genetics & addiction jonathan d. pollock, ph.d. division of neuroscience & behavioral...
Post on 22-Dec-2015
221 Views
Preview:
TRANSCRIPT
Genetics & Addiction
Jonathan D. Pollock, Ph.D.
Division of Neuroscience & Behavioral Research
National Institute on Drug AbuseNational 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
DRUG Males FemalesHeroin (opiates)
Sedatives
Marijuana
Cocaine
Hallucinogens
Nicotine
54% (Tsuang et al., 1996)
87% (Kendler, et al., 2000)
33% (Tsuang et al., 1996)58% (Kendler, et al., 2000)
44% (Tsuang et al., 1996)79% (Kendler et al., 2000)
79% (Kendler, et al., 2000)
53% (Carmelli et al., 1990)
79% (Kendler & Prescott, 1998)
81% (Kendler et al., 1999)
72% (Kendler et al., 1999)
Addiction is a Heritable Disorder: Twin Studies
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
• 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 AddictionCandidate Genes
• 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 beassociated 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
ADH2ADH3
ALDH2ALDH3
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 forGenetic 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
NORMALCONTROL
COCAINEWITHDRAWAL
Walker, Feinberg & Self, 2000, unpublished
Gene Expression by Microarray Profiling
Lowlevel
Highlevel
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
• Tolerance:– Beta-Arrestin
• Details
• Withdrawal – CREB
• Details
• Addiction– Delta-fosB
• Details
Genetic Organisms are UncoveringMechanisms 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
top related