RESEARCH REPORT
© 2006 American Psychiatric Association. Journal compilation © 2006 Society for the Study of Addiction
Addiction,
101
(Suppl. 1), 23–30
The neurobiology of addiction
George F. Koob
Correspondence to:
George F. Koob, Molecular and Integrative Neurosciences Department, The Scripps Research Institute, 10550 North Torrey Pines Road,
SP30-2400, La Jolla, CA 92037, USA. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
RESEARCH REPORT
The neurobiology of addiction: a neuroadaptational
view relevant for diagnosis
George F. Koob
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA, USA
ABSTRACT
Aims
The purpose of this review is to provide a synthesis of our knowledge of the neurobiological bases of addiction
relevant for the diagnosis of addiction.
Methods
A heuristic framework of neuroadaptive changes within key brain
neurocircuitry responsible for different stages of the addiction cycle is outlined and linked to human studies to provide
important future translational links for diagnosis.
Results
Animal studies have revealed dysregulation of specific
neurochemical mechanisms (dopamine, opioid peptides) in the brain reward systems and recruitment of brain stress
systems (corticotropin-releasing factor) during the development of dependence that convey vulnerability to relapse.
Animal studies have implicated the prefrontal cortex and basolateral amygdala in drug- and cue-induced relapse,
respectively, and the brain stress systems in stress-induced relapse. Genetic studies suggest roles for the genes encoding
the neurochemical elements involved in both the brain reward and stress systems in the vulnerability to addiction, and
molecular studies have identified transduction and transcription factors that may mediate dependence-induced reward
dysregulation. Human imaging studies reveal similar neurocircuits involved in acute intoxication, chronic drug
dependence and vulnerability to relapse.
Conclusions
Major neurobiological changes in substance abuse disorders
common to human and animal studies relevant for diagnosis include a compromised reward system, overactivated
brain stress systems and compromised orbitofrontal/prefrontal cortex function. No biological markers of substance
abuse disorders currently exist, but there are many promising neurobiological features of substance abuse disorders
that will eventually aid in the specific diagnoses of substance use, misuse and dependence.
Keywords
Addiction, animal models, extended amygdala, reward, stress.
NEUROCIRCUITRY OF DRUG REWARD,
DEPENDENCE AND CRAVING
Substance dependence is a chronically relapsing disorder
characterized by: (1) compulsion to seek and take the
drug, (2) loss of control in limiting intake and (3) emergence
of a negative emotional state (e.g. dysphoria, anxiety,
irritability) when access to the drug is prevented
(defined here as dependence) [1]. Addiction and substance
dependence (as currently defined by the
Diagnostic
and Statistical Manual of Mental Disorders
, fourth edition)
will be used interchangeably throughout this text to refer
to a final stage of a usage process that moves from drug
use to abuse to addiction. As such, it can be defined by its
diagnosis, etiology and pathophysiology as a chronic
relapsing disorder. Clinically, the occasional but limited
use of a drug with the potential for abuse or dependence
is distinct from escalated drug use and the emergence of a
chronic drug-dependent state. 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 to the loss of behavioral
control over drug-seeking and drug-taking that
defines chronic addiction.
Much of the recent progress in understanding the
mechanisms of addiction has derived from the study of
animal models of addiction on specific drugs, such as opiates,
stimulants and alcohol [2]. While no animal model
of addiction fully emulates the human condition, animal
models do permit investigation of specific elements of the
process of drug addiction. Such elements can be defined
by models of different systems, models of psychological
constructs such as positive and negative reinforcement
© 2006 American Psychiatric Association. Journal compilation © 2006 Society for the Study of Addiction
Addiction,
101
(Suppl. 1), 23–30
24
George F. Koob
and models of different stages of the addiction cycle.
While much focus in animal studies has been on the
synaptic sites and molecular mechanisms in the nervous
system on which drugs with dependence potential act initially
to produce their positive reinforcing effects, new
animal models of components of the negative reinforcing
effects of dependence have been developed and are beginning
to be used to explore how the nervous system adapts
to drug use. The neurobiological mechanisms of addiction
that are involved in various stages of the addiction
cycle have a specific focus on certain brain circuits and
the neurochemical changes associated with those circuits
during the transition from drug taking to drug
addiction, and how those changes persist in the vulnerability
to relapse [3].
A key element of drug addiction is how the brain
reward system changes with the development of addiction,
and one must understand the neurobiological bases
for acute drug reward to understand how these systems
change with the development of addiction [1,4]. A principle
focus of research on the neurobiology of the positive
reinforcing effects of drugs with dependence potential
has been the origins and terminal areas of the mesocorticolimbic
dopamine system, and there is compelling evidence
for the importance of this system in drug reward.
This specific brain circuit has been broadened to include
the many neural inputs and outputs that interact with
the ventral tegmental area and the basal forebrain, and
as such has been termed by some as the mesolimbic
reward system. More recently, specific components of the
basal forebrain that have been identified with drug
reward have focused on the ‘extended amygdala’ [3,5].
The extended amygdala is comprised of the bed nucleus of
the stria terminalis (BNST), the central nucleus of the
amygdala and a transition zone in the medial subregion
of the nucleus accumbens (shell of the nucleus accumbens).
Each of these regions has certain cytoarchitectural
and circuitry similarities [6]. As the neural circuits for the
reinforcing effects of drugs with dependence potential
have evolved, the role of neurotransmitters/neuromodulators
have also evolved, and four of those systems have
been identified to have a role in the acute reinforcing
effects of drugs: mesolimbic dopamine, opioid peptide,
γ
-
aminobutyric acid (GABA), endocannabinoid.
The neural substrates and neuropharmacological
mechanisms for the negative motivational effects of drug
withdrawal may involve disruption of the same neural
systems implicated in the positive reinforcing effects of
drugs. Measures of brain reward function during acute
abstinence from all major drugs with dependence potential
have revealed increases in brain reward thresholds
as measured by direct brain stimulation reward
[7,8,9,10,11,12]. These increases in reward thresholds
may reflect changes in the activity of reward
neurotransmitter systems in the midbrain and forebrain
implicated in the positive reinforcing effects of drugs.
Examples of such changes at the neurochemical level
include decreases in dopaminergic and serotonergic
transmission in the nucleus accumbens during drug
withdrawal as measured by
in vivo
microdialysis [13,14],
increased sensitivity of opioid receptor transduction
mechanisms in the nucleus accumbens during opiate
withdrawal [15], decreased GABAergic and increased
N
-
methyl-D-aspartate (NMDA) glutamatergic transmission
during alcohol withdrawal [16–19] and differential
regional changes in nicotine receptor function [20,21].
The decreases in reward neurotransmitters have been
hypothesized to contribute significantly to the negative
motivational state associated with acute drug abstinence
and long-term biochemical changes that contribute to
the clinical syndrome of protracted abstinence and vulnerability
to relapse [3].
Different neurochemical systems involved in stress
modulation also may be engaged within the neurocircuitry
of the brain stress systems in an attempt to overcome
the chronic presence of the perturbing drug and to
restore normal function despite the presence of drug.
Both the hypothalamic–pituitary–adrenal axis and the
brain stress system mediated by corticotropin-releasing
factor (CRF) are dysregulated by chronic administration
of drugs with dependence potential with a common
response of elevated adrenocorticotropic hormone and
corticosterone and amygdala CRF during acute withdrawal
from all major drugs with a potential toward
abuse or dependence [22–27]. Acute withdrawal from
drugs also may increase the release of norepinephrine in
the BNST and decrease levels of neuropeptide Y (NPY) in
the central and medial nuclei of the amygdala [28].
These results suggest, during the development of
dependence, not only a change in function of neurotransmitters
associated with the acute reinforcing effects of
drugs (dopamine, opioid peptides, serotonin and GABA)
but also recruitment of the brain stress system (CRF and
norepinephrine) and dysregulation of the NPY brain
antistress system [3]. Activation of the brain stress systems
may contribute to the negative motivational state
associated with acute abstinence [29]. Thus, reward
mechanisms in dependence are compromised by disruption
of neurochemical systems involved in processing
natural rewards and by recruitment of antireward systems
[30].
The neuroanatomical entity termed the extended
amygdala [6] may thus represent a common anatomical
substrate for acute drug reward and a common neuroanatomical
substrate for the negative effects on reward
function produced by stress that help drive compulsive
drug administration. The extended amygdala receives
numerous afferents from limbic structures such as the
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© 2006 American Psychiatric Association. Journal compilation © 2006 Society for the Study of Addiction
Addiction,
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(Suppl. 1), 23–30
basolateral amygdala and hippocampus, and sends efferents
to the medial part of the ventral pallidum and a large
projection to the lateral hypothalamus, thus further
defining the specific brain areas that interface classical
limbic (emotional) structures with the extrapyramidal
motor system [31].
Animal models of ‘craving’ involve the use of drugprimed
reinstatement, cue-induced reinstatement or
stress-induced reinstatement in animals that have
acquired drug self-administration and have then been
subjected to extinction from responding for the drug [2].
Most evidence from animal studies suggests that druginduced
reinstatement is localized to the medial prefrontal
cortex/nucleus accumbens/ventral pallidum circuit
mediated by the neurotransmitter glutamate [32]. In
contrast, neuropharmacological and neurobiological
studies using animal models for cue-induced reinstatement
involve the basolateral amygdala as a critical substrate
with a possible feed-forward mechanism through
the prefrontal cortex system involved in drug-induced
reinstatement [33,34]. Stress-induced reinstatement of
drug-related responding in animal models appears to
depend on the activation of both CRF and norepinephrine
in elements of the extended amygdala (central nucleus of
the amygdala and BNST) [35,36].
In summary, three neurobiological circuits have been
identified that have heuristic value for the study of the
neurobiological changes associated with the development
and persistence of drug dependence. The acute reinforcing
effects of drugs of abuse that comprise the binge/
intoxication stage of the addiction cycle most probably
involve actions with an emphasis on the extended
amygdala reward system and inputs from the ventral tegmental
area and arcuate nucleus of the hypothalamus. In
contrast, the symptoms of acute withdrawal important
for addiction, such as negative affect and increased anxiety
associated with the withdrawal/negative affect stage,
most probably involve decreases in function of the
extended amygdala reward system but also a recruitment
of brain stress neurocircuitry. The craving stage, or
preoccupation/anticipation stage, involves key afferent
projections to the extended amygdala and nucleus
accumbens, specifically the prefrontal cortex (for druginduced
reinstatement) and the basolateral amygdala (for
cue-induced reinstatement). Compulsive drug-seeking
behavior is hypothesized to be driven by ventral striatal–
ventral pallidal–thalamic–cortical loops (Fig. 1) [37].
MOLECULAR AND CELLULAR TARGETS
WITHIN THE BRAIN CIRCUITS
ASSOCIATED WITH ADDICTION
Acknowledging that all drugs of abuse share some
common neurocircuitry actions, namely inhibition of
medium spiny neurons in the nucleus accumbens either
through dopamine or other G
i
-coupled receptors, the
search at the molecular level has led to examining how
repeated perturbation of intracellular signal transduction
pathways leads to changes in nuclear function and
altered rates of transcription of particular target genes.
Altered expression of such genes would lead to altered
activity of the neurons where such changes occur, and
ultimately to changes in neural circuits in which those
neurons operate.
Two transcription factors in particular have been
implicated in the plasticity associated with addiction:
cyclic adenosine monophosphate (cAMP) response element
binding protein (CREB) and
Δ
FosB. CREB regulates
the transcription of genes that contain a CRE site (cAMP
response element) within the regulatory regions and can
be found ubiquitously in genes expressed in the central
nervous system such as those encoding neuropeptides,
synthetic enzymes for neurotransmitters, signaling proteins
and other transcription factors. CREB can be phosphorylated
by protein kinase A and by protein kinases
regulated by growth factors, putting it at a point of convergence
for several intracellular messenger pathways
that can regulate the expression of genes.
Much work in the addiction field has shown that activation
of CREB in the nucleus accumbens, one part of the
brain reward circuit, is a consequence of chronic exposure
to opiates, cocaine and alcohol, and deactivation in
the central nucleus of the amygdala, another part of the
reward circuit. The activation of CREB is linked to the
activation of the ‘dysphoria’-inducing
κ
opioid receptor
binding the opioid peptide dynorphin and has led one
researcher, Eric Nestler, to argue:
There is now compelling evidence that up-regulation
of the cAMP pathway and CREB in this brain region
(nucleus accumbens) represents a mechanism of
‘motivational tolerance and dependence’: these
molecular adaptations decrease an individual’s sensitivity
to the rewarding effects of subsequent drug
exposures (tolerance) and impair the reward pathway
(dependence) so that after removal of the drug the
individual is left in an amotivational, dysphoric, or
depressed-like state [38].
In contrast, decreased CREB phosphorylation has
been observed in the central nucleus of the amygdala
during alcohol withdrawal and has been linked to
decreased NPY function and consequently the increased
anxiety-like responses associated with acute alcohol
withdrawal [39]. These changes are not necessarily
mutually exclusive and point to transduction mechanisms
that could produce neurochemical changes in the
neurocircuits outlined above as important for breaks
with reward homeostasis in addiction.
© 2006 American Psychiatric Association. Journal compilation © 2006 Society for the Study of Addiction
Addiction,
101
(Suppl. 1), 23–30
26
George F. Koob
The molecular changes associated with long-term
changes in brain function as a result of chronic exposure
to drugs of abuse have been linked to changes in transcription
factors, factors that can change gene expression
and produce long-term changes in protein expression
and, as a result, neuronal function. While acute administration
of drugs of abuse can cause a rapid (within
hours) activation of members of the Fos family, such as cfos
, FosB, Fra-1 and Fra-2 in the nucleus accumbens,
other transcription factors (isoforms of
Δ
FosB) accumulate
over longer periods of time (days) with repeated drug
administration. Animals with activated
Δ
FosB have exaggerated
sensitivity to the rewarding effects of drugs of
abuse. Nestler has argued that
Δ
FosB may be a sustained
molecular ‘switch’ that helps to initiate and maintain a
state of addiction. How changes in
Δ
FosB that can last for
days can translate into vulnerability to relapse remains a
challenge for future work [38].
Genetic and molecular genetic animal models have
provided a convergence of data to support the neuropharmacological
substrates identified in neurocircuitry
studies. High-alcohol-preferring rats have been bred that
show high voluntary consumption of alcohol, increased
anxiety-like responses and numerous neuropharmacological
phenotypes, such as decreased dopaminergic
activity and decreased NPY activity [40,41]. In an
alcohol-preferring and -non-preferring cross, a quantitative
trait locus was identified on chromosome 4, a region
Figure 1
Key common neurocircuitry elements in drug-seeking behavior of addiction. Three major circuits that underlie addiction can be
distilled from the literature. A drug-reinforcement circuit (‘reward’ and ‘stress’) is comprised of the extended amygdala, including the central
nucleus of the amygdala, the bed nucleus of the stria terminalis and the transition zone in the shell of the nucleus accumbens. Multiple modulator
neurotransmitters are hypothesized, including dopamine and opioid peptides for reward and corticotropin-releasing factor and norepinephrine
for stress. The extended amygdala is hypothesized to mediate integration of rewarding stimuli or stimuli with positive incentive
salience and aversive stimuli or stimuli with negative aversive salience. During acute intoxication, valence is weighted on processing rewarding
stimuli, and during the development of dependence aversive stimuli come to dominate function. A drug- and cue-induced reinstatement
(‘craving’) neurocircuit is comprised of the prefrontal (anterior cingulate, prelimbic, orbitofrontal) cortex and basolateral amygdala with a primary
role hypothesized for the basolateral amygdala in cue-induced craving and a primary role for the medial prefrontal cortex in druginduced
craving, based on animal studies. Human imaging studies have shown an important role for the orbitofrontal cortex in craving. A
drug-seeking (‘compulsive’) circuit is comprised of the nucleus accumbens, ventral pallidum, thalamus and orbitofrontal cortex. The nucleus
accumbens has long been hypothesized to have a role in translating motivation to action and forms an interface between the reward functions
of the extended amygdala and the motor functions of the ventral striatal–ventral pallidal–thalamic–cortical loops. The striatal–pallidal–thalamic
loops reciprocally move from prefrontal cortex to orbitofrontal cortex to motor cortex, leading ultimately to drug-seeking behavior. Note
that for the sake of simplicity, other structures are not included, such as the hippocampus (which presumably mediates context-specific learning,
including that associated with drug actions). Also note that dopamine and norepinephrine both have widespread innervation of cortical
regions and may modulate function relevant to drug addiction in those structures. DA, dopamine; ENK, enkephalin; CRF, corticotropinreleasing
factor; NE, norepinephrine;
β
-END,
β
-endorphin (reproduced with permission from Koob & Le Moal [37])
The neurobiology of addiction
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to which the gene for NPY has been mapped. In the
inbred preferring and non-preferring quantitative trait
loci analyses, loci on chromosomes 3, 4 and 8 have been
identified which correspond to loci near the genes for the
dopamine D
2
and serotonin 5HT
1B
receptors [42].
Advances in molecular biology have led to the ability
to inactivate systematically the genes that control the
expression of proteins that make up receptors or neurotransmitter/
neuromodulators in the central nervous
system using the gene knock-out approach. Knock-out
mice have a gene inactivated by homologous recombination.
A knock-out mouse deficient in both alleles of a gene
is homozygous for the deletion and is termed a null mutation
(–/–). A mouse which is deficient in only one of the
two alleles for the gene is termed a heterozygote (
+
/–).
Transgenic knock-in mice have an extra gene introduced
into their germ line. An additional copy of a normal gene
is inserted into the genome of the mouse to examine the
effects of overexpression of the product of that gene.
Alternatively, a new gene, not normally found in the
mouse, can be added, such as a gene associated with specific
pathology in humans. Wild-type controls are animals
bred through the same breeding strategies involving
mice that received the transgene injected into the fertilized
egg (transgenics) or a targeted gene construct
injected into the genome via embryonic stem cells
(knock-out) but lacking the mutation on either allele of
the gene in question. While such an approach does not
guarantee that these genes are the ones that convey vulnerability
in the human population, they provide viable
candidates for exploring the genetic basis of endophenotypes
associated with addiction [43].
Notable positive results with gene knock-out studies in
mice have focused on knock-out of the
μ
opioid receptor,
which eliminates opioid, nicotine and cannabinoid
reward and alcohol drinking in mice [44]. Opiate (morphine)
reinforcement as measured by conditioned place
preference or self-administration is absent in
μ
knock-out
mice, and there is no development of somatic signs of
dependence to morphine in these mice. Indeed, to date all
morphine effects tested, including analgesia, hyperlocomotion,
respiratory depression and inhibition of gastrointestinal
transit are abolished in
μ
knock-out mice
[45].
Selective deletion of the genes for expression of different
dopamine receptor subtypes and the dopamine transporter
has revealed significant effects to challenges with
psychomotor stimulants [46,47]. Dopamine D
1
receptor
knock-out mice show no response to D
1
agonists or
antagonists and show a blunted response to the locomotor-
activating effects of cocaine and amphetamine. D
1
knock-out mice also are impaired in their acquisition of
intravenous cocaine self-administration compared with
wild-type mice. D
2
knock-out mice have severe motor
deficits and blunted responses to psychostimulants and
opiates, but the effects on psychostimulant reward are
less consistent. Dopamine transporter knock-out mice
are dramatically hyperactive but also show a blunted
response to psychostimulants. Although developmental
factors must be taken into account for the compensatory
effect of deleting any one or a combination of genes, it is
clear that D
1
and D
2
receptors and the dopamine transporter
play important roles in the actions of psychomotor
stimulants [48].
BRAIN IMAGING CIRCUITS INVOLVED IN
HUMAN ADDICTION
Brain imaging studies using positron emission tomography
with ligands for measuring oxygen utilization or glucose
metabolism or using magnetic resonance imaging
techniques are providing dramatic insights into the neurocircuitry
changes in the human brain associated with
the development and maintenance and even vulnerability
to addiction. These imaging results bear a striking
resemblance to the neurocircuitry identified by human
studies. During acute intoxication with alcohol, nicotine
and cocaine there is an activation of the orbitofrontal
cortex, prefrontal cortex, anterior cingulate, extended
amygdala and ventral striatum. This activation is often
accompanied by an increase in availability of the neurotransmitter
dopamine. During acute and chronic withdrawal
there is a reversal of these changes with decreases
in metabolic activity, particularly in the orbitofrontal cortex,
prefrontal cortex and anterior cingulate, and
decreases in basal dopamine activity as measured by
decreased D
2
receptors in the ventral striatum and prefrontal
cortex. With limited studies, cue-induced reinstatement
appears to involve a reactivation of these
circuits resembling acute intoxication [49–51]. Two
strongly represented markers for active substance dependence
in humans across drugs of different neuropharmacological
actions are decreases in prefrontal cortex
metabolic activity and decreases in brain dopamine D
2
receptors that are hypothesized to reflect decreases in
brain dopamine function.
CONCLUSIONS
Much progress in neurobiology has provided a heuristic
neurocircuitry framework with which to identify the
neurobiological and neuroadaptive mechanisms involved
in the development of drug addiction. The brain reward
system implicated in the development of addiction is comprised
of key elements of a basal forebrain macrostructure
termed the extended amygdala and its connections.
Neuropharmacological studies in animal models of
addiction have provided evidence for the dysregulation of
© 2006 American Psychiatric Association. Journal compilation © 2006 Society for the Study of Addiction
Addiction,
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(Suppl. 1), 23–30
28
George F. Koob
specific neurochemical mechanisms in specific brain
reward neurochemical systems in the extended amygdala
(dopamine, opioid peptides, GABA and endocannabinoids).
There also is recruitment of brain stress systems
(CRF and norepinephrine) and dysregulation of brain
antistress systems (NPY) that provide the negative motivational
state associated with drug abstinence. The
changes in reward and stress systems are hypothesized to
remain outside a homeostatic state, and as such convey
the vulnerability for development of dependence and
relapse in addiction. Additional neurobiological and neurochemical
systems have been implicated in animal models
of relapse with the prefrontal cortex and basolateral
amygdala (and glutamate systems therein) being implicated
in drug- and cue-induced relapse, respectively. The
brain stress systems in the extended amygdala are
directly implicated in stress-induced relapse. Genetic
studies to date in animals suggest roles for the genes
encoding the neurochemical elements involved in the
brain reward (dopamine, opioid peptide) and stress (NPY)
systems in the vulnerability to addiction, and molecular
studies have identified transduction and transcription
factors that may mediate the dependence-induced
reward dysregulation (CREB) and chronic-vulnerability
changes (
Δ
FosB) in neurocircuitry associated with the
development and maintenance of addiction. Human
imaging studies reveal similar neurocircuits involved in
acute intoxication, chronic drug dependence and vulnerability
to relapse.
While no exact imaging results necessarily predict
addiction, two salient changes in established and unrecovered
substance-dependent individuals that cut across
different drugs are decreases in orbitofrontal/prefrontal
cortex function, decreases in brain dopamine D
2
receptors
and overactive brain stress systems. No biochemical
markers are sufficiently specific to predict a given stage of
the addiction cycle, but changes in certain intermediate
early genes with chronic drug exposure in animal models
show promise of long-term changes in specific brain
regions that may be common to all drugs of abuse.
Although there are no biological markers of substance
abuse disorders on the immediate horizon, there are
many promising and continually evolving biological and
neurobiological features of substance use disorders that
eventually will aid in the specific diagnoses of substance
use, misuse and dependence.
Acknowledgements
Research was supported by National Institutes of Health
grants AA06420 and AA08459 from the National Institute
on Alcohol Abuse and Alcoholism, DA04043 and
DA04398 from the National Institute on Drug Abuse,
and DK26741 from the National Institute of Diabetes and
Digestive and Kidney Diseases. Research also was supported
by the Pearson Center for Alcoholism and Addiction
Research at The Scripps Research Institute. The
author would like to thank Mike Arends for his assistance
with manuscript preparation. This is publication number
18120-MIND from The Scripps Research Institute.
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