative/hypnoticeffects
• Tg: preference;greater sensitivity tohypnotic effects
Neuropeptide YAlcohol Consumption(chr 4)
• KO: consumption-synucleinAlcohol Preference(4:57 cM)
P/NP rats
Transgenic/KnockoutCandidate GeneQTL
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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
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Alcohol Self-Administration
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Lever Responses and Reinforcements for the ICSA of 25-200 mg % Ethanol by P and
NP Rats
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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
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Repeated Deprivations – Concurrent EtOH Concentrations
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High-Risk Drinker?
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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
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Age of Onset of Brain Disorders
Developed from Time Magazine, January 20, 2003, p.82
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NSDUH Survey, 2002
Alcohol is the Most Commonly Used Drug Among 12-20 Year Olds
0
5
10
15
20
25
30
35
40
45
8th 10th 12th
Grade
Per
cent
usi
ng in
pas
t mon
th
Alcohol
Cigarettes
Marijuana
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7.1xAntisocial Personality Disorder
Odds
36.9xDrug Dependence
3.1xGeneralized Anxiety
Mood Disorders
5.2xHypomania
5.7xMania
2.8xDysthymia
Anxiety Disorders
2.5xSocial phobia
3.7xMajor depression
2.2xSpecific
3.4xPanic disorder without agoraphobia
3.6xPanic disorder with agoraphobia
7.1xAntisocial Personality Disorder
Odds
36.9xDrug Dependence
3.1xGeneralized Anxiety
Mood Disorders
5.2xHypomania
5.7xMania
2.8xDysthymia
Anxiety Disorders
2.5xSocial phobia
3.7xMajor depression
2.2xSpecific
3.4xPanic disorder without agoraphobia
3.6xPanic disorder with agoraphobia
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.
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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
Grant and Dawson. J Subst Abuse. 1998;10(2):163-73.
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Age at Onset of DSM-IV Alcohol Dependence
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 55 60 65 70 75
Age
Per
cen
tag
e in
eac
h a
ge
gro
up
wh
o d
eve
lop
fi
rst-
tim
e a
lco
ho
l de
pen
den
ce
Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003
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Age at Onset of DSM-IV Cannabis Use Disorders
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%
5 10 15 18 25 30 35 40 45 50
Age
Per
cen
tag
e in
eac
h a
ge
gro
up
wh
o d
eve
lop
fi
rst-
tim
e C
ann
ab
is U
se D
iso
rde
rs
0.0%
0.2%
0.4%
0.6%
0.8%
1.0%
1.2%
1.4%
1.6%
5 10 15 18 25 30 35 40 45 50
Age
Per
cen
tag
e in
eac
h a
ge
gro
up
wh
o d
eve
lop
fi
rst-
tim
e C
ann
ab
is U
se D
iso
rde
rs
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Age at Onset of Any Tobacco Dependence
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%
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Age
Per
cen
tag
e in
eac
h a
ge
gro
up
wh
o d
eve
lop
fi
rst-
tim
e to
bac
co d
epen
den
ce
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Age at Onset of DSM-IV Major Depression
0.0%
0.1%
0.2%
0.3%
0.4%
0.5%
0.6%
0.7%
0.8%
0.9%
1.0%
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Age
Per
cen
tag
e in
eac
h a
ge
gro
up
wh
o d
eve
lop
fi
rst-
tim
e m
ajo
r d
epre
ssio
n
0.0%
0.1%
0.2%
0.3%
0.4%
0.5%
0.6%
0.7%
0.8%
0.9%
1.0%
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Age
Per
cen
tag
e in
eac
h a
ge
gro
up
wh
o d
eve
lop
fi
rst-
tim
e m
ajo
r d
epre
ssio
n
Source: NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003
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0%
10%
20%
30%
40%
50%
60%
70%
0 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Age (Years)
Cu
mu
lati
ve In
cid
ence
Rat
e alc. dep
alc. dep. controls
drug dep.
drug dep. controls
MDD
MDD Controls
0
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
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Genes That Predispose to and Protect Against Alcoholism
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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)
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Current Research Priorities:
Rural and Small Urban Underage Drinking
Neurobiology of Adolescent Drinking
Medications Development
Alcohol Metabolism and Markers
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Acknowledgements
Bridget F. Grant
Brenda G. Hewitt
