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

By Koob, George F.; Simon, Eric J. | Journal of Drug Issues, Summer 2009 | Go to article overview

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


Koob, George F., Simon, Eric J., Journal of Drug Issues


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 identified both at the initial site of action and in the circuitry involved. In human imaging studies, decreases in dopaminergic function have been identified 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 deficits 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 and the molecular biology of addiction targets. Advances in several areas have dominated the field 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 identified 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 identified 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 deficits 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 reflections 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 specific neurocircuits that mediate the transition from occasional, controlled drug use and the loss of behavioral control over drug-seeking, and drug-taking that defines chronic addiction. …

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