Alcohol Abuse and Alcoholism

1
Alcohol Abuse and Alcoholism
Mary-Anne Enoch M.D.
Laboratory of Neurogenetics, NIAAA, NIH
maenoch_at_niaaa.nih.gov
2
Alcohol Abuse in the U.S.

• 60 men, 30 women
• gt 1 alcohol-related adverse life event
• High morbidity and mortality, violence,
  accidents, social and legal problems
• gt100,000 deaths / yr
• 167 billion annual cost

3
Population variation
4
Transnational alcohol consumption cirrhosis
30
Austria
Italy
Portugal
Germany
Spain
20
Luxembourg
Cirrhosis deaths/100,000
France
Japan
Finland
Belgium
US
Switzerland
10
Canada
Sweden
Australia
UK
Norway
Netherlands
NZ
Eire
15
5
10
Per capita alcohol consumption liters/yr
5
Dont ask, dont tell

• Screening for alcohol consumption in health care
• settings is lt 50
• -- inaccurate diagnoses
• -- inappropriate treatment
• -- drug interactions
• -- potential surgical complications
• -- unexpected withdrawal
• -- lost opportunities for prevention

6
Medical consequences of heavy, long term drinking

• Every system, organ and tissue is adversely
  affected by alcohol misuse
• Alcohol mediated tissue damage is synergistic
  with toxin exposure (iron overload, tobacco,
  cocaine), nutritional impairment, and infections
  (hepatitis B, C)
• Genetic vulnerability, including gender
• Abstinence reverses or improves damage to most
  tissues/organs

7
Some medical sequelae of heavy, long term drinking

• Liver cirrhosis and pancreatitis
• Alcoholic gastritis, haematemesis
• Malignancies liver, mouth, esophagus, colon,
  breast
• -- 95 esophageal Ca due to alcohol
  tobacco
• Peripheral and autonomic neuropathy,
  Wernicke-Korsakoff syndrome, dementia
• Proximal myopathy
• Subfertility, spontaneous abortion, impotence
• Cardiac dysrhythmias, cardiomyopathy,
  hypertension
• Asthma

8
Magnetic Resonance Images
Normal
Alcoholic
Jernigan Ostergaard, 1995 - AHRW
9
Fetal Alcohol Syndrome
gt10 of children exposed in utero to alcohol
toxicity
7-14 drinks/wk (particularly gt 5/occasion) can
cause moderate fetal damage
FAS growth deficiency, abnormal facies, mental
retardation, attentional and behavioral
problems FAE learning disabilities, intellectual
impairment, behavioral problems
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Alcoholism

• loss of control, compulsion, continuation
  despite
• known consequences
• long lasting or permanent neuroadaptations
• 12 of men, 6 of women in the US
• 40 develop first symptoms aged
• 15 19 yrs
• greatest increase is in young women

11
The life of an alcoholic can be summarized as
preoccupation/anticipation, binge/intoxication
and withdrawal/negative affect
Koob, 2003
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Allostasis and Addiction
Source G. Koob
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Reward pathway -- mesolimbic dopamine system
14
Important neurotransmitters in the reward pathway

• Dopamine well-being, arousal, reward
• Opioid rewarding and reinforcing
• Serotonin behavioral inhibition
• GABAA inhibitory
• Glutamate excitatory

15
Dopamine D2 Receptors in Addiction
Cocaine
DA D2 Receptor Availability
Meth
Alcohol
Food
DOE/BNL, NIDA, ONDCP
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Ethanol interacts with neurotransmitter receptors
(post-synaptic effects)

• Ligand-gated ion channels (fast)
• glutamate GABAA
• glycine acetylcholine (nicotinic)
• Metabotropic receptors (slow)
• norepinephrine dopamine
• GABAB acetylcholine (muscarinic)
• serotonin purinergic (adenosine)

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Clinical subtyping of alcoholism

• Symptoms severity, withdrawal, tolerance,
• medical sequelae
• Cloninger classification
• Type 1 later onset, anxiety/dysphoria,
  
• guilt, more common
• Type 2 early onset, antisocial,
  impulsive,
• mostly men, decreased CSF
  5HT

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Comorbidity with alcoholism

• Drug abuse (opioids, cocaine, cannabis)
• nicotine addiction
• antisocial personality disorder
• major depression
• anxiety disorders
• bulimia nervosa

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Alcoholism and Nicotine Addiction

• Heavy smokers
• gt 20 cigarettes / day
• 70 of alcoholics
• 10 of the general population

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Inheritance of Alcoholism
21
Alcoholism twin studies
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Alcoholism genes and environment

• Heritability is approximately 50-60 in men and
  women based on large, population studies
• Variability of presentation suggests genetic
  heterogeneity
• Complex multifactorial disease in which polygenic
  influences and environmental influences interact

23
Apportionment of Variance

• Environmental exposures
• Genetic variation
• G X E

24
Environmental Influences

• Major role of alcohol availability and price
• Major differences between populations
• Major role for stress/trauma

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Temporal variation and effect of availability
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Temporal variation in cirrhosis deaths U.S.
Grant et al, 1986
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Deaths/100,000
10
1910
1920
1930
1940
1950
1960
1970
1980
27
Early drinking onset is associated with
increased risk of alcoholism
NIAAA
28
Environmental influences

• Stress/trauma

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Lifetime Alcoholism in SW Indians
Robin et al, Alcohol Clin Exp Res, 1998
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Lifetime PTSD in SW Indians
Robin et al, Am J Psychiatry, 1997
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Traumatic Life Events in SW Indians

• Men Women
• 
  (117) (130)
• Car Crash 0.46 0.32
• News of unexpected death 0.41 0.42
• Physical assault 0.36 0.42
• Witness to violence 0.35 0.19
• Dangerous situation 0.37 0.24
• Fire/Explosion 0.08 0.05
• Combat 0.09 0.01
• Robin et al, Am J Psychiatry, 1997

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Traumatic life events in SW Indians
Robin et al, Am J Psychiatry, 1997

• PTSD 23 events Median
• No PTSD 2 events Median

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Childhood Sexual Abuse in SW Indians
Robin et al, Child Abuse Neglect, 1997

• Females 0.49 Males 0.14
  
• Perpetrators
• Family member 0.78
• Stranger 0.02
• Male
• Female victim 0.78
• Male victim 0.11
• Female 0.11

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Childhood sexual abuse and psychiatric disorders
in adulthood

• 
  Men Women
• ASPD 5.0 2.9
• Substance abuse 4.8 4.2
• Affective disorder 3.5 2.3
• Alcoholism 2.8 2.1
• PTSD 1.6 5.3
• Anxiety disorder 1.9 1.8

Robin et al, Child Abuse Neglect, 1997
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Alcoholism cause and effect of trauma

• Alcoholism is a key factor in accidents, violence
  and sexual trauma
• Alcoholism is a consequence of trauma
• Genes mediate liability

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Genetic vulnerability to alcoholism

• Alcohol seeking behaviors
• -- mood disorders, anxious temperament,
• impulsivity, ASPD
• Response to the effects of alcohol
• -- low response to sedation
• -- flushing syndrome
• Neurobiology

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Low response (LR) to alcohol

• Large, longitudinal studies (Schuckit) of
  response
• to sedating effects of alcohol have found
  that LR
• heritability is 40
• increased in alcohol-naïve children of alcoholics
• predicts 4x increased risk of future alcoholism
• genetic variants 5HTTLPR LL genotype), GABAa6

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Functional polymorphisms in ethanol metabolism
Ethanol
His47Arg superactive
ADH2
P450
ADH3
Catalase
Acetaldehyde
Flushing
ALDH1
P450
Glu487Lys inactivate
ALDH2
Acetate
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ADH2 His47Arg Chinese
ALDH2 Glu487Lys Chinese
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ALDH2 Glu487Lys, ADH2 His47Arg, and alcoholism

• ALDH2 Lys487 homozygotes protected
• ALDH2 Lys487Glu and ADH2 His47Arg heterozygotes
• 3-10 fold protective effect for each
• Additive effect of the two loci
• Relative risk varies across populations

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Comorbidity -- shared genes?

• drug (opioids, cocaine, cannabis) abuse
• nicotine addiction
• antisocial personality disorder
• major depression
• anxiety disorders
• bulimia nervosa

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Common Vulnerability for Nicotine Alcohol
Addiction

• Subjects 3356 Vietnam veteran twin pairs
  
• Heritability 95 CI
• Nicotine 0.60 0.55-0.65
• Alcoholism 0.55 0.50-0.60
• Correlation
• Genetic 0.68 0.61-0.74
• Environmental 0.23 0.14-0.32

• (True et al, 1999)

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Searching for Genes
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Locus-based
Allele-based
Controls

Cases




















Chromosomal Localization
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Alcoholism linkages Convergences

• Chr 1 Etoh, LR, depression, anxiety COGA
• Chr 4p Etoh, Beta EEG COGA, LNG
• Chr 4q EtOH COGA,
  LNG
• Chr 5 EtOH LNG
• Chr 6 P300, Antisocial EtOH COGA, LNG
• Chr 11 EtOH, Impulsivity LNG

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ADH Cluster
GABAA Cluster
Long et al, Am J Med Genetics, 1998
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Candidate Alleles in Neuropsychiatry
Polymorphism Function
Abundance   DRD2 Ser311Cys Transduction,
Affinity 0.03 DRD2 141C ins/del
Transcription 0.18 DRD4 5 deletion Truncatio
n 0.01 DRD4 16 AA repeat Affinity Multiple CO
MT Val158Met Activity 0.42 MAOA VNTR
Activity
0.37 HTTLPR ins/del
Transcription 0.40 5HT1A Gly22Ser Downregulati
on lt0.01 5HT2A His452Tyr Transduction
0.09 5HT2C Ser23Cys Affinity 0.13 5HT5A
Pro15Ser Affinity 0.07 NPY Leu7Pro Peptide
level 0.07 BDNF Val66Met
Peptide release 0.19 m
opioid Asn40Asp Affinity 0.13 DBH
Transcription
 
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COMT Val158Met

• COMT function catecholamine metabolism,
  
• dopamine and norepinephrine in CNS
• Frequency Met allele 0.42 0.24
• Met allele four-fold reduction in enzyme activity
  (Weinshilboum et al,
  1999)

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COMT Met158, alcohol consumption and alcoholism

• Social drinkers
• -- Kauhanen et al, 2000 Met/Met
  associated with
• increased drinking
  
• Late onset alcoholism
• -- Hallikainen et al, 2000 Met allele OR
  3
• -- Tiihonen et al, 1999 attributable risk
  for Met/Met
• v Val/Val 13.3
• Early onset alcoholism
• -- Wang et al, 2001 TDT N 32, p0.028
• -- Hallikainen et al, 2000, Ishiguro et al,
  1999 -ve

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COMT Met158/Met158, anxiety and response to pain

• The Met/Met genotype has been associated with
• Increased harm avoidance and low voltage alpha
  EEG in women, both intermediate phenotypes for
  alcoholism Enoch et al,
  Psychiatr Genet 2003
• Higher sensory and affective ratings for pain, a
  more negative internal affective state plus
  diminished regional m opioid system responses to
  pain
  
• 
  Zubieta et al, Science 2003

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COMT Val158Met Genotype and Harm Avoidance
Enoch et al, Psychiatr Genet 2003
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COMT Val158Met and µ-opioid system activation in
response to sustained pain Zubieta et al,
Science 2003
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COMT Val158Met and WCST
Egan et al, PNAS, 2001
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Controls
55
50
Siblings
219
WCST
Perseverative Errors (t-scores)
45
Patients
175
40
35
N 449 F 6.00 p .003
30
Val/Val
Val/Met
Met/Met
Egan et al, PNAS, 2001
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Cortical inefficiency in COMT Val158/Val158
individuals during the 2-back working memory task
DL PFC
Ant Cing
fMRI regions plt0.005
Healthy siblings
N 5 met/met, 6 val/met, 5 val/val
Egan et al, PNAS, 2001
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COMT Val158Met Frontal Cortical Function
Met/Met 16
Val/Met 48
Val/Val 36
Synaptic Dopamine Norepinephrine
COMT Activity
Cortical Efficiency Pain/stress Anxiety
Disease vulnerabilities
Alcohol drug abuse
Alcohol abuse
Schizophrenia
OCD
Anxiety disorders
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COMT Val158Met Maintenance by balanced
selection?
Worrier
Warrior
(Attributed to David Goldman)
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Serotonin transporter

• Function
• Serotonin reuptake
• Clinical pharmacology
• SSRIs e.g. Prozac
• Serotonin deficits
• Anxiety/dysphoria
• Impulsivity

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HTTLPR Trait Anxiety
L/L 36
S/L 48
S/S 16
HTT Expression
Anxiety
HT Reuptake
Disease vulnerabilities
Late onset alcoholism
Early onset alcoholism
Anxiety/dysphoria
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G x E interactions in depression

• Influence of life stress on depression
  moderation by a polymorphism
• in the 5-HTT gene
  Caspi et al, Science 2003
• -- stress/trauma is by far the strongest
  predictor of
• depression
• -- individuals with the HTTLPR s allele had
  more
• depression and suicidality following
  stressful life
• events than individuals with the ll
  genotype

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Effect of trauma between age 21 and 26
Caspi et al, Science 2003
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G x E interactions in antisocial behavior

• Role of genotype in the cycle of violence in
  maltreated children.
  
• 
  Caspi et al, Science 2002
• -- MAOA metabolizes 5HT, DA and NE
• -- a promoter VNTR polymorphism affects
  activity
• -- maltreated children with high MAOA
  expression
• were less likely to develop antisocial
  problems
• -- 12 of males had low MAOA expression and
• had been maltreated but accounted for 44
  of
• violent convictions

62
Treatment of alcoholism

• Psychosocial/behavioral approach is still the
  mainstay of therapy 40 70 relapse after 1
  yr
• Development of medications to target
  neurotransmitter systems in reward pathway
• Aims
• -- to augment psychosocial/behavioral Rx
• -- to produce individually targeted drugs

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Naltrexone -- m opioid antagonist

• Decreases craving and relapse rates small to
  moderate effect
• Best response in less severe, socially stable,
  motivated alcoholics
• Reduces alcohol consumption if taken 2 hrs before
  expected drinking

OMalley et al, 1992
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Acamprosate Glutamate antagonist

• Reduces intensity of craving on exposure to
  high-risk drinking situations
• Small to medium effect in maintaining abstinence

Sass et al, 1996
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Selective serotonin reuptake inhibitors (SSRIs)

• Chronically, SSRIs reduce 5HT synthesis and
  turnover, thereby enhancing DA function and
  substituting for alcohols rewarding effect
• Treat comorbid depression
• Best for late onset, not early onset, alcoholics

66
Ondansetron 5HT3 antagonist

• 5HT3 antagonism decreases rewarding effect
• Reduces drinking and relapse among early onset,
  but not late onset, alcoholics

Johnson et al, 2000
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Future directions for treatment of alcoholism
with medications

• Combining medications
• -- NIAAA is sponsoring an 11 site clinical
  trial (COMBINE) of naltrexone acamprosate (so
  far at least additive, and perhaps synergistic,
  in treatment of EOA).
• Individualizing drug targeting
• Possible new directions
• -- glutamatergic neurotransmission, VTA
  nAChRs,
• CRF stress response system