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Genetics Addiction Jonathan D. Pollock, Ph.D. Division of Neuroscience Behavioral Research National Institute on D

NIDA'S GENETICS PROGRAM. Extramural Program:Genetic EpidemiologyTwin StudiesAdoption studiesMolecular Genetic Studies Model Genetic OrganismsMice C. elegansZebra fishDrosophilaIntramural Research Program (NIDA-IRP). Addiction is a Heritable Disorder. Evidence:Twin StudiesAdoption StudiesInbred Rodent Strains.

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Genetics Addiction Jonathan D. Pollock, Ph.D. Division of Neuroscience Behavioral Research National Institute on D

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    2. 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)

    3. Addiction is a Heritable Disorder Evidence: Twin Studies Adoption Studies Inbred Rodent Strains

    5. 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

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

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

    8. 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

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

    15. 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

    16. Tolerance: Beta-Arrestin Details Withdrawal CREB Details Addiction Delta-fosB Details

    17. Why do Genes Matter Better understanding of environmental factors in addiction Will improve treatment interventions Facilitate understanding the neurobiology of addiction and drug abuse

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