The Neurobiology of Addiction: Where We Have Been and Where We Are Going

• DOI: 10.1177/002204260903900110
• Published date: 01 January 2009
• Date: 01 January 2009
• Author: George F. Koob,Eric J. Simon
• Subject Matter: Article

© 2009 BY THE JOURNAL OF DRUG ISSUES

JOURNAL OF DRUG ISSUES 0022-0426/09/01 115-132

__________

George F. Koob, Ph.D., is Professor and Chairman of the Committee on the Neurobiology of Addictive

Disorders at The Scripps Research Institute and Adjunct Professor in the Departments of Psychology

and Psychiatry and the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University

of California, San Diego. He specializes on the neurobiology and theoretical constructs of drug addic-

tion, reward, and stress. Dr. Eric J. Simon is Professor of Psychiatry and Pharmacology at New York

University Medical Center. Dr. Simon’s laboratory has done pioneering research on the mode of action

of narcotic analgesics. In 1973 his laboratory, and others, discovered the opiate receptors in the brain.

He and his collaborators have continued to work on opiate receptors and endogenous opioid peptides

and have published 250 papers in excellent journals. He coined the widely used term “endorphins.”

THE NEUROBIOLOGY OF A DDICTION: WHERE WE HAVE

BEEN AND WHERE WE ARE GOING

GEORGE F. KOOB, ERIC J. SIMON

A number of dramatic breakthroughs in the neurobiology of addiction have

occurred in the past 40 years. Two domains will be highlighted: the neurocircuitry

of addiction and the molecular biology of addiction targets. The neurobiological

substrates for the reinforcing effects of drugs of abuse have been largely identif‌i ed

both at the initial site of action and in the circuitry involved. In human imaging

studies, decreases in dopaminergic function have been identif‌i ed as a key element

of addiction, lending support for research on the role of dopamine in addiction. Three

novel areas currently are emerging: the role of def‌i cits in frontal cortex functioning,

changes in the brain neurocircuitry that convey long-term vulnerability to relapse, and

the role of nondopaminergic systems in the neuroadaptations associated with the

development of drug dependence. Parallel to these functional changes have been

major advances in our understanding of the molecular biology of addiction; the

greatest contribution has been in the understanding of the molecular mechanisms

of opioid action. This paper reviews the major developments in our understanding

of the molecular biology of the endogenous opioid system and the use of genomics

to advance our knowledge of the function and regulation of opioid receptors and

endorphins.

THE PAST AND THE PRESENT

A number of dramatic breakthroughs in the neurobiology of addiction have

occurred in the past 40 years with the support of the National Institute on Drug

Abuse (NIDA). Two domains will be highlighted here: the neurocircuitry of addiction

116 JOURNAL OF DRUG ISSUES

KOOB, SIMON

and the molecular biology of addiction targets. Advances in several areas have

dominated the f‌i eld in the neurocircuitry of addiction. Behaviorists in the United

States laid the groundwork for the development of the animal models of addiction.

The neurobiological substrates for the reinforcing effects of drugs of abuse have

been largely identif‌i ed both at the initial site of action (receptor, reuptake site, etc.) as

well as the circuitry involved (mesocorticolimbic dopamine system and endogenous

opioid systems). In human imaging studies, decreases in dopaminergic function

have been identif‌i ed as a key common element of addiction, lending support to

what became a strong program on the role of dopamine in addiction (Volkow &

Fowler, 2000).

However, as we move into current research, three novel areas are emerging.

The role of def‌i cits in frontal cortex functioning has become an area of intense

investigation. The changes in the brain neurocircuitry that convey long-term

vulnerability to relapse are being studied. The role of nondopaminergic systems in

the neuroadaptations associated with the development of drug dependence has also

moved to the forefront.

Parallel to these functional changes in the neurobiology of addiction have been

major advances in our understanding of the molecular biology of addiction. Perhaps

one of the greatest contributions has been in the understanding of the molecular

mechanisms of opioid action. Dr. Simon’s contribution to these ref‌l ections will be

to review some of the major developments (“breakthroughs”) in our understanding

of the molecular biology and biochemistry of opiate action and the endogenous

opioid system. Clearly, the list of breakthroughs discussed is not exhaustive, and

the topics chosen are those deemed most important by Dr. Simon and within his

areas of interest and expertise.

CONCEPTUAL FRAMEWORK FOR ADDICTION

Drug addiction, or substance dependence, is a chronically relapsing disorder

characterized by: (a) compulsion to seek and take the drug, (b) loss of control in

limiting intake, and (c) emergence of a negative emotional state (e.g., dysphoria,

anxiety, irritability) when access to the drug is prevented. Clinically, the occasional

but limited use of an abusable drug is distinct from escalated drug use and the

emergence of chronic drug dependence. An important goal of current neurobiological

research is to understand the neuropharmacological and neuroadaptive mechanisms

within specif‌i c neurocircuits that mediate the transition from occasional, controlled

drug use and the loss of behavioral control over drug-seeking, and drug-taking that

def‌i nes chronic addiction. Drug addiction has been conceptualized as a disorder that

moves from impulsivity to compulsivity in a collapsed cycle of addiction comprised