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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
    • NIDA’S 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)
    • Addiction is a Heritable Disorder
      • Evidence :
        • Twin Studies
        • Adoption Studies
        • Inbred Rodent Strains
    • Addiction is a Heritable Disorder: Twin Studies
      • 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
      Addiction is a Heritable Disorder: Inbred Strains of Rodents
      • Possible designs:
        • heritability estimates
        • genome wide scans
        • candidate gene studies
      • Types of studies:
        • sib pairs
        • family studies
        • association studies
      Research Designs for Human Genetic Studies
      • Genes are part of addiction vulnerability:
        • Initiation (limited genetic influence?)
        • Dependence
        • Withdrawal
        • Medical Consequences
      • Some specific genes have been implicated in addiction
      Genes Implicated in Addiction Candidate Genes
      • Variants of genes associated with drug abuse:
        • FAAH missense mutation is associated with drug dependence
        • Dopamine beta-hydroxylase (D BH) – 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
      Genes Implicated in Addiction
    • Genes Affecting Drug metabolism
      • 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
      ADH2 ADH3 ALDH2 ALDH3 CYP2A6
    • SNP Genome Wide Association Scan and Polydrug Abuse
      • NIDA Genetics Consortium –established1999
        • 17 researchers from 11 different institutions
      • Studies focusing on addiction to:
        • Opiates
        • Cocaine
        • Nicotine
        • Poly drug abuse
      Extramural Program: Human Molecular Genetics
    • 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
    • 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
    • NORMAL CONTROL COCAINE WITHDRAWAL Walker, Feinberg & Self, 2000, unpublished Gene Expression by Microarray Profiling Low level High level
        • 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
      Mouse Knockouts: Finding Drug Targets for Treatment ofDrug Abuse
      • Tolerance:
        • Beta-Arrestin
          • Details
      • Withdrawal
        • CREB
          • Details
      • Addiction
        • Delta-fosB
          • Details
      Genetic Organisms are Uncovering Mechanisms of Action of Drugs of Abuse
    • Why do Genes Matter
      • Better understanding of environmental factors in addiction
      • Will improve treatment interventions
      • Facilitate understanding the neurobiology of addiction and drug abuse