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