1. 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

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

4. Addiction is a Heritable Disorder: Twin Studies

5. 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

6. 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

7. 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

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 Genes Implicated in Addiction

9. 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

10. SNP Genome Wide Association Scan and Polydrug Abuse

11. 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

12. 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

13. 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

14. NORMAL CONTROL COCAINE WITHDRAWAL Walker, Feinberg & Self, 2000, unpublished Gene Expression by Microarray Profiling Low level High level

15. 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

16. Tolerance: –Beta-Arrestin Details Withdrawal –CREB Details Addiction –Delta-fosB Details Genetic Organisms are Uncovering Mechanisms of Action of Drugs of Abuse

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