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Article

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York

Abstract

I. Introduction

II. Addictions

A. Opiates and Other Opioids

1. Heroin.

2. Codeine.

3. Noncodeine Prescription Opioids.

B. Cocaine

III. Molecular Genetics of Opioid and Cocaine Addictions

A. Epidemiology

B. Molecular Genetic Studies

1. Family and Linkage Studies.

2. Case Control-Association Studies.

3. Haplotype Analysis.

C. Selected Identified Genes

1. Opioid-Related Genes.

a. µ Opioid Receptor Gene (OPRM1).

b. {kappa} Opioid Receptor Gene (OPRK1).

c. {delta} Opioid Receptor Gene (OPRD1).

d. Preproenkephalin Gene (PENK).

e. Preprodynorphin Gene (PDYN).

2. Monoaminergic-Related Genes.

a. Dopamine {beta}-Hydroxylase Gene (D{beta}H).

b. Dopamine Receptor D2 Gene (DRD2).

c. Dopamine Transporter Gene (SLC6A3).

d. Serotonin Transporter Gene (SLC6A4).

e. Norepinephrine Transporter Gene (SLC6A2).

IV. Treatment of Addictions

A. Pharmacotherapies

1. Opiate and Opioid Addictions.

a. Methadone.

b. Levo-{alpha}-acetylmethadol.

c. Buprenorphine.

d. Naltrexone.

e. Clonidine.

2. Cocaine Addiction.

a. Antidepressants.

b. Disulfiram.

c. Dopaminergic Agents.

d. GABAA-GABAB Directed Drugs

V. Pharmacogenetics Related to the Treatment of Addictions

A. Metabolism/Biotransformation of Opiates and Other Opioids

1. Morphine and Heroin.

2. Codeine.

3. Methadone, Levo-{alpha}-acetylmethadol, and Buprenorphine.

B. Metabolism/Biotransformation of Cocaine

VI. Summary

Opiate and cocaine addictions are major social and medical problems that impose a significant burden on society. Despite the size and scope of these problems, there are few effective treatments for these addictions. Methadone maintenance is an effective and most widely used treatment for opiate addiction, allowing normalization of many physiological abnormalities caused by chronic use of short-acting opiates. There are no pharmacological treatments for cocaine addiction. Epidemiological, linkage, and association studies have demonstrated a significant contribution of genetic factors to the addictive diseases. This article reviews the molecular genetics and pharmacogenetics of opiate and cocaine addictions, focusing primarily on genes of the opioid and monoaminergic systems that have been associated with or have evidence for linkage to opiate or cocaine addiction. This evidence has been marshaled either through identification of variant alleles that lead to functional alterations of gene products, altered gene expression, or findings of linkage or association studies. Studies of polymorphisms in the µ opioid receptor gene, which encodes the receptor target of some endogenous opioids, heroin, morphine, and synthetic opioids, have contributed substantially to knowledge of genetic influences on opiate and cocaine addiction. Other genes of the endogenous opioid and monoaminergic systems, particularly genes encoding dopamine -hydroxylase, and the dopamine, serotonin, and norepinephrine transporters have also been implicated. Variants in genes encoding proteins involved in metabolism or biotransformation of drugs of abuse and also of treatment agents are reviewed.

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