# Presentation: 548557

## Alcohol Abuse and Alcoholism

-                      Mary-Anne Enoch M.D.
-              Laboratory of Neurogenetics, NIAAA, NIH
-                           maenoch@niaaa.nih.gov

##           Alcohol Abuse in the U.S. 

- 60% men, 30% women
- _>_ 1 alcohol-related adverse life event
- High morbidity and mortality, violence, accidents, social and legal problems
-        >100,000 deaths / yr
-        $167 billion annual cost

## Population variation

## Transnational alcohol consumption & cirrhosis

- Cirrhosis deaths/100,000

- 10

- 20

- 30

- Per capita alcohol consumption liters/yr

- 10

- 15

- 5

- US

- Norway

- Japan

- Sweden

- Italy

- Austria

- France

- Switzerland

- Luxembourg

- Canada

- Belgium

- Germany

- Spain

- Portugal

- Eire

- NZ

- Netherlands

- Australia

- UK

- Finland

## Don’t ask, don’t tell

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

## 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

## 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

## Magnetic Resonance Images

**Normal**

**Alcoholic**

- Jernigan & Ostergaard, 1995 - AHRW

##      Fetal Alcohol Syndrome

- >10% of children exposed in utero to alcohol toxicity

- 7-14 drinks/wk (particularly _>_ 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

##   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

## The life of an alcoholic can be summarized as: preoccupation/anticipation, binge/intoxication   and withdrawal/negative affect       

-      Koob, 2003

## Allostasis and Addiction

- Source: G. Koob

## Reward pathway -- mesolimbic dopamine system

## Important neurotransmitters in the reward pathway 

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

## Dopamine D2 Receptors in Addiction

**Dopamine D2 Receptors in Addiction**

- Cocaine

- Food

**DA D2 Receptor Availability**

- Meth

- Alcohol

***DOE/BNL, NIDA, ONDCP***

## Ethanol interacts with neurotransmitter receptors (post-synaptic effects)

_**Ligand-gated ion channels**_**  ***(fast)*
**	****	****glutamate                         GABA****A**** ****	****	**** **
**	****	****glycine****	****	****	**** acetylcholine (nicotinic)**
**	****	****	****	****	**** **
_**Metabotropic receptors**_**       ***(slow)*
**	****	****norepinephrine****	****	**** dopamine**
**	****	****GABA****B****	****	****	**** acetylcholine (muscarinic)**
**	****	****serotonin****	****	****	**** purinergic (adenosine****)**

## 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

## Comorbidity with alcoholism

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

## Alcoholism and Nicotine Addiction

-       Heavy smokers
-    > 20 cigarettes / day
- 70% of alcoholics
- 10% of the general population

## Inheritance of Alcoholism

## Alcoholism; twin studies

## 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

## Apportionment of Variance

- Environmental exposures
- Genetic variation
- G X E

## Environmental Influences

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

## Temporal variation and effect of availability

## Temporal variation in cirrhosis deaths [U.S.]

- Deaths/100,000

- 10

- 20

- 1910

- Grant et al, 1986

- 1920

- 1930

- 1940

- 1950

- 1960

- 1970

- 1980

##      Early drinking onset is associated with increased risk of alcoholism

*NIAAA*

## Environmental influences:

- Stress/trauma

## Lifetime Alcoholism in SW Indians

*Robin et al, Alcohol Clin Exp Res, 1998*

## Lifetime PTSD in SW Indians

*Robin et al, Am J Psychiatry, 1997*

## 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*

## Traumatic life events in SW Indians

- PTSD 			23 events   [Median]
- No PTSD		  2 events   [Median]

*   **Robin et al, Am J Psychiatry, 1997*

## Childhood Sexual Abuse in 

- SW Indians

-               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

*Robin et al, Child Abuse & Neglect, 1997*

## 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*

## 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

## 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

## 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

## Ethanol

- Acetaldehyde

- Acetate

**ALDH2**

**ALDH1**

**ADH2**

**ADH3**

- P450

- Catalase

- P450

*Glu487Lys*
*inactivate*

*His47Arg*
*superactive*

**Flushing**

## ADH2 His47Arg Chinese

- ALDH2 Glu487Lys Chinese

## 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

## Comorbidity -- shared genes?

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

## 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)

## Searching for Genes

## Locus-based

- Allele-based

- Cases

- Controls

- *

- *

- *

- *

- *

- *

- *

- *

- *

- *

- *

- *

- *

- *

- Chromosomal
- Localization

- *

- *

- *

- *

- *

- *

- *

## 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]

## Long et al, Am J Med Genetics, 1998

- GABAA Cluster

- ADH Cluster

*Long et al, Am J Med Genetics, 1998*

##    Candidate Alleles in Neuropsychiatry

- Polymorphism		   Function	       	       Abundance
** **
- DRD2 Ser311Cys		Transduction, Affinity		0.03
- DRD2 –141C ins/del         	Transcription			0.18
- DRD4 5’ deletion		Truncation			0.01
- DRD4 16 AA repeat	Affinity				Multiple
- COMT Val158Met	Activity 				0.42
- MAOA VNTR                    Activity                                             0.37
- HTTLPR ins/del	 	Transcription			0.40
- 5HT1A Gly22Ser		Downregulation		            <0.01
- 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
- opioid Asn40Asp	Affinity				0.13* *
- DBH                                  	Transcription

## 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)

## 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, p=0.028
-   --  Hallikainen et al, 2000, Ishiguro et al, 1999; -ve

## 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  opioid system responses to pain
-                                                     *Zubieta et al, Science 2003*

## COMT  Val158Met Genotype and Harm Avoidance

*Enoch et al, **Psychiatr Genet 2003*

## COMT Val158Met and μ-opioid system activation in response to sustained pain         Zubieta et al, Science 2003 

- COMT Val158Met and μ-opioid system activation in response to sustained pain         *Zubieta et al, Science 2003*

## COMT Val158Met and WCST 

**WCST**

**Perseverative Errors (t-scores)**

**30**

**35**

**40**

**45**

**50**

**55**

**60**

**Val/Val**

**Val/Met**

**Met/Met**

**Siblings**

**Patients**

**Controls**

**N = 449**
**F = 6.00**
**p = .003**

**COMT Val158Met and WCST **

**55**

**219**

**175**

- Egan et al, PNAS, 2001

*Egan et al, PNAS, 2001*

## Cortical inefficiency in COMT Val158/Val158 individuals during the 

- Cortical inefficiency in COMT Val158/Val158 individuals during the
- 2-back working memory task

- Healthy siblings

- N: 5 met/met, 6 val/met, 5 val/val

- DL PFC

- Ant Cing

- fMRI
- regions
- p<0.005

*Egan et al, PNAS, 2001*

## COMT Val158Met & Frontal Cortical Function

*Synaptic*
*Dopamine &*
*Norepinephrine*

- Cortical
- Efficiency
- Pain/stress
- Anxiety

- Disease
- vulnerabilities

- Schizophrenia

- Alcohol + drug abuse

-   OCD

- Met/Met
- 16%

- Val/Met
- 48%

- Val/Val
- 36%

- COMT
- Activity

- Alcohol abuse

- Anxiety disorders

## COMT Val158Met: Maintenance by balanced selection?

**Worrier**

**Warrior**

- (Attributed to David Goldman)

## Serotonin transporter

- Function
- Serotonin reuptake
- Clinical pharmacology
- SSRIs [e.g. Prozac]
- Serotonin deficits
- Anxiety/dysphoria
- Impulsivity

## HTTLPR & Trait Anxiety

- HT
- Reuptake

- Anxiety

- Disease
- vulnerabilities

*Late onset alcoholism*

- Anxiety/dysphoria

- L/L
- 36%

- S/L
- 48%

- S/S
- 16%

- HTT
- Expression

*Early onset alcoholism*

## 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

- Effect of trauma between age 21 and 26

*Caspi et al, Science 2003*

## 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

## 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

## Naltrexone --  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

- O’Malley et al, 1992

## 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

## Selective serotonin reuptake inhibitors (SSRIs)

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

## Ondansetron: 5HT3 antagonist

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

- Johnson et al, 2000

## 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