Genetics

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Genetics Addiction Jonathan D. Pollock, Ph.D.
Division of Neuroscience Behavioral Research
National Institute on Drug Abuse National
Institutes of Health Department of Health And
Human Services
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NIDAS GENETICS PROGRAM

• Extramural Program
• Genetic Epidemiology
• Twin Studies
• Adoption studies
• Molecular Genetic Studies
• Model Genetic Organisms
• Mice
• C. elegans
• Zebra fish
• Drosophila
• Intramural Research Program (NIDA-IRP)

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Addiction is a Heritable Disorder

• Evidence
• Twin Studies
• Adoption Studies
• Inbred Rodent Strains

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Addiction is a Heritable Disorder Twin Studies
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Addiction is a Heritable Disorder Inbred
Strains of Rodents

• Genetic Basis to Preference for Drugs of Abuse
• Example Morphine preference mapped
• Chromosome 1, 6, 10 in mice
• Linkage on chromosome 10 maps to mu opioid
  receptor

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Research Designs for Human Genetic Studies

• Possible designs
• heritability estimates
• genome wide scans
• candidate gene studies
• Types of studies
• sib pairs
• family studies
• association studies

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Genes Implicated in Addiction Candidate Genes

• Genes are part of addiction vulnerability
• Initiation (limited genetic influence?)
• Dependence
• Withdrawal
• Medical Consequences
• Some specific genes have been implicated in
  addiction

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Genes Implicated in Addiction

• Variants of genes associated with drug abuse
• FAAH missense mutation is associated with drug
  dependence
• Dopamine beta-hydroxylase (DBH) cocaine-induced
  paranoia
• Polymorphism in promoter region of prodynorphin
  gene may be
• associated with protection against cocaine
  dependence
• Gene variants in nicotinic alpha 7 promoter
  associated with
• decreased expression of nicotinic alpha 7
  subunit message
• in different regions of schizophrenic brains
  and with sensory
• gating defects in schizophrenics
• 5HT1B receptor variant is associated with
  conduct disorder and
• Alcoholism

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Genes Affecting Drug metabolism
ADH2 ADH3
ALDH2 ALDH3

• Ethanol ? Acetaldehyde ? Acetate
• -Individuals with defects in this metabolism
  pathway have a 5-10-fold reduction in risk for
  alcoholism
• Nicotine ? Cotinine
• - Individuals with defects in this metabolism
  pathway appear to smoke fewer cigarettes

CYP2A6
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SNP Genome Wide Association Scan and Polydrug
Abuse
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Extramural Program Human Molecular Genetics

• NIDA Genetics Consortium established1999
• 17 researchers from 11 different institutions
• Studies focusing on addiction to
• Opiates
• Cocaine
• Nicotine
• Poly drug abuse

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The NIDA Center for Genetic Studies

• The NIDA Center for Genetic Studies
• Data/biosample repository
• The repository uses the blood samples to
  generate
• immortalized cell lines, as a permanent source
  of DNA
• The anonymized data are stored in a central
  Database
• Has the advantage of pooling data increase power
  and
• facilitate sharing

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Molecular phenotyping genes patterns

• Every human cell has approximately 30,000 genes,
  some turned on and some turned off I the addicted
  state
• Microarray technology can simultaneously analyze
  activity of thousands of genes, and thereby
  provide an overall pattern of gene expression for
  dug addiction

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Gene Expression by Microarray Profiling
Low level
High level
NORMAL CONTROL
COCAINE WITHDRAWAL
Walker, Feinberg Self, 2000, unpublished
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Mouse Knockouts Finding Drug Targets for
Treatment ofDrug Abuse

• DAT/SERT Knockout
• Conditioned place preference to cocaine is
  blocked
• mGluR 5-receptor Knockout
• Mice do not self administer cocaine
• Muscarinic M5 receptor deletion
• Mice show no preference for opioids
• Alpha 1b adrenergic receptor knockout
• Oral self-administration of cocaine and morphine
  decreased
• Substance P receptor knockout
• Rewarding effects of opiates but not cocaine are
  absent
• Cannabinoid CB1 receptor knockout
• Self-administer cocaine but not morphine

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Genetic Organisms are Uncovering Mechanisms of
Action of Drugs of Abuse

• Tolerance
• Beta-Arrestin
• Details
• Withdrawal
• CREB
• Details
• Addiction
• Delta-fosB
• Details

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Why do Genes Matter

• Better understanding of environmental factors in
  addiction
• Will improve treatment interventions
• Facilitate understanding the neurobiology of
  addiction and drug abuse