This article was downloaded by: [Adelphi University]

On: 22 August 2014, At: 23:33

Publisher: Routledge
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK

Neuropsychoanalysis: An Interdisciplinary Journal for

Psychoanalysis and the Neurosciences
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/rnpa20

Commentary on Understanding Addictive

Vulnerability
a

George F. Koob Ph.D.

a

The Scripps Research Institute, La Jolla, Calif., U.S.A.

Published online: 09 Jan 2014.

To cite this article: George F. Koob Ph.D. (2003) Commentary on Understanding Addictive Vulnerability,
Neuropsychoanalysis: An Interdisciplinary Journal for Psychoanalysis and the Neurosciences, 5:1, 35-39, DOI:
10.1080/15294145.2003.10773406
To link to this article: http://dx.doi.org/10.1080/15294145.2003.10773406

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the Content) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Neuro-Psychoanalysis, 2003, 5 (1)

35

Commentary on Understanding Addictive Vulnerability

George F. Koob

Downloaded by [Adelphi University] at 23:33 22 August 2014

THE NEUROBIOLOGY OF SELF-REGULATION

FAILURE IN ADDICTION: AN ALLOSTATIC VIEW

Dr. Khantzian provides a cogent and scholarly argument for a psychodynamic view of addiction with a
focus on what factors lead to the vulnerability for
addiction. He identifies two critical elements (disordered emotions and disordered self-care) and
two contributory elements (disordered self-esteem
and disordered relationships). He further argues
strongly for a modern self-medication hypothesis
where individuals with substance-use disorders are
hypothesized to take drugs as a means to cope with
painful and threatening emotions. Khantzian
makes the case that addicted individuals experience
states of subjective distress and suffering that may
or may not be associated with conditions meeting
DSM-IV criteria for a psychiatric diagnosis (American Psychiatric Association, 1994) and consist
mainly of feelings that are overwhelming and unbearable, but also may consist of an affective life
that is absent and nameless.
Drug addiction is viewed as an attempt to medicate such a negative affective state, and Khantzian
marshals significant psychodynamic evidence not
only for the negative affective state, but also for the
self-medication hypothesis. In addition, he argues
that self-medication may be drug-specific, in that
patients may have a preferential use of drugs that
fits with the nature of the painful feeling states that
they are self-medicating (e.g., opiates to counter
intense anger and rage, stimulants as augmenting
agents for high-energy individuals, energizing
agents for low-energy individuals, and depressants
for individuals who are tense and anxious). The
common element argued by Khantzian is that each
class of drugs serves as antidotes or correctives to
dysphoric states and acts as a replacement for a
defect in the psychological structure (Kohut, 1971)
of such individuals.
Khantzian further argues that disordered selfcare combines malignantly with the disordered
emotional life to become the principal determinant
of SUDs. Self-care deficits reflect an inability to
ensure ones self-preservation and are characterized
by an inability to anticipate or avoid harmful and
dangerous situations and an inability to use approGeorge F. Koob, Ph.D.: The Scripps Research Institute, La Jolla,
Calif., U.S.A.

priate judgment and feelings as guides in the face

of danger. In other words, self-care deficits reflect
an inability to appropriately experience emotions
and appreciate the consequences of dangerous behaviors. Thus, the core element of his psychodynamic perspective is a dysregulated emotional
system, or systems, in individuals vulnerable to
addiction, and a dysregulation in how the emotions
are expressed, experienced, and corrected.
This psychodynamic approach resonates extremely well with a growing amount of evidence for
a critical role of dysregulated brain reward and
stress systems from studies on the neurobiology of
addiction using animal models that have developed
from a physiological framework. However, from a
neurobiological perspective, the present evolving
psychodynamic view has left out possibly half the
story. Khantzians scholarly contribution explores
the personality and character traits that lead to addiction to drugs but largely ignores what the drugs
do not only to perpetuate such character flaws but
actually to create them. The present commentary
summarizes a physiological view of disordered
emotions that this author believes, as with
Khantzian, is critical for the development of the
self-regulation failures associated with addiction
and addiction-like disorders. In addition, the present
commentary explores how the self-regulation failures can derive not only from what one brings to
drug seeking but also from engaging in the addiction
cycle, thus causing, perpetuating, or worsening the
self-regulation failures, and how this view can explain persistent vulnerability to relapse.
Koob and Le Moal (1997) conceptualized addiction as a continuous process of hedonic homeostatic
dysregulation. They argued that multiple sources of
reinforcement can be identified in a spiraling cycle
of addiction that can provide a heuristic framework
for the self-regulation failures associated with addiction-like behavior, the phenomenology of current
psychiatric diagnoses of addiction, and the neurobiological changes that accompany the development
of addiction (see Figure 1). Three stages of addiction were described that derived from the social
psychological elements of failure to self-regulate
that are observed not only in addiction to drugs
but in addiction-like patterns of behavior seen in
other atypical impulse control disorders: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. Critical for the conceptual

Downloaded by [Adelphi University] at 23:33 22 August 2014

36

George F. Koob

Figure 1
1. Diagram describing the spiraling distressaddiction cycle from three conceptual perspectives: social psychological, psychiatric,
and dysadaptational. Note that the addiction cycle is conceptualized as a spiral that increases in amplitude with repeated experience,
ultimately resulting in the pathological state known as addiction. (A) The three major components of the addiction cyclepreoccupation/
anticipation, binge/intoxication, and withdrawal/negative affectand some of the sources of potential self-regulation failure in the form of
underregulation and misregulation. (B) The same three major components of the addiction cycle with the different criteria for substance
dependence from DSM-IV incorporated (American Psychiatric Association, 1994). (C) The hypothetical role of different neurochemical and
endocrine systems in the addiction cycle. Small arrows refer to increased or decreased functional activity. DA, dopamine; CRF,
corticotropin-releasing factor. (Reproduced by permission from Koob & Le Moal, 1997.)

framework outlined by Koob and Le Moal (1997)

was the negative-affect stage, which was hypothesized to grow larger and larger and to lead to
spiraling distress fueled by various lapse activated
causal patterns associated with self-regulation failure (Baumeister, Heatherton, & Tice, 1994) and that
presumably have neurobiological bases.
The neurobiological basis for the negative affective state important for the development of addiction, and the vulnerability to relapse is argued to
include counteradaptive neurochemical events
within the brain emotional systems normally used to
maintain emotional homeostasis. These include decreases in dopaminergic, serotonergic, and opioid
peptidergic function in specific forebrain areas associated with a macrostructure termed the extended amygdala (Alheid & Heimer, 1988), as well
as recruitment of brain stress systems such as CRF
in this same extended amygdala macrostructure.
The extended amygdala is comprised of several
structures that share similarities in morphology,
neurochemistry, and connectivity and include the
central nucleus of the amygdala, the bed nucleus of
the stria terminalis, and a transition zone in the
medial part of the nucleus accumbens. The extended
amygdala not only has reciprocal connections with
other forebrain structures that process critical information regarding the environment past and present,

but also has major reciprocal connections to the

hypothalamic areas involved in the expression of
emotions.
That drugs are interfacing with the same neural
substrates of emotions that are of evolutionary
significance for emotional fitness has been hypothesized by Panksepp and colleagues based on
studies in rodents (Panksepp, Knutson, & Burgdorf,
2002). Two distinct emotional systemsrewardseeking and separation distressare conceptualized
that are based on changes in rodent ultrasonic vocalization. Drug reward, anticipation of brain-stimulation reward, anticipation of play, and tickling
activate 50-kHz vocalizations in rodents (Burgdorf,
Knutson, & Panksepp, 2000; Burgdorf, Knutson,
Panksepp, & Ikemoto, 2001; Burgdorf & Panksepp,
2001; Knutson, Burgdorf, & Panksepp, 1998,
1999), whereas removal of brain-stimulation reward
and cues that predict aversive outcomes elicit 20kHz vocalizations (Burgdorf, Knutson, & Panksepp,
2000; Burgdorf, Knutson, Panksepp, & Shippenberg, 2001). These studies suggest that the brain
reward systems compromised during the development of addiction and the brain aversive (stress)
systems recruited during development of dependence are the same brain circuits that are part of
normal homeostatic emotional control without
drugs and may be the substrate for the psychody-

Downloaded by [Adelphi University] at 23:33 22 August 2014

Understanding Addictive Vulnerability Commentaries

namic dysregulations that lead to SUDs as described

by Khantzian.
Thus, neurotransmitter systems in specific reward or emotional circuits are hypothesized to function in a normal state in a homeostatically regulated
hedonic system. However, such a hedonic system
has limited resources, and dysregulation of this homeostatic systemeither by constitutive elements
(genetics or development history) or by a history of
drug takingare hypothesized to lead to an allostatic state. This allostatic state in the brain reward
system (or emotional systems, as per Khantzian) not
only produces vulnerability to become addicted but
perpetuates addiction and vulnerability to relapse
(Koob & Le Moal, 2001). In this context, allostasis
is defined as the process of achieving stability
through change; allostatic state is defined as a state
of chronic deviation of the regulatory system from
its normal (homeostatic) operating level; allostatic
load is the cost to the brain and body of the deviation, accumulating over time, and reflected in many
cases by pathological states and accumulation of
damage. More specifically, allostasis from the drugaddiction perspective is a chronic elevation in the set
point for reward as part of the process of maintaining apparent reward-function stability by changes in
reward and stress system neurocircuitry. Decreases
in the function of dopamine, serotonin, and opioid
peptides as well as recruitment of brain stress systems such as CRF are hypothesized to contribute to a
shift in reward set point.

37

The dark side of addiction, or a chronic elevation in reward thresholds, was elaborated further in
Koob and Le Moal (2001) as the driving force for
addiction and as setting up other sources of selfregulation failure (self-care deficits, as defined by
Khantzian) and persistent vulnerability to relapse
(protracted abstinence; see Figure 2). More and
more evidence has accumulated in animal models of
elevations in reward thresholds following acute
withdrawal from all major drugs of abuse (nicotine:
Epping-Jordan, Watkins, Koob, & Markou, 1998;
ethanol: Schulteis, Markou, Cole, & Koob, 1995;
amphetamine: Paterson, Myers, & Markou, 2000;
cocaine: Markou and Koob, 1991; opiates:
Schulteis, Markou, Gold, Stinus, & Koob, 1994;
tetrahydrocannabinol: Gardner & Vorel, 1998).
Even more compelling, in a recent study brainstimulation reward thresholds were shown to increase as a function of escalation of cocaine intake
in an animal model of extended access to the drug
(Ahmed, Kenny, Koob, & Markou, 2002). In the
Ahmed et al. study, there was a significant elevation
in brain-stimulation reward thresholds observed just
after and just before daily intravenous cocaine selfadministration, and this correlated highly with the
significant escalation in drug intake in animals with
extended access to the drug. A driving force for
these changes in brain reward thresholds has been
hypothesized to be recruitment of brain stress systems, since increased activity of these systems also
has been observed during acute withdrawal from

Figure 2. Diagram illustrating an extension of Solomon and Corbits (1974) opponent-process model of motivation to outline the
conceptual framework of the allostatic hypothesis. Both panels represent the affective response to the presentation of a drug. (Top) This
represents the initial experience of a drug with no prior drug history; the a-process represents a positive hedonic or positive mood state, and
the b-process represents the negative hedonic or negative mood state. The affective stimulus (state) has been argued to be a sum of both an aprocess and a b-process. An individual who experiences a positive hedonic mood state from a drug of abuse with sufficient time between readministering the drug is hypothesized to retain the a-process. In other words, an appropriate counteradaptive opponent-process (b-process)
that balances the activational process (a-process) does not lead to an allostatic state. (Bottom) The changes in the affective stimulus (state)
in an individual with repeated frequent drug use that may represent a transition to an allostatic state in the brain reward systems and, by
extrapolation, a transition to addiction. Note that the apparent b-process never returns to the original homeostatic level before drug taking is
reinitiated, thus creating a greater and greater allostatic state in the brain reward system. In other words, the counteradaptive opponentprocess (b-process) does not balance the activational process (a-process) but in fact shows a residual hysteresis. While these changes are
exaggerated and condensed over time in the present conceptualization, the hypothesis here is that even during postdetoxification, a period of
protracted abstinence, the reward system is still bearing allostatic changes. (Reproduced by permission from Koob & Le Moal, 2001.)

Downloaded by [Adelphi University] at 23:33 22 August 2014

38

virtually all major drugs of abuse (Merlo-Pich et al.,

1995; Rodriguez de Fonseca, Carrera, Navarro,
Koob, & Weiss, 1997; Richter & Weiss, 1999;
Zorrilla, Valdez, & Weiss, 2001). The allostatic
view (Figure 2) extends the original view proposed
by Solomon and Corbits (1974) opponent-process
model to changes in the affective state in an individual with repeated frequent drug use and may
represent a transition to an allostatic state in the
brain reward (emotional) systems, and thus a transition to addiction. Under this formulation the apparent counteradaptational b-process (see Figure 2)
never returns to the original homeostatic level before the reinstatement of drug taking but shows a
residual hysteresis, thus creating a greater and
greater elevation of brain reward thresholds, or
greater dysphoria and emotional distress.
This conceptualization is a critical addition to our
thinking about drug addiction, even from a psychodynamic perspective. Although Khantzian discusses it (individuals self-medicate their pain with
drugs at the same time that they continue the pain
and make it worse), he argues that this observation
is a contradiction. From a biological allostatic perspective, it is not a contradiction but wholly consistent. The motivational aspects of drug withdrawal
grow and grow with repeated drug taking, according
to an allostatic hypothesis. Thus, drug taking only
temporarily alleviates the negative affective state
and in the process makes the residual negative affective state or the constitutive negative affective state
worse. The key element missing in Khantzians
psychodynamic perspective is the feedback of the
brains normal, but now abnormal, counteradaptive
mechanisms caused by the drug-taking itself. Add
this element to the equation, and one has an even
more powerful dysregulated emotional system and a
much more debilitated individual from an emotional
perspective.
Finally, as to the pleadings for a measure of
marginality with seeking more ways to integrate
those domains as we focus upon and emphasize our
preferred ones and wait[ing] on the rare Renaissance person, one can support the former (seeking) but not the latter (waiting). As should be
evident by this commentary, there are more areas
for bridging, rather than separating, our psychodynamic and neurobiological domains. We do not
need to wait for an bermensch. We simply need to
read each others work and make commentaries!
REFERENCES

Ahmed, S. H., Kenny, P. J., Koob, G. F., & Markou, A.

(2002). Brain reward deficit drives compulsive drug use,
Nature Neuroscience, 5: 625626.
Alheid, G. F., & Heimer, L. (1988). New perspectives in

George F. Koob
basal forebrain organization of special relevance for neuropsychiatric disorders: The striatopallidal, amygdaloid,
and corticopetal components of substantia innominata.
Neuroscience, 27: 139.
American Psychiatric Association (1994). Diagnostic and
Statistical Manual of Mental Disorders, 4th edition.
Washington, DC: American Psychiatric Press.
Baumeister, R. F., Heatherton, T. F., & Tice, D. M. (1994).
Losing Control: How and Why People Fail at SelfRegulation. San Diego, CA: Academic Press.
Burgdorf, J., Knutson, B., & Panksepp, J. (2000). Anticipation of rewarding electrical brain stimulation evokes
ultrasonic vocalization in rats. Behavioral Neuroscience,
114: 320327.
Burgdorf, J., Knutson, B., Panksepp, J., & Ikemoto, S.
(2001). Nucleus accumbens amphetamine microinjections unconditionally elicit 50-kHz ultrasonic vocalizations in rats. Behavioral Neuroscience, 115: 940944.
Burgdorf, J., Knutson, B., Panksepp, J., & Shippenberg, T.
S. (2001). Evaluation of rat ultrasonic vocalizations as
predictors of the conditioned aversive effects of drugs.
Psychopharmacology, 155: 3542.
Burgdorf, J., & Panksepp, J. (2001). Tickling induces reward in adolescent rats. Physiology and Behavior, 72:
167173.
Epping-Jordan, M. P., Watkins, S. S., Koob, G. F., &
Markou, A. (1998). Dramatic decreases in brain reward
function during nicotine withdrawal. Nature, 393: 7679.
Gardner, E. L., & Vorel, S. R. (1998). Cannabinoid transmission and reward-related events. Neurobiology of Disease, 5: 502533.
Knutson, B., Burgdorf, J., & Panksepp, J. (1998). Anticipation of play elicits high-frequency ultrasonic vocalizations in young rats. Journal of Comparative Psychology,
112: 6573.
Knutson, B., Burgdorf, J., & Panksepp, J. (1999). Highfrequency ultrasonic vocalizations index conditioned
pharmacological reward in rats. Physiology and Behavior, 66: 639643.
Kohut, H. (1971). The Analysis of the Self. New York:
International Universities Press.
Koob, G. F., & Le Moal, M. (1997). Drug abuse: Hedonic
homeostatic dysregulation. Science, 278: 5258.
Koob, G. F., & Le Moal, M. (2001). Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology, 24: 97129.
Markou, A., & Koob, G. F. (1991). Postcocaine anhedonia:
An animal model of cocaine withdrawal. Neuropsychopharmacology, 4: 1726.
Merlo-Pich, E., Lorang, M., Yeganeh, M., Rodriguez de
Fonseca, F., Raber, J., Koob, G. F., & Weiss, F. (1995).
Increase of extracellular corticotropin-releasing factorlike immunoreactivity levels in the amygdala of awake
rats during restraint stress and ethanol withdrawal as
measured by microdialysis. Journal of Neuroscience, 15:
54395447.
Panksepp, J., Knutson, B., & Burgdorf, J. (2002). The role
of brain emotional systems in addictions: A neuro-evolutionary perspective and new self-report animal model.
Addiction, 97: 459469.
Paterson, N. E., Myers, C., & Markou, A. (2000). Effects of
repeated withdrawal from continuous amphetamine ad-

Understanding Addictive Vulnerability Commentaries

Downloaded by [Adelphi University] at 23:33 22 August 2014

ministration on brain reward function in rats. Psychopharmacology, 152: 440446.

Richter, R. M., & Weiss, F. (1999). In vivo CRF release in
rat amygdala is increased during cocaine withdrawal in
self-administering rats. Synapse, 32: 254261.
Rodriguez de Fonseca, F., Carrera, M. R., Navarro, M.,
Koob, G. F., & Weiss, F. (1997). Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science, 276: 20502054.
Schulteis, G., Markou, A., Cole, M., & Koob, G. F. (1995).
Decreased brain reward produced by ethanol withdrawal.
Proceedings of the National Academy of Sciences USA,
92: 58805884.

39

Schulteis, G., Markou, A., Gold, L. H., Stinus, L., & Koob,
G. F. (1994). Relative sensitivity to naloxone of multiple
indices of opiate withdrawal: A quantitative dose-response analysis. Journal of Pharmacology and Experimental Therapeutics, 271: 13911398.
Solomon, R. L., & Corbit, J. D. (1974). An opponentprocess theory of motivation: 1. Temporal dynamics of
affect. Psychological Review, 81: 119145.
Zorrilla, E. P., Valdez, G. R., & Weiss, F. (2001). Changes
in levels of regional CRF-like-immunoreactivity and
plasma corticosterone during protracted drug withdrawal
in dependent rats. Psychopharmacology, 158: 374
381.