October 2011, Vol. 101, No. 10 SAMJSouth African Medical .docx

October 2011, Vol. 101, No. 10 SAMJ
South African Medical Journal
First published January 1884
October 2011, Vol. 101, No. 10 SAMJ
673
Addiction
By addiction we usually mean continued involvement and
dependence
on drugs, including alcohol and tobacco. But addiction can also
include an abnormal dependency on many other things,
including
pornography, gambling and food.
South Africa’s 2nd Biennial Anti-Substance Abuse Summit in
Durban, with the theme ‘An Integrated Approach: Towards a
Drug-
free Society’, was recently hosted by the Department of Social
Development and the Central Drug Authority (CDA) and was
attended by many ministers and top politicians. However,
Charles
Parry and Bronwyn Myers in this issue1 argue persuasively that
it is
time to move away from the outdated political rhetoric of a
‘drug-free
society’ and to engage in the work of formulating and
implementing
an evidence-based policy.

Problem gambling, another destructive form of addiction, also
potentially has devastating effects on individuals and their
families.
Collins and colleagues,2 also in this issue, describe the
effective
management of this problem by the industry-supported National
Responsible Gambling Programme (NRGP).
Substance abuse can be classified in terms of its potential
harms.
Nutt and colleagues3 ranked drugs on the basis of their
potential
for physical harm, dependence (addiction), and effects on
families,
communities and society, thereby offering a rational solution to
a
previously arbitrary classification. Tobacco is one of the most
addictive
substances, although its harmful effects are usually only
apparent
after long periods of time. Addiction to the more psychoactive
drugs often poses more immediate and bigger problems to
families
and societies. It is in the management of these that supporters
and
opponents of the decriminalisation of drugs often share a
common
view, namely that such people require expert medical and other
help
and support and not stigmatisation or incarceration in jail.
A recent book Recovery RSA: A Resource Book for Those
Affected
by Addiction4 has made a timely appearance. Compiled by
Barbara
Hutton, it draws on the experiences of many experts in the field

and is
aimed at addicts, families, significant others, professionals and
support
people. There is something of value for everyone with an
interest in the
field. The somewhat uneven length and quality of the chapters
and the
interspaced personal experiences of those with addictions
strangely do
not detract from the value of the book – professionals and lay
people
will return to the areas that most interest them.
The reasons for people becoming addicted to psychoactive
substances are dealt with by Rodger Meyer. He describes the
pathogenesis and the process of becoming addicted and notes
that
there is still very little agreement among authorities regarding
the
true nature of the condition. People commence drug or alcohol
use
for reasons that by and large are obvious: most people start
using
drugs or alcohol in the pursuit of intoxication, much like a
primitive
biological drive for needs like shelter, food, water and sex;
curiosity
initiates much alcohol and drug use; people commence drug or
alcohol use as the cultural norm of celebration; some use drugs
and
alcohol as a deliberate form of deviation; others commence
substance
use as a form of medication; some use substances to blur the
jagged
edges of their confused lives (obfuscation); and finally, some
use

drugs or alcohol in an attempt to destroy themselves
(annihilation).
Several chapters deal with different aspects of treatment of
substance abuse and addiction. Most professionals acknowledge
that addiction is an illness that affects the brain and that the
addict
needs treatment, like anyone suffering from a disease. There is
also
little doubt that environmental and social factors impact on the
addict and have to be acknowledged and dealt with if treatment
is
to be successful. Katy Mennell describes the dramatic effects
that
addiction can have on families and ‘concerned others’,
interspersed
with personal tales of those who had such tough experiences.
Family members may be helpful in the process of treatment, but
may also be unwitting enablers of continuing the addiction. For
all of them knowledge of the nature and effects of addiction is
an
important starting point. Medical and/or psychiatric illnesses
can be
caused by or associated with the addiction, or they can be
present
coincidentally, i.e. together with or alongside the addiction.
This
co-morbidity is dealt with in a chapter by Anthony Teggin.
The paper ‘Time to decriminalise drugs?’5 in South Africa
evoked
considerable comment, the majority favouring
decriminalisation.
Many who opposed such moves6 were people who had close
experience

with the harms of addiction. We all agree that the abuse of
drugs is
a scourge that is harmful to individuals, their families and
society.
However, because of the failure of the decades-long ‘war on
drugs’,
the need to reconsider drug policies and provide better solutions
is
gaining worldwide traction, e.g. the feature article of Time
magazine
of 11 July dealt with the tragedy of Mexico’s drug wars, which
resulted
in over 15 000 deaths due to violence in 2010; the New England
Journal of Medicine7 lamented the ‘epidemic of incarceration in
the
United States’, noting that the US has 5% of the world’s
population but
25% of people incarcerated, much due to the war on drugs; and
the
‘Report of the Global Commission on Drug Policy’8 concluded
inter
alia: ‘End the criminalization, marginalization and
stigmatization of
people who use drugs but who
do no harm to others. Challenge
rather than reinforce common
misconceptions about drug
markets, drug use and drug
dependence.’
The government can provide
leadership by re-evaluating the
whole question of substance
abuse based on the best
evidence. But individuals and
society must all contribute to

this effort.
J P de V van Niekerk
Managing Editor
1. Parry C, Myers B. Beyond the rhetoric: Towards a more
effective and humane drug policy framework
in South Africa. S Afr Med J 2011;101:704-706.
2. Collins P, Stein DJ, Pretorius A, et al. Addressing problem
gambling: South Africa’s National
Responsible Gambling Programme. S Afr Med J 2011;101:722-
723.
3. Nutt D, King LA, Saulsbury W, Blakemore C. Development
of a rational scale to assess the harm of
drugs of potential misuse. Lancet 2007;369:1047-1053.
4. Hutton B. Recovery RSA: A Resource Book for Those
Affected by Addiction. Auckland Park:
Stonebridge Books, 2011.
5. Van Niekerk JPdeV. Time to decriminalise drugs? S Afr Med
J 2011;101:79-80.
6. Van Eeden A. Harm reduction – more than just side-effects. S
Afr Med J 2011;101:358-359.
7. Rich JD, Wakeman SE, Dickman SL. Medicine and the
epidemic of incarceration in the United States.
N Engl J Med 2011;364:2081-2083.
8. Report of the Global Commission on Drug Policy June 2011.
www.globalcommissionondrugs.org
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Assignment 2 Uses of Statistical Information Paper
Prepare a 700- to 1,050-word paper in which you describe the
use of statistics within your workplace or a company with which
you are familiar. Address the following questions in your paper.
·
·
used in your workplace?
·
used in your workplace?
· of the four levels of
measurement used in your workplace? If your workplace does
not use all four levels, describe how such data could be used.
·
interpretation of statistical information to improve
decision making in your organization? Format your paper
consistent with APA (6th edition) guidelines.
Addiction as a psychological symptom
Lance M. Dodes*
Harvard Medical School, Boston, MA, USA

Psychodynamic understanding of addiction has advanced greatly
in the
recent decades. At the same time, there has been a tendency in
both
popular and academic discussions of addiction to overlook its
psychological explanation in favour of a neurobiological view.
In this
paper I will summarize the understanding of the psychological
nature of
addiction I have described over the past 20 years, as well as the
current
state of neurobiological knowledge of addictive behaviour and
define
where each is clinically applicable. Addictive behaviour can be
shown to
nearly always be a purely psychological symptom, a type of
psychological compulsion. Neurobiological factors can be
shown to be
operative in impulsive and conditioned behaviours which are
also,
confusingly, called ‘addictions’. The fact that very different
clinical
entities share the same name has contributed to the ongoing
misunderstanding between psychological and neurobiological
views. A
blurring of the differences between human psychology and
behaviour in
lower animals has also contributed to the problem, leading some
neurobiological researchers to mistakenly generalize
conclusions about
human addictive behaviour from animal models.
Keywords: addiction; psychology; compulsion; treatment;
substance
abuse; neurobiology

Introduction
There has been considerable interest in both psychological and
neurobiolo-
gical investigations of addiction in recent years. While many
clinicians have the
view that both neurobiological and psychological factors may
play a role in
addiction, these perspectives diverge greatly in their
conclusions about the
very nature of addiction, as well as its proper treatment. Hence,
while each has
applicability, it is not correct to assume that both are operative
in any given
clinical situation. The choice of treatment approaches, and the
ability to help
patients to understand the nature of their particular problem,
hinges on which
view applies to that clinical condition. Indeed, these disparate
views describe
*Email: [email protected]
Psychodynamic Practice
Vol. 15, No. 4, November 2009, 381–393
ISSN 1475-3634 print/ISSN 1475-3626 online
� 2009 Taylor & Francis
DOI: 10.1080/14753630903230468
http://www.informaworld.com
very different phenomena which are, unfortunately, both called
‘addiction’.

Contemporary psychological and neurobiological views will be
examined and
a proposal made for defining the roles of each.
A contemporary view of the psychology of addiction
1
Earlier psychological views of addiction centred on addictive
behaviour as a
self-medication (Khantzian, 1985; Milkman & Frosch, 1973), as
a substitute
for a lost person (Krystal & Raskin, 1970; Wieder & Kaplan,
1969; Wurmser,
1974), as a rebellion against self-punishing thoughts (Wurmser,
1984), and as a
solution for narcissistic injury (Kohut & Wolf, 1978; Wurmser,
1974), among
others. More recently I have proposed a view which is
consistent with but
considerably extends earlier formulations (Dodes, 1990, 1996,
2002). The
following briefly summarizes the three central parts of this view
(a fuller
discussion of this perspective may be found in the references
cited).
The psychological function of addiction
New (not continuously occurring) addictive acts are preceded by
a feeling of
overwhelming helplessness or powerlessness. These feelings are
not restricted
to deprivation of basic needs such as food or sex (as will be
seen to be the model
for neurobiological views), but vary depending upon what is
emotionally

important to the individual. Consequently, issues that may
create the
experiences of overwhelming helplessness which precede
addictive acts are
highly varied. They include developmentally early
deprivation/attachment
failures, conflicts around control and competitiveness with
corresponding
feelings of humiliation and narcissistic injury (shame), and
indeed every
variation and level of psychopathology. Inunderstanding and
treating any one
person it is essential to discover the specific kinds of
helplessness which are
significant for that individual. Addictive behaviour, indeed even
just the
decision to take an addictive action, functions to repair this
underlying feeling
of helplessness because the very decision to act undoes a sense
of power-
lessness. Taking drugs is particularly suitable for the purpose of
regaining a
sense of control because drugs are an especially good way to
choose one’s
emotional state. However, many other activities such as
gambling, exercising
or cleaning may carry the meaning of regaining control. This
reversal of
helplessness may be described as the psychological function of
addiction. It
must be repeated as the experience of helplessness recurs,
resulting in the
repetitive, compulsive act we know as the addiction.
The emotional drive behind addiction

States of overwhelming helplessness inevitably produce a kind
of rage – an
essentially normal fury at the loss of ability to be in control of
one’s own life
382 L.M. Dodes
(Dodes, 1990, 1996; Kohut, 1972). The extent of this rage
corresponds to the
severe narcissistic injury inherent in overwhelming
helplessness, and it is
accurately called ‘narcissistic rage’. Notably, narcissistic rage
has specific
characteristics which are identical to those of addiction. This
rage has been
well-described as a
deeply anchored, unrelenting compulsion [with] utter disregard
for reasonable
limitations [and] ‘boundless’ qualities . . . narcissistic rage
enslaves the [person]
and allows [him] to function only as its tool and rationalizer.
[In chronic
narcissistic rage] . . . ideation, in particular as it concerns the
aims and goals of
the personality, becomes more and more subservient to the
pervasive rage
(Kohut, 1972, pp. 382, 387, 396).
Substituting the word ‘addiction’ for the term ‘narcissistic rage’
in this
description creates a near-perfect clinical picture of addiction.
In my view,
this is precisely because it is the narcissistic rage at

helplessness that is
present in all addictive acts that is the drive behind addiction.
Said another
way, it is narcissistic rage at helplessness that gives to
addiction its most
significant clinical properties, as described above.
Despite the central role of narcissistic rage in addiction, it is
important to
emphasize that people with addictions do not as a group suffer
with any one
psychopathology, and specifically do not suffer with a
narcissistic character.
Narcissistic injuries serious enough to lead to addiction as an
attempted
solution may occur at any developmental level without
producing a
character that is dominantly narcissistic.
In treatment with patients with addiction, it is frequently
helpful for
them to understand this emotional mechanism. It helps to clarify
that their
seemingly irrational behaviour, along with its apparent
disregard of its
harmful effects on themselves and others, is not a sign of moral
turpitude or
other weakness. It is a compulsion whose nature and basis can
be
understood and even has some aspects that are quite normal,
although
misplaced (see below).
Addiction as a displaced action
In addictions, the emotional purpose and drive described above

are always
expressed in displacement – in a substitute action. Several
clinical examples
are presented below. Displacements are psychologically
necessary because
taking a direct (non-displaced) action to respond to perceived
helplessness
(fighting back in some direct way) is usually inhibited as
morally
unacceptable or otherwise forbidden. The result of this is a
compulsion to
repeat the substitute action, which now carries the meaning and
impetus to
reverse helplessness. This final event is what is called the
addiction. Indeed,
we name addictions by the displacement. If the drive to reverse
a sense of
helplessness is displaced to drinking, we say the addiction is
alcoholism. If it
Psychodynamic Practice 383
is displaced to gambling, it is ‘pathological gambling’ and so
forth. The fact
that addictions may be understood as displacements helps to
explain why
people with addictions can so often shift from one addictive
behaviour to
another, whether from one drug to another or from a drug to a
non-drug
addiction such as gambling (Steinberg, Kosten, & Rounsaville,
1992) or to
many other compulsive behaviours such as compulsive cleaning.
They have

simply shifted their displacement.
Vignette 1 (Dodes, 1996)
A business owner who had a history of alcoholism had been
robbed for
years by his son’s embezzlement from the family company.
When he
discovered that the son’s thefts from the company were far
greater than he
had known, he ended many months of sobriety in a two-day
alcoholic binge.
Investigation in psychotherapy revealed the long-standing
helpless rage he
had felt about his son’s thefts, a helplessness that was produced
by his
internal moral prohibition about firing his son (‘You don’t fire
your own’,
he’d said). He reported that he finally had the thought, ‘The hell
with it!’,
drinking was ‘the only thing left that I could do’. His drinking
reasserted an
internal sense of power (he had to do something to not feel
helpless) and it
was fuelled by his rage at his helplessness (despite months of
effort to stay
sober he finally said, ‘The hell with it!’). However, his
inhibition about
taking action against his son required that he repair his
powerlessness via a
displacement: he drank instead of firing his son.
Of course, more deeply his behaviour was the result of
conflictual
feelings about the relationship between a father and his son,
including that

with his own father in the past. The addiction, then, was a
symptom that
arose from the conflict between wanting to destroy and protect
his son (and
father), and it arose when he was faced with his helplessness
around acting
upon this central psychological issue. In his psychotherapy, it
was critical to
understand this relationship between his most important
psychological
issues and his addiction. Conversely, when urges to drink
recurred, we could
make good use of them to see how his key emotional issues
were arising
invisibly in his life.
A 32-year-old married woman drank excessively and
destructively in the
context of unexpressed and barely conscious rage, mostly
toward her husband
who regularly slighted and insulted her. In turn, she responded
with passive
acquiescence but then secretly drank, reasserting herself against
her (self-
imposed) helplessness to deal with him forcefully and directly.
On one
occasion, she reported that her husband gave her a letter to mail
in his usual
imperious style. Instead of obeying then drinking, this time she
lost the letter.
384 L.M. Dodes

A short time later she found it, whereupon she lost it again. Her
repeatedly
losing the letter was a parapraxis – an unconscious
psychologically-
determined action that accomplished the same reversal of
helplessness as her
drinking had done, and replaced drinking as a means of
accomplishing this.
Her ability to substitute a different psychological symptom for
her drinking
underscores the nature of addiction as itself a psychological
symptom. In
treatment, the investigation of this new parapraxis symptom and
its ability to
replace her drinking was likewise helpful for her. Her usual
shame-filled
attitude toward her alcoholism lessened as she could see that
her drinking was
an understandable emotional symptom neither more nor less
morally tinged
than her inadvertent misplacement of the letter.
Another woman who addictively used the drug Percocet also
had a verbally
abusive husband. He repeatedly called her in the middle of her
day with the
command to prepare a fancy dinner for business guests that
evening. She
hated these dinners but always agreed on the phone, followed
immediately
by an overwhelming urge to take some of the Percocets she kept
in supply at
home. After a period of time in psychotherapy, when she had

begun to
understand the emotional mechanism of her addiction, she
reported the
following story. Her husband had once again called to tell her to
prepare
dinner for guests that evening. After meekly acquiescing she
walked over to
the medicine cabinet where she kept her Percocets. She was just
standing
there, she said, when she came up with a solution. She said she
knew by now
that she ought to have stood up to her husband, but she couldn’t
bring
herself to do that. However, it suddenly occurred to her that
there was
another way out – she could order Chinese food to be delivered
for dinner.
At that moment, she reported her addictive craving vanished.
In this case, this woman was able to find a more direct way than
repeating
her addictive drug use to reverse her usual helplessness. Having
another way of
performing this psychological task, her need to repeat her
addictive behaviour
disappeared. In psychotherapeutic treatment of people with
addictions,
finding a more direct way to repair feelings of overwhelming
helplessness is a
common, helpful result. It becomes possible when they
recognize the specific
issues within them that produce their addictive urges and which
produce them
at just the point that they occur. Resolution of deeper causes of
the propensity
to feel helpless regularly takes longer, but addictive behaviour

often ceases to
be a problem from an early point in treatment.
2
Addiction and compulsion
The psychology of addiction as described is equally applicable
to many of the
psychologically-generated symptoms called ‘compulsions’ (as
distinguished
from the biological entity Obsessive-Compulsive Disorder
[OCD], whose
cause is unknown but whose manifestations are frequently well-
treated with
SSRI medication, something not true for psychologically-based
compulsions).
The mechanism of displaced expression of drive is fundamental
to the action of
compulsions, and addictions are neither more nor less than one
form of
compulsion. The unity of addictions and compulsions is evident
clinically in
the common ability of people to substitute other compulsive
behaviours
(exercizing, obsession with the internet, etc.) for behaviours
historically called
addictions. Recognizing this unity is often helpful to patients in
treatment
when they shift their focus from a behaviour known as an
addiction to another

compulsive behaviour which is not usually thought of as an
addiction. It
enables both patient and treater to see the new behaviour as
simply a change in
displacement rather than a truly new symptom (Dodes, 1996,
2002).
The identity of addictions and compulsions also dispels an old
myth
about addiction: that people with addictions have a single
psychodynamic
explanation, often historically postulated to be primitive, and
are
untreatable by psychodynamic therapy or psychoanalysis itself.
This is
decidedly untrue (Dodes, 2004, 2005). In fact, as mentioned
above, the
issues provoking feelings of severe helplessness in people may
involve any
developmental level and as a group addicts run the gamut of
mental health
from the severely disturbed to quite healthy neurotic levels
(Dodes, 1990,
1996; Johnson, 1992). This is possible because, as with
compulsions in
general, the addictive mechanism I have described may be
present within
any personality structure. Consequently, as with people who
have other
compulsions, those with addictions may be fully capable of
psychodynamic
or even psychoanalytic treatment. Their suitability for such
treatment will
depend not on the severity of the addiction (measured by its
effects on their
lives) but on the capacity of their underlying character to

engage in the
psychotherapeutic work.
The fact that the use of an addictive mechanism may occur
within a broad
range of personality structures, including quite healthy
individuals, is one
reason that psychotherapeutic treatment of addiction should
excite more
optimism than is often the case. A degree of pessimism about
treatment of
people with addictions has also been the consequence of its
treatment having
failed to focus on the central issues as described. Too often,
treatment efforts
stress motivational issues which presume that compulsive
behaviour is
repeated because of a lack of motivation to stop it; or taking
valuable time
focusing on the consequences, rather than the causes, of
addictive behaviour;
or ignoring the addictive behaviour altogether, instead sending
patients away
to addiction counsellors as if the addiction could be treated as
an unrelated
behavioural aberration while the psychotherapy proceeds
separately. Given
appropriate attention to the psychodynamic nature of addiction
as described
here, the prognosis for people with addictive behaviour is the
same as for those
with other compulsions.
386 L.M. Dodes

Brief summary of neurobiological factors in addiction
In contrast with a psychological understanding of addiction,
recent
neurobiological investigation has led to the proposal that drug
addiction
is the result of enhanced responsiveness of the reward-seeking
structure of
the brain. A full review of this literature is beyond the scope of
this paper
but it has been reviewed elsewhere (Kalivas & Volkow, 2005;
Nestler, 2002;
Volkow, Fowler, Wang, Swanson, & Telang, 2007). The central
findings of
this view are briefly summarized below.
A number of systems and receptor targets have been identified
as the
principal sites of action of different drugs. These systems are
related to
reward pathways and presumably evolved to respond to natural
rewards
such as food and sex (Nestler, 2002). Cravings and associated
relapse are
thought to be related to ongoing alterations in these reward
systems which
can persist beyond the last drug use. Specifically, many drugs
of abuse
increase extracellular concentration of dopamine in the area of
the brain
called the nucleus accumbens. Firing of dopamine cells may
also occur in
response to salient stimuli which are associated with drugs (e.g.
drug
paraphernalia). This finding has been interpreted by some

researchers to
mean that addiction is a ‘chronic brain disease’ in which the
brain is
hyperresponsive to cues in the environment, setting off an
uncontrollable
urge to repeat use of a drug. This would be a physiological,
rather than
psychological, conditioned response, producing ‘automatic’
behaviours,
compulsions and habits (Volkow et al., 2007). This conditioned
response can
be demonstrated in rats, and has been extrapolated to humans
because
humans possess similar systems (although humans also possess
higher
functions that are capable of interacting with and mediating the
expression
of basic drives). In addition, long-term drug use is associated
with decreased
dopamine function and reduced activity of frontal areas of the
brain. This
finding has been seen as possibly leading to loss of ‘executive
control’
(Kalivas & Volkow, 2005; Volkow et al., 2007) possibly
contributing to
impulsive behaviour. This could apply to addictive acts when
they are
impulsive, i.e. not planned or delayed.
A number of studies have also shown a significant role for
genetics in
addictions. Investigations have involved multiple techniques
including twin
studies, family studies, adoption studies, and direct efforts to
locate genes or
areas on chromosomes that might be linked with expression of

an addictive
behaviour such as alcoholism (Dodes, 2002). Among the
findings of these
studies is the interesting result that people with the same genes
(identical
twins) have a less than 50% concordance for alcoholism (i.e. if
one twin has
alcoholism, it is statistically likely that the other does not).
Although no
genes have ever been found that are linked to addiction, these
studies have
led to the hypothesis that there may be many ‘susceptibility’
genes which
could bear on the final behaviour (Foroud & Li, 1999;
Schumann et al.,
2008). While the kinds of addictive behaviours that are
influenced by genetic
susceptibility have not been defined, it is reasonable to assume
that genetic
factors play the greatest role in the form of ‘addiction’ that is
described by
the neurobiological model.
The role of complexity theory
The word ‘addiction’ has been used to describe two very
different
phenomena, with very different clinical significance and
applicability.
However, the extent of this dichotomy between psychological
and

neurobiological views has received scant attention. Partly this is
because
for some there is no dichotomy – the mind is seen as simply the
result of
functions of the brain, as expressed in the maxim: ‘the mind is
what the
brain does’. This view fails to take into account the modern
physics of
Complexity Theory (Waldrop, 1992), a science that describes
the creation of
novel phenomena in complex systems. These ‘emergent’
phenomena
(phenomena that emerge only when a system becomes
sufficiently complex)
are neither present nor predictable from the basic elements of
the system.
The fluid properties of water, for example, are neither present
nor
predictable from the physics of a single water molecule. Life is
another
emergent phenomenon, neither present nor predictable from the
chemicals
that comprise living things. Likewise, human psychology is an
emergent
phenomenon not present in the neurons and neurotransmitters of
the brain
and not predictable from knowledge of them. Consequently,
purely
psychological findings must be understood in their own terms
and cannot
be reduced to the physiological elements of the brain. The
aphorism that ‘the
mind is what the brain does’ is not correct and, in terms of the
present
subject, neurobiological findings cannot replace or better
explain the

psychological basis of addiction. Neurobiological findings have
in fact
been based largely on animal studies (mostly with rodents).
These animals
do not possess a brain complex enough to provide the substrate
for the
emergent phenomena of higher psychological functions such as
defences
within a complex character structure. Conclusions drawn about
human
addiction from such studies should consequently be approached
cautiously.
The applicability of neurobiological factors is discussed below.
Discussion
Johnson (2003) suggested dividing addiction into three types:
psychological,
physical, and what he termed addictive character. Others have
claimed that
neurobiological factors alone explain all addiction, that
addiction is a
‘chronic relapsing disease of the brain’. Some have said that the
very fact of
vulnerability to relapse in addicts implies that addiction must be
caused by
long-lasting changes in brain function (Kalivas & Volkow,
2005). However,
relapse to old symptomatology is also a well-known property of
human
388 L.M. Dodes
psychology, due to the lasting nature of character and emotional

conflict
over a lifetime. A unitary neurobiological view also does not
take into
account the fact that chronic drug use does not necessarily lead
to addiction
at all, as shown by Robins, Helzer, & Davis (1975). Robins’
findings
(summarized below) suggest that a neurobiological conditioning
effect either
does not occur in most cases of chronic drug use, or if it occurs,
leads to
addiction in very few cases.
Robins showed that Vietnam veterans were able to stop their
extensive use
of heroin upon return to the USA despite having become
physically dependent
and presumably having developed the brain changes known to
occur with
prolonged drug use. In contrast, heroin addicts from the same
time who
remained in the USA could not stop use after the same
detoxification
treatment. Given that the drug was the same for both groups
3
this large-scale
unplanned experiment suggests that for many people brain
alterations due to
prolonged drug use are not able to turn them into addicts. Put
another way, the
veterans had the form of ‘addiction’ that is described by
physical dependency:
they had (only) a physical addiction (physical dependency) that
was resolvable

with detoxification. This is the same use of the term ‘addiction’
that describes
many cigarette smokers and others whose use is not determined
by
psychological factors but rather by physiologically-induced
cravings (due to
withdrawal) and habit. In contrast, the addicts who stayed at
home were using
heroin as a psychological symptom as described above, a kind
of addiction
that cannot be resolved by detoxification. Another way to draw
this distinction
is to say that the veterans used heroin as a response to the stress
of being in a
war far from home: an external factor. The addicts who
remained in the USA
used heroin as a psychological symptom: an internal factor.
A physiological conditioned response as described by the
current
neurobiological view, however, may apply to some cases of
repetitive
drug-seeking behaviour. Specifically, those instances when
addictive acts are
impulsive (unplanned, not delayed) and immediately or
impulsively
responsive to salient environmental cues are likely to fit the
neurobiological
view. This behaviour would presumably be produced via hyper-
responsive-
ness of the brain’s reward system to the external cues. In
addition, addicts
with significant loss of frontal lobe functioning would
presumably be more
likely to have such impulsive drug use, so where there is loss of
‘executive

control’ there may be a role for frontal lobe damage due to
chronic drug use.
Such responses are, however, not central in human addiction
which is
mostly delayed and often planned in advance. People with
addictions
regularly wait until after work to have a drink, or they drive
long distances
to reach a casino, or they carefully arrange to meet their drug
supplier at a
future time. In all these cases there is not a salient
environmental cue, but
rather a critically important emotional experience. For these
most common
instances of addiction, the behaviour is best understood as a
psychological
symptom.
Because of its ubiquity, mention should be made of the DSM-IV
and
its approach to addiction. Since the DSM-IV does not recognize
the unity
of symptoms that share the same psychological basis, it has no
section
entitled ‘Addictions’ (for example, compulsive or ‘pathological’
gambling
is mistakenly placed in the category of ‘impulse control
disorders’ even
though it is a compulsive behaviour rarely performed on
impulse, and is a
true addiction). In its section on ‘Substance-related Disorders’

addiction is
described by the DSM-IV in terms of the presence or absence of
physical
dependency, of common clinical signs such as unsuccessfully
attempting to
decrease use, and of effects (not causes) of addiction such as
loss of usual
social functioning. Neither psychological nor current
neurological views
factoring in the aetiology of addiction are considered. The
book’s
emphasis on the significance of physical dependency as a
measure of
severity (it is the major difference between ‘Dependence’ and
‘Abuse’) is
also unwarranted, since physical dependency can be present
only with
certain drugs whose use, or not, does not bear on the diagnosis
or the
severity of addiction (it is possible to destroy one’s life by use
of
hallucinogens that cannot produce physical dependency and to
function
quite well with regular use of a benzodiazepine that rapidly
induces
physical dependence). Further, it is possible to become
physically
dependent without having an addiction in any meaningful sense;
anyone
who takes enough of an addictive drug will become physically
dependent,
as in the case of the Vietnam soldiers. Current thinking from
both a
psychological and neurobiological standpoint recognizes that
physical
dependency, while a potentially serious medical problem, is of

little
significance in understanding addiction. In its emphasis on it,
and its
failure to recognize that addictions include non-drug
behaviours, the
DSM-IV has added to the confusion about the nature of
addiction that
this paper is an attempt to clarify.
Conclusions
The term ‘addiction’ has been used to describe very different
phenomena,
resulting in views of its cause and nature that are also very
different.
Nearly all instances of addiction can be shown to be a
psychologically-
based compulsion in the same group with other psychological
compul-
sions. The unity of these behaviours is indicated by the fact that
they can
substitute for each other, and may even be replaced by other
kinds of
purely psychological symptomatology such as psychologically-
induced
forgetting.
Neurobiological findings of impulsive, conditioned responses
that arise
from more evolutionarily basic levels of drive and reward
seeking can be
demonstrated largely via animal experimentation. This model is
applicable in repetitive, drug-seeking behaviour in humans that
is a reflexive
390 L.M. Dodes

or habit-based response to particular external cues.
Psychological findings,
on the other hand, explain addictive activity that is planned,
anticipated,
delayed, and intended (not impulsive) although not necessarily
wanted. Such
psychologically-based compulsive behaviours are the result of
higher
functions of the mind such as emotional defences, including the
ability to
displace actions to substitute activities (which are then called
addictions or
compulsions), and the presence of a conscience and the capacity
for internal
conflict which leads to inhibition of direct action, thereby
requiring a
displacement. These kinds of functions distinguish humans from
lower
animals, and cannot be seen or studied in animal models
because they are
not present in them.
In the treatment of patients with addictions it is necessary to
ascertain
whether their behaviour is limited to settings in which the
addictive object (a
drug, a casino, or associated stimuli) is present. In these cases a
neurobiological model may be applicable. Correspondingly, in
these
instances there may be a role for medication and/or impulsivity
counselling.
When addictive behaviour is planned in advance and thoughts of
performing the behaviour can be shown to have been

precipitated by
emotional factors such as frustration, anger or sadness, patients
should
receive a careful psychological evaluation and treatment based
on a
contemporary psychological understanding of addiction.
Such an understanding shows that addictive acts are precipitated
by
feelings of overwhelming helplessness. The specific forms of
helplessness are
highly individualized and always reflect what is most
emotionally important
to that person. Addiction reverses and repairs the sense of
helplessness
because it is a way to reassert control over one’s emotional
state.
Correspondingly, the drive behind addiction can be shown to be
the
powerful rage always associated with fundamental challenges to
one’s power
and psychological integrity, a rage at helplessness that in itself
is quite
normal. Finally, the addiction itself may be understood to be a
displacement
of the drive to reverse helplessness to another activity. This
displaced
enactment is what appears as the addiction.
Psychological treatment of addiction involves recognition of
this pattern,
understanding the forms of helplessness at work for each
patient, and
undoing the displacement to take actions that are a more direct
(and
appropriate) expression of the need to reassert power. In

ongoing
psychological treatment, the issues behind the addictive
symptom are
simultaneously explored to alleviate the risk of relapse of
symptomatology,
including relapse of the addiction.
Notes
1. In this paper I will focus on the psychodynamic
understanding of addiction.
Social, economic, cultural and other factors are certainly
relevant to addiction
but they are beyond the scope of this paper.
2. A reader of this paper noted that two of the vignettes
presented involve
sadomasochistic relationships and wondered if that is separate
from the question
of helplessness. As with all psychopathology, sadomasochistic
issues commonly
produce feelings of helplessness – over accepting the
masochistic position or guilt
over enacting either the masochistic or sadistic position.
However, numerous
other issues of very different types may produce a degree of
helplessness sufficient
to precipitate addictive behaviour. For example, a person whose
addictive
behaviour was precipitated by the anniversary of the death of a
parent illustrated
how the presence of overwhelming hopelessness and

helplessness associated with
an inability to grieve could serve as the substrate for addictive
acts (Dodes,
2002). In addition, beyond her overtly sadomasochistic
marriage, a deeper issue
for the woman in Vignette 3 was her helpless inability to
separate from her
mother, later repeated with her husband via her masochistic
attachment.
3. Reports from veterans suggest that the drug was actually
more potent in
Vietnam.
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progress

nature genetics • volume 26 • november 2000 277
Genes and addiction
Eric J. Nestler
Department of Psychiatry and Center for Neuroscience, The
University of Texas Southwestern Medical Center, Dallas,
Texas, USA (e-mail:
[email protected]).
Introduction
Social and psychological factors contribute to addiction, but it
is
clear that genetic factors also weigh in. Epidemiological studies
have long established that alcoholism, for example, is familial,
with estimates that genetic factors account for 40–60% of risk1.
More recent studies indicate similar rates of heritability for
other
drug addictions, including addiction to opiates and cocaine2,3.
Numerous linkage and association studies are now underway,
with a view to identifying specific genetic variants that confer
risk4,5. Several relatively large
chromosomal regions have
been implicated in addiction
vulnerability—although spe-
cific genetic polymorphisms
have yet to be identified by this
approach. It has been estab-
lished, however, that some East
Asian populations carry varia-
tions in enzymes (for example,
the alcohol and aldehyde dehy-
drogenases) that metabolize
alcohol. Such variants increase
sensitivity to alcohol, dramati-

cally ramping up the side effects
of acute alcohol intake6,7. Con-
sequently, alcoholism is exceedingly rare in individuals, for
exam-
ple, that are homozygous for the ALDH2*2 allele, which
encodes a
less active variant of aldehyde dehydrogenase type2.
It is well established that inbred strains of mice and rats show
robust differences in behavioural and biochemical responses to
drugs of abuse8–11. Lines of rodents have been selectively bred
for
increased or decreased responsiveness to alcohol or other
drugs12,13. They have also been bred for altered rates of
alcohol
drinking. Whereas genetic variations found in these models may
be different from those of humans, their identification should
shed light on mechanisms underlying the addiction process.
Accordingly, several groups are attempting to identify the
genetic
basis of these behavioural differences among rodent strains and
lines by use of quantitative trait locus (QTL) analysis. In one
early
study, a predeliction for drinking water laced with morphine
was
mapped to three large chromosomal regions11. Several other
groups have identified chromosomal regions that may contain
QTLs related to particular responses to alcohol, cocaine or opi-
ates. But as is the case with humans, no genetic polymorphism
has yet been identified with certainty8.
The difficulty in finding genes that contribute to risk for
addiction
parallels the difficulty in finding genes for other psychiatric
disorders

and, in fact, for most common
diseases. There are many reasons
for this difficulty14,15, including
the fact that addiction is a com-
plex trait. And so any single gene
might produce a relatively small
effect and would therefore be
difficult to detect experimentally.
It is also possible that variants in
different genes may contribute to
addiction in different lineages.
And, as epidemiological studies
have shown, non-genetic factors
(for example, poverty, crime and
delinquency) also affect risk,
although they remain vaguely
defined. Animal studies also show that environmental factors
such
as stress can interact with an animal’s genotype to determine its
ulti-
mate response to a drug of abuse16. As a result, delineating the
mech-
anisms by which specific genetic variations and environmental
factors interact (see Fig. 1) is an important focus of
investigation.
Another obstacle to identifying genes that determine
vulnerability
to addiction is the difficulty in quantifying behavioural
endpoints,
which have a greater degree of variance and are perhaps more
sus-
ceptible to environmental influence than many non-behavioural
phenotypes. A major focus of behavioural research is to

establish
behavioural endpoints with the same degree of sophistication
and
interassay reliability as is the case for non-behavioural traits.
(See the
Correspondence17 on page 263 for discussion of this issue.)
Drug addiction, like all psychiatric disorders, is defined solely
in behavioural terms. For example, addic-
tion can be considered a loss of control over drug-taking, or
compulsive drug-seeking and -taking despite
horrendous consequences. Abnormal behaviours are a
consequence of aberrant brain function, which
means that it is a tangible goal to identify the biological
underpinnings of addiction. The genetic basis of
addiction encompasses two broad areas of enquiry. One of these
is the identification of genetic varia-
tion in humans that partly determines susceptibility to
addiction. The other is the use of animal models
to investigate the role of specific genes in mediating the
development of addiction. Whereas recent
advances in this latter effort are heartening, a major challenge
remains: to understand how the many
genes implicated in rodent models interact to yield as complex a
phenotype as addiction.
© 2000 Nature America Inc. • http://genetics.nature.com
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A gene might contribute to addiction vulnerability in several
ways. A mutant protein (or altered levels of a normal protein)
could change the structure or functioning of specific brain cir-
cuits during development or in adulthood. These altered brain
circuits could change the responsiveness of the individual to
ini-
tial drug exposure or the adaptations that occur in the brain
after
repeated drug exposure (see Fig. 1). In a similar manner, envi-
ronmental stimuli could affect addiction vulnerability by influ-
encing these same neural circuits. Perhaps combining genetic
approaches with one of these specific (and more narrowly
defined) phenotypes would facilitate the identification of addic-
tion vulnerability genes in both humans and animal models.
In contrast with the slow progress in identifying genes that
affect
risk for addiction in humans, great strides have been made in
demonstrating the role of specific gene products as assessed in
ani-
mal models. The general strategy is to modify the amount of a
par-
ticular gene product or the product itself, and to characterize
the
consequences of such modifications in behavioural tests. Mice
with
constitutive mutations continue to deliver insights into drug

mech-
anisms, and mice with inducible and tissue-specific mutations
(Table 1) are increasingly used to overcome limitations of
constitu-
tive mutants18. Other genetic approaches include viral-mediated
gene transfer, intra-cerebral infusions of antisense
oligonucleotides
and mutations in non-mammalian model organisms.
Behavioural tests
Animals with altered levels of a particular gene product in the
brain are subjected to a variety of behavioural tests to assess
their responses to drugs of abuse (Table 2). These include mea-
sures of locomotor activity (most drugs of abuse increase activ-
ity when given acutely), and the progressive increase in
locomotor activity (locomotor sensitization) that occurs with
repeated drug exposure19–21. The rationale behind these tests
rests on the finding that locomotor responses are mediated by
the mesolimbic dopamine system, which is also implicated in
reward and addiction22–26, but it should be noted that the rela-
tionship between locomotor responses, drug reward and addic-
tion is a matter of some debate.
A more direct measure of drug reward is conditioned place
preference, where an animal learns to prefer an environment
that
is paired with drug exposure22. It, too, is mediated partly by the
mesolimbic dopamine system and is thought to model some of
the powerful conditioning effects of drugs of abuse that are seen
in humans. As with measures of locomotor activity, place-
condi-
tioning assays are amenable to relatively high-throughput
design,
which explains their popularity. But neither test directly mea-
sures the behavioural abnormalities (compulsive drug-seeking

and -taking) that are the core features of human addiction.
To get closer to such abnormalities, operant tests must be
applied, including self-administration, intracranial self-stimula-
tion and conditioned reinforcement paradigms23–26 (Table 2).
These tests, however, are quite complicated. Indeed, because of
their intricacy, especially in mice, they have been used on a
com-
paratively small number of genetically altered animals27,28. A
major challenge is to devise schemes that make application of
these behavioural tests more widely available. One approach is
to
use oral self-administration procedures, which are much easier
to
implement than intravenous methods11,28.
Other aspects of drug exposure have been studied in genetic
models. For example, withdrawal symptoms have been used as a
measure of opiate dependence on many occasions29. The
aversive
(negative emotional) effects of drug withdrawal can be
measured by
conditioned place-avoidance assays, in which animals learn to
avoid
an environment associated with withdrawal. Moreover,
investiga-
tors have measured the rate and degree of tolerance (or
insensitiv-
ity) to the analgesic effects of opiates30,31. This is important
because
the molecular basis of tolerance, which limits the use of opiates
in
the treatment of chronic pain, is poorly understood.
Confirming initial drug targets
A straightforward use of genetic tools in the dissection of

addic-
tion is in the confirmation of targets of drugs. Pharmacological
approaches can be used to identify drug targets, but they fre-
quently fail to identify which of several subtypes is most
relevant.
In contrast are studies involving ‘knockout’ mice, which have
led
to the identification of the µ-opioid receptor, the dopamine
transporter, the CB1 cannabinoid receptor and the β2 nicotinic
acetylcholine receptor as targets that mediate rewarding and
other effects of opiates, stimulants, cannabinoids and nicotine,
respectively32–34. Such success inspires hope that knockouts
will
also lead to targets (of drugs of abuse) where none are presently
known—for example, inhalants. In some cases, knockout of the
primary drug target has revealed the existence of secondary tar-
gets that partially compensate the loss of the primary target35.
The neurotransmitters
In addition to secondary targets, there are numerous neurotrans-
mitters, their receptors and post-receptor signalling pathways
that modify responses to acute and chronic drug exposure.
Genetic tools have not only confirmed pharmacological studies
that implicate neurotransmitter pathways, they have provided
fundamentally new insights into their mechanism.
For example, several behavioural aspects of mice lacking the
serotonin 5HT1B receptor indicate enhanced responsiveness to
cocaine and alcohol; notably, they self-administer both drugs at
higher levels than wild-type controls27,28. The mice also
express
higher levels of ∆FosB (a Fos-like transcription factor
implicated in
addiction) under basal conditions. These observations point to
the
involvement of serotonergic mechanisms in addiction. There are

many other such examples. Mice deficient in the dopamine D2
receptor or the cannabinoid CB1 receptor have a diminished
rewarding response to morphine, implicating dopaminergic sys-
tems and endogenous cannabinoid-like systems in opiate
action34,36. Mice lacking the β2 subunit of nicotinic
cholinergic
receptors show reduced rewarding responses to cocaine37.
progress
278 nature genetics • volume 26 • november 2000
drug
synaptic structure
and function
stable changes in
synaptic structure
and function
addiction
genes environment
Fig. 1 Scheme showing genetic and environmental factors
combining to influ-
ence the process by which repeated exposure to a drug of abuse
causes addic-
tion. Genetic and environmental factors, by establishing all
aspects of normal
synaptic structure and function, determine an individual’s
inherent sensitivity
to initial drug exposure. These factors also establish how
individual nerve cells,

and the circuits in which they operate, adapt over time to
chronic drug expo-
sure, which in turn determines the development of addiction.
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Several neuropeptides are implicated in drug responses. Mice
with low levels of neuropeptide Y drink more alcohol—and
those
with high levels are more likely to abstain38,39. Mice deficient
in
certain neurotrophic factors have abnormal behavioural
responses
to opiates and to cocaine—BDNF knockouts show reduced
responsiveness, whereas GDNF knockouts are more respon-
sive40,41. These findings support the view that trophic
mechanisms
(for example, alterations in neural structure) may mediate some
of
the effects of drug administration on brain function.
Even though they may not develop the more complex aspects
of addiction seen in mammals, non-mammalian model organ-
isms can be used to identify biochemical pathways through
which drugs act42–44. A recent study determined that the
Drosophila melanogaster mutant inactive, which is deficient in
tyrosine decarboxylase and therefore cannot synthesize tyra-
mine, remains sedate despite repeated doses of cocaine43. This
abnormality is reversed by administration of tyramine and
raises the possibility that related biochemical pathways in mam-
mals may modulate long-term adaptation to chronic drug
exposure. In addition, the locomotor responses of flies to
cocaine (acting through dopamine pathways) are remarkably
similar to those of mammals, indicating that dopaminergic
pathways were obligated in neuronal circuits controlling move-
ment over one billion years ago.
Transcriptional mechanisms
The stability of the behavioural abnormalities that characterize
addiction indicates that drug-induced changes in gene expres-
sion may be involved45. As classic pharmacological agonists
and

antagonists to most proteins are not available, genetic tools are
all
the more attractive.
One demonstration of this approach is in the exploration of
∆FosB, a Fos-like transcription factor. ∆FosB accumulates in
the
nucleus accumbens (a target of the mesolimbic dopamine sys-
tem) after chronic, but not acute, exposure to any of several
drugs
of abuse46,47, including opiates, cocaine, amphetamine,
alcohol,
nicotine and phencyclidine (also known as PCP or ‘angel dust’).
This is in contrast with other Fos-like proteins, which are much
less stable than ∆FosB and induced only transiently after acute
drug administration. Consequently, ∆FosB persists in the
nucleus accumbens long after drug-taking ceases. Adult mice in
which ∆FosB can be induced selectively within the same subset
of
neurons in the nucleus accumbens as those in which it is
induced
by drug administration show a marked predilection for
cocaine46–48. It would seem that ∆FosB is a relatively
sustained
molecular ‘switch’ that contributes to a state of addiction.
The expression of another transcription factor, CREB, is also
important. CREB knockout mice are less likely to develop
opiate
dependence29—observing the effects of injecting antisense
Table 1 • Genetic tools to study addiction
Genetic tool Advantages Disadvantages
Constitutive mutations in mice complete loss of gene product

for many knockouts, loss
(knockouts and overexpressors) (in case of knockout) of
multiple gene products
methods well established developmental adaptations
complicate interpretation
of adult studies
ubiquity of mutation
complicates interpretation
for particular brain regions
differences in genetic
background between
mutants and wild types
complicate interpretation of
the role of a particular gene
Inducible and cell-type specific mutations time that mutation is
methods not yet perfected
in mice (knockouts and overexpressors) expressed can be
controlled
cell type in which mutation longer times to generate mice
is expressed can be controlled
multiple genes required,
complicating breeding strategies
Viral-mediated gene transfer highly circumscribed toxicity,
inflammation, and other
spatial and temporal possible changes due to viral
resolution of mutation infection or intracerebral injections
can be developed quickly not all neurons in injected area are
compared with mutant mice infected (incomplete effect)

functional knockouts possible transient expression of mutation
by overexpressing dominant
negative mutants
Antisense oligonucleotides highly circumscribed toxicity due to
oligonucleotides
spatial and temporal or intracerebral injections
resolution of mutation possible sequence-specific effects
can be developed quickly of oligonucleotides not mediated
compared with mutant mice via the targeted mRNA
incomplete knockout of gene
product
cannot be used to increase
expression of protein of interest
Mutations in non-mammalian rapid, high-throughput assays
relevance to addiction requires
model organisms analysis in mammalian systems
potential for discovery of
novel genes and biochemical
pathways involved in adaptations
to repeated drug exposure
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280 nature genetics • volume 26 • november 2000
oligonucleotides to CREB into different parts of the brain points
to
the locus coeruleus (a brain region important for such
dependence)
as one relevant site of action49. Overexpression of CREB in the
nucleus accumbens counters the rewarding properties of opiates
and cocaine; overexpression of a dominant-negative CREB
mutant
has the opposite effect50,51. These findings suggest that CREB
pro-
motes certain aspects of addiction (for example, physical depen-
dence), while opposing others (for example, reward), and
highlight
that the same biochemical adaptation can have very different
behavioural effects depending on the type of neuron involved.
A challenge of current research is to identify target genes
through which ∆FosB, CREB and other transcription factors act.
Two strategies are used. One considers candidate genes: for
example, genes that contain putative response elements for the
transcription factor in question or whose products are

implicated
in relevant mechanisms in a relevant region of the brain. This
approach has led to the identification of the AMPA glutamate
receptor subunit GluR2 as a mediator of ∆FosB action46. In a
similar manner, the opioid peptide dynorphin was identified as a
target for CREB, and shown to partly mediate CREB-induced
repression of drug reward50.
New molecular substrates
Candidate gene approaches are limited by our rudimentary
knowledge of the gene products and the complex mechanisms
underlying addiction. As a result, more open-ended strategies
are
needed, such as those based on analysis of differential gene
expression in certain brain regions under control and drug-
treated conditions. Differential display, for example, enabled
the
identification of NAC-1, a transcription factor-like protein,
which is induced in nucleus accumbens by chronic cocaine and
is
now known to modulate the locomotor effects induced by
cocaine52. The neuropeptide CART was also first identified by
differential display of mRNA in the nucleus accumbens before
and after drug exposure. Whereas it may have a role in
addiction,
its current claim to fame is as a potent anorexigenic (anti-
appetite) factor53 that acts in the hypothalamus.
Various types of microarray analysis have led to the identifica-
tion of large numbers of drug-regulated genes; it is typical for
1–5% of the genes on an array to show consistent changes in
response to drug regulation54. But without a better means of
evaluating this vast amount of information (other than exploring
the function of single genes using traditional approaches), it is
impossible to identify those genes that truly contribute to addic-

tion. Strategies under current evaluation include the analysis of
detailed time courses of drug action and expression changes
unique to carefully characterized behavioural states.
And, in the end…
Animal models have proved to be pivotal to our understanding
of
neurobiological mechanisms involved in the addiction process.
One drawback (and one that is not limited to the field of addic-
tion) is that sometimes a genetic mutation is found to result in a
phenotype without any plausible scheme as to how the mutation
actually causes that phenotype. Fortunately, the increasing
sophistication of genetic tools, together with the increasing pre-
dictive value of animal models of addiction, makes it
increasingly
feasible to fill in the missing pieces—to understand the cellular
mechanisms and neural circuitry that ultimately connect molec-
ular events with complex behaviour.
Received 7 June; accepted 7 September 2000.
Table 2 • Some behavioural tests commonly used to study
addiction
Behavioural test Description
Acute locomotor activation acute increase in locomotor activity
after initial administration of a drug of abuse
Locomotor sensitization progressive increase in locomotor
activity after repeated administration
of a drug of abuse
Conditioned locomotor sensitization increase in locomotor
activity seen in environment (for example, testing chamber)
where animals received repeated administration of a drug of

abuse
Conditioned place preference development of preference for an
environment (for example, one side of testing chamber)
associated with repeated administration of a drug of abuse
Oral self-administration development of voluntary drinking of a
drug of abuse in a palatable
(for example, sucrose-containing) solution
Self-administration (operant-controlled)
Acquisition development of volitional (voluntary)
administration (intravenous or intracerebral)
of a drug of abuse by performing some task (for example, lever
pressing)
Stable maintenance amount of drug of abuse self-administered
over a range of doses, providing a
measure of the acute reinforcing value of the drug
Progressive ratio determination of how hard an animal will
work (for example, how many lever
presses/unit time) to self-administer a drug of abuse
Extinction progressive decrease in drug-associated task (for
example, lever pressing)
when drug is no longer available
Relapse (reinstatement) return to drug-associated task (for
example, lever pressing) even when drug of abuse
is not available; this can be stimulated by acute challenge with
the drug itself,
a drug-associated cue (for example, light or tone), or stress
Intracranial self-stimulation volitional (voluntary) electrical

stimulation of particular brain regions by performing
a task (for example, lever pressing), and potentiation of this
behaviour by a drug of abuse
Conditioned reinforcement development of volitional
(voluntary) effort to receive an otherwise neutral stimulus
(for example, light) associated with a reward (for example, a
natural reward such as water),
and potentiation of this behaviour by a drug of abuse
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Reproduced with permission of the copyright owner. Further
reproduction prohibited without permission.
Circumspectives

The Development and Maintenance of Drug Addiction
Roy A Wise*,1 and George F Koob2
1Department of Behavioral Neuroscience, Intramural Research
Program, National Institute on Drug Abuse, National Institutes
of Health,
Baltimore, MD, USA; 2Committee on the Neurobiology of
Addictive Disorders, The Scripps Research Institute, La Jolla,
CA, USA
Neuropsychopharmacology (2014) 39, 254–262;
doi:10.1038/npp.2013.261; published online 6 November 2013
Keywords: substance abuse; dependence; motivation; incentive
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What is the defining property of addiction? We dust off a
several-decades-long debate about the relative importance
of two forms of reinforcement—positive reinforcement,
subjectively linked to drug-induced euphoria, and negative
reinforcement, subjectively linked to the alleviation of
pain—both of which figure importantly in addiction theory;
each of these forms has dominated addiction theory in its
time. We agree that addiction begins with the formation of
habits through positive reinforcement and that drug-
opposite physiological responses often establish the condi-
tions for negative reinforcement to come into play at a time
when tolerance, in the form of increasing reward thresholds,
appears to develop into positive reinforcement. Wise’s work
has tended to focus on positive-reinforcement mechanisms
that are important for establishing drug-seeking habits and
reinstating them quickly after periods of abstinence,
whereas Koob’s work has tended to focus on the negative-
reinforcement mechanisms that become most obvious in
the late stages of sustained addiction. While we tend to
agree with each other about the early and late stages of
addiction, we hold different views as to (i) the point
between early and late at which the diagnosis of ‘addiction’
should be invoked, (ii) the relative importance of positive
and negative reinforcement leading up to this transition,
and (iii) the degree to which the specifics of negative
reinforcement can be generalized across the range of
addictive agents.
POSITIVE REINFORCEMENT IN ADDICTION: ISSUES
OF CAUSE AND CONSEQUENCE (ROY A WISE)
All things have a root and a top
All events an end and a beginning
Whoever understands correctly

What comes first and what follows
Draws nearer to Tao
(Hughart, 1984)
What is the defining property of addiction; what comes
first and what follows? Is positive reinforcement sufficient
to establish an addiction? Or must negative reinforcement
come into play before an individual is past the point of
improbable return? Here we have little agreement. The
continuing debate over whether cannabis is addictive; the
historical debate over whether nicotine is addictive; and the
emerging debates over whether compulsive gambling, video
gaming, and sexual behavior are addictive all result from
the fact that there is no widely accepted scientific definition
that allows us to identify the point at which addiction
emerges from a casual or ‘recreational’ habit. In the first
place, the committees of clinical experts that set forth
diagnostic criteria for such groups as the American
Psychiatric Association (APA) and the World Health
Organization do not offer a scientific definition (Schuckit,
2012); in the second, there is little agreement between
(Edwards, 2012), or even within, these scholarly groups
(O’Brien et al, 2006). Instead of ‘addiction,’ the Diagnostic
and Statistical Manual of Mental Disorders (DSM) (like
Koob in his first quotation below) stresses the term
‘dependence’ (also a fuzzy term, one that sometimes refers
to ‘physical’ dependence and sometimes to questionably
defined ‘psychic’ dependence). Thus, not surprisingly, the
reliability of diagnosis using the DSM—the authority on
which new animal models have recently been based
(Deroche-Gamonet et al, 2004; Vanderschuren and Everitt,
2004)—has been poor and is getting worse (Hasin et al,
2013). In truth, in our use of the word ‘addiction,’ we share
the sorry condition articulated by Humpty Dumpty: ‘When

I use a word it means just what I choose it to mean—neither
more nor less’ (Norman White used this quotation earlier in
a related context; White, 1989).
There are good reasons that the word ‘addiction’ does not
appear as a diagnostic category in the DSM. It simply means
different things to different people—even to different
experts (including Koob and me). When some people think
of addiction, they think of the condition of addiction, the
*Correspondence: Dr RA Wise, Behavioral Neuroscience,
Intramural
Research Program, National Institute on Drug Abuse, National
Institutes of Health, 251 Bayview Boulevard, 5500 Nathan
Shock Dr,
Suite 2000, Baltimore, MD 21224, USA, Tel: +443 740 2460,
Fax:
+443 740 2728, E-mail: [email protected]
Received 29 July 2013; revised 11 September 2013; accepted 12
September 2013; accepted article preview online 11 October
2013
Neuropsychopharmacology (2014) 39, 254–262
& 2014 American College of Neuropsychopharmacology. All
rights reserved 0893-133X/14
www.neuropsychopharmacology.org
http://dx.doi.org/10.1038/npp.2013.261
mailto:[email protected]
http://www.neuropsychopharmacology.org
condition of someone at the stage of asking for treatment
or of causing problems for others: someone who has

progressed to the later stages of this progressive process.
This is a useful clinical perspective; it focuses on the variety
of symptoms that require attention and for which medica-
tions might be developed. Others, however, are thinking of
the process of addiction, looking for the necessary and
sufficient conditions for the development of addiction, the
transition from volitional to compulsive drug use. This is a
scientific perspective, probing the differences between cause
(what comes first) and consequence (what follows). The
first use of the word differentiates the extremes of addiction:
it differentiates the end points from the drug-naive starting
point. The second seeks an intermediate point, a point of
no return, a point partway down the slippery slope of
increasingly compulsive intake. It is problematic for those
interested in process that addiction does not suddenly
appear like a fever or a boil at some relatively well-defined
and finite point along the way. Rather, it begins to grow
with the first reinforced response and strengthens incre-
mentally thereafter, even in the case of a classic addiction
such as opiate addiction (McAuliffe and Gordon, 1980).
Opiate addiction offers a good case in point. Opiate
addiction is the addiction against which all others are
traditionally compared (Tatum and Seevers, 1931). Repeated
use of opiates usually, but not always (Zinberg and Jacobson,
1976), leads to tolerance and dependence (Tatum and
Seevers, 1931), conditions in which progressively higher
doses are required to maintain initial drug effectiveness and
in which abrupt drug abstinence results in a largely
autonomic withdrawal syndrome involving thermoregulatory
(chills and sweats) and gastrointestinal (cramps, diarrhea)
disturbances. The chills, sweats, cramps, and diarrhea
associated with opiate withdrawal have traditionally been
considered to be what maintains opiate addiction; the idea
was that opiate use becomes compulsive when continued
intake becomes required to avoid these and other unpleasant

withdrawal symptoms. Much of classic addiction theory has
dealt with the mechanisms of the tolerance and withdrawal
distress on this assumption that they motivate increasing
intake and increasing compulsion to continue opiate use
(Collier, 1980; Goldstein and Goldstein, 1961; Himmelsbach,
1943; Jaffe and Sharpless, 1968; Koob et al, 1989a;
Lindesmith, 1947). However, while the desire to relieve
withdrawal distress can add to the motivation to continue
self-administration of opiates, it has long been recognized
that compulsive drug intake can develop before the
development of physiological dependence: ‘Dependence and
tolerance are neither necessary nor sufficient conditions for
the compulsive self-administration of a drug, a behavior that
common parlance has defined very well as ‘addiction’’
(Goldstein, 1983; see also Deneau et al, 1969; Seevers and
Schuster, 1967; and Woods and Schuster, 1971). Indeed, rats
will repeatedly self-administer morphine locally into the
ventral tegmental area of the brain without signs of tolerance
or dependence, whereas they will not self-administer the drug
into the periaqueductal gray, where it does cause classic
dependence signs (Bozarth and Wise, 1984).
What comes after cannot explain what comes first. That is,
withdrawal distress cannot explain the habit that initially
established physical dependence, nor can it explain the
rapidity of relapse in addicts that have been detoxified
(Stewart and Wise, 1992). Consider the cases of cocaine
and alcohol self-administration. The ultimate end points
of intravenous cocaine addiction in laboratory animals
(Bozarth and Wise, 1985; Deneau et al, 1969; Johanson et al,
1976) and alcoholism in humans (McKeon et al, 2008) are
convulsions and death, but we do not consider convulsions
and impending death to be causes of addiction—they are
consequences that need treatment and that are worth
modeling, but they are not consequences that help us

understand the nature of the compulsion that led to their
development. They are part of the disease state caused by
addiction; they are not part of the cause of addiction.
While dependence theory is intuitively satisfying and
was central to early theories of addiction (Collier, 1965;
Goldstein and Goldstein, 1961; Himmelsbach, 1943;
Lindesmith, 1947; Tatum and Seevers, 1931), it did not
explain the rapid acquisition of intravenous drug taking in
laboratory animals (Deneau et al, 1969; Schuster and
Thompson, 1969) and it did not appear to explain the
self-administration of psychomotor stimulants such as
cocaine and amphetamine (Pickens and Harris, 1968;
Wise and Bozarth, 1987).
Although the simple laws of instrumental habit reinforce-
ment (Johanson, 1978; Katz, 1989; Wise, 1987) dominated the
addiction literature in the 1970s and 1980s, in recent years it
has been pointedly argued that mere drug self-administra-
tion—the dominant animal model of addiction over the past
half-century—does not, by itself, constitute addiction. This is,
of course, true and is seemingly confirmed by self-report in a
widely cited comorbidity study (Anthony et al, 1994).
However, it is dangerous to generalize across drug classes,
particularly from survey or introspectional data. Such
statements as ‘This pathological behavior appears only in a
small proportion (15–17%) of those using drugs’ (Deroche-
Gamonet et al, 2004) generalizes across such different drugs
as cannabis, on which less than 10% of users reported
dependence, and tobacco, on which more than 30% reported
dependence. It also generalizes from a single culture; surely
the numbers worldwide depend on conditions of drug
availability, social disapproval, and other environmental
factors (compare the rates of alcoholism between the Czech
Republic and Saudi Arabia). Finally, it lumps together self-
reported intranasal use of cocaine by some and smoking or

intravenous use of the drug by others; the statement that
not all individuals who use drugs become addicted to them
should be qualified by some kind of objective and
quantitative statement as to the degree of drug use that is
insufficient to establish addiction. In the Anthony survey
(Anthony et al, 1994), there were only minimal guidelines as
to what constituted significant ‘using’ of drugs, and there was
no differentiation between routes of administration. Trying
cocaine by the intranasal route and getting away with it
should not encourage us to try it by smoking it or taking it
intravenously. Moreover, the question of how many who use
a drug become addicted to it depends on what level of drug
use or drug seeking we define as the first stage of addiction.
While it is obviously true that simply trying drugs is not a
sufficient condition for becoming addicted to them, I would
argue that this is not equally true for humans and for
laboratory animals. It is clearly true in the case of alcohol;
like most humans, most laboratory rats will not drink
alcohol to the point of physical dependence (Wise, 1975), let
Positive and negative reinforcement in addiction
RA Wise and GF Koob
255
alone to the point of convulsions and death. Alcohol is
simply not a very powerful reinforcer for laboratory rats;
this is not surprising, as it causes only a modest 100%
increase in extracellular levels of the reward transmitter
dopamine (Di Chiara and Imperato, 1988). But what about
intravenous cocaine or amphetamine, which drive extra-

cellular dopamine levels many times higher (Pettit and
Justice, 1989; Ranaldi et al, 1999; Wise et al, 1995b)? In the
case of intravenous cocaine, I believe that quite limited
initial self-administration of the drug is a sufficient
condition for addiction, at least in laboratory rats.
If given unlimited access to intravenous cocaine, rats or
monkeys that learn to respond regularly for the drug will,
unless their veins or catheters fail, almost invariably take
cocaine to the point of convulsions and death (Bozarth and
Wise, 1985; Deneau et al, 1969; Johanson et al, 1976). Even
if given access to intravenous cocaine for as little as 2 h per
day, most animals take the drug steadily, and, if testing
continues for weeks or perhaps months, many reach the
point of being willing to take the drug despite painful
footshock (Deroche-Gamonet et al, 2004) or merely the
threat of painful footshock (Vanderschuren and Everitt,
2004). In my lab in Montreal, where we gave animals 4 h of
daily access to intravenous cocaine at 1 mg/kg/injection,
89% learned within 1–5 days to take cocaine steadily and
without stopping until the drug was withdrawn. While the
time between injections was initially quite variable, the
variability narrowed to levels that meet my operational
definition of compulsive drug taking (Figure 1) (Wise,
1996). We had similar results (88 and 91%) with
amphetamine (0.25 mg/kg/injection) and heroin (0.1 mg/
kg/injection). We did not food-restrict, prime, or shape
these animals; we simply placed rats with jugular catheters
for 4 h a day in chambers where accidental or intentional
lever pressing resulted in intravenous injections. For the
most part, the 10% of our animals that did not learn to take
the drug regularly within 5 days could be attributed to
catheter or vein problems rather than to ambivalence for the
drug. Animals trained in the same way and given unlimited
access to intravenous cocaine invariably continued to take
the drug, with little variation in rate (except for periods of

collapse and sleep), to the point of convulsions and death
(Bozarth and Wise, 1985).
Thus, in the case of intravenous cocaine, amphetamine,
or heroin, my view is that simple unfettered exposure to the
drug is a sufficient condition for addiction in rats—rats
sampling these drugs at above-threshold doses and by this
route of administration learn to take it compulsively and
would continue to do so without remission if we did not
limit their access to the drug. I would not generalize this to
other drugs, to other routes of administration, or even to
marginal doses of these drugs (an ED50 means, by
definition, a dose that is ineffective in half the population),
nor would I generalize it to the specific conditions of limited
access used in some animal studies (Ahmed and Koob,
1998; Deroche-Gamonet et al, 2004; Vanderschuren and
Everitt, 2004) or to the addiction-resistant Fischer rat,
which, although equally sensitive to cocaine reward, is
reluctant to lever-press the first time, let alone enough times
to learn about the drug’s rewarding consequences (Ranaldi
et al, 2001). Most of all, I would not generalize it to humans.
Humans are informed about health risks that are not
understood by laboratory animals, and it is anticipated rather
than immediate consequences that are arguably the strongest
deterrent to human addiction, particularly in the case of
tobacco smoking. No such communicated deterrent exists for
laboratory animals, and in my experience laboratory animals
that start taking intravenous cocaine, amphetamine, or heroin
never stop taking them voluntarily except when they collapse
from exhaustion or convulsions (Bozarth and Wise, 1985;
Deneau et al, 1969; Johanson et al, 1976; Pickens and Harris,
1968). I would argue that animals are addicted when they take
these drugs as compulsively as do our animals, even when we
limit their collateral health problems by restricting their drug
access to a few hours a day.

I do not question that addiction can often develop
through the three stages outlined by Koob (Koob and Le
Moal, 1997b), nor do I question the argument that
avoidance of aversive consequences of drug withdrawal
can contribute importantly to compulsive drug seeking in
established addicts. I do, however, argue that the animals
can become addicted long before these stages have
progressed significantly. How do we make objective the
criteria of compulsive drug intake? To my mind the most
important criteria are not whether the animal develops
allostatic neuronal or hormonal adaptations and whether
the animal persists in drug taking despite footshock. To my
mind the rat is addicted when its drug taking becomes
regular, predictable, and uninterrupted except by exhaus-
tion or restricted drug intake. Figure 1 illustrates the
regularity of intake that I offer as evidence of compulsive
cocaine intake in the rat.
My definition of addiction is behavioral. I see addiction as
the result of self-administration (Wise, 1988) of drugs that
more strongly elevate extracellular dopamine levels
(Ranaldi et al, 1999; Wise et al, 1995a; Wise et al, 1995b)
than do such natural rewards as food (Hernandez and
Hoebel, 1988) or sex (Pfaus et al, 1990), and from the
stamping in (Wise, 2004) of the memory traces associated
with that self-administration. The alternatives proposed by
Koob and others (Kalivas, 2009; Nestler, 1992; Robinson
and Berridge, 1993) involve the neuropharmacological
consequences of—that is, the neuroadaptations caused
Day 1 Day 10
Day 11
Day 12

Day 13
Day 14
Day 15
Day 16
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Figure 1 From the Wise perspective. Interresponse interval
histograms
from a rat lever-pressing for intravenous cocaine in 4-h daily
sessions at a
dose per injection of 1 mg/kg. Of interest is the decrease in
variability across
days of testing. The narrowing of the distribution of
interresponse times
over days offers an objective measure of the steady progress to
compulsive
cocaine taking that develops even with limited daily access to
the drug.
Wise offers the ratio of mean to standard deviation (M/SD)

interresponse
time as an objective measure of the subjective label
‘compulsive.’
Positive and negative reinforcement in addiction
RA Wise and GF Koob
256
by—the drug itself, and if that were a sufficient condition
for addiction, then simply making animals dependent on
alcohol should give us rodents that drink compulsively to
maintain their dependent state by self-medicating with-
drawal symptoms. To the surprise of many, this approach
has failed multiple times to work in rodents (Lester, 1966;
Wise, 1975), and, indeed, even human alcoholics often fail
to drink to alleviate withdrawal distress but nonetheless
begin drinking again after the severe distress signs have
abated (Mello and Mendelson, 1972).
Addiction changes the brain in two ways (Berke and
Hyman, 2000). First, the brain is changed by repeated drug
exposure, whether self-administered or not (Lüscher and
Malenka, 2011; Nestler, 1992); this is the drug-generated
sensitization of anti-reward in Koob’s formulation. Second,
the brain is changed by the development of memory traces
for the drug experience. I would argue that it is this second
form of brain change—the emerging memory for the drug
experience—that is the more critical difference between the
addicted and the nonaddicted brain. Just as the memory
of one’s first ejaculation can cause sexual cravings and
compulsive masturbation, so can the memory of an initial

euphoric drug experience cause drug cravings and compul-
sive drug seeking (Bijerot, 1980; McAuliffe and Gordon,
1980). It is becoming increasingly clear that self-adminis-
tration of addictive drugs causes brain and peripheral
changes above and beyond those caused by passive receipt
of the drug (Caillé et al, 2009; Chen et al, 2008; Dumont et al,
2005; Krawczyk et al, 2013; Wang et al, 2005; Wang et al,
2013; Wise et al, 2008; You et al, 2007). These changes
determine, in part, when drug availability is expected (Wang
et al, 2013; Wise et al, 2008; You et al, 2007). In the case of
smokers, at least, it is when the next cigarette will become
available, rather than how long the smoker has been without
one, that is the primary stimulus for craving (Dar et al, 2010;
Dar et al, 2005). Thus, my feeling is that we should use the
term ‘addiction’ in relation to early signs of compulsive drug
taking and the cravings associated with it rather than in
relation to the subsequent bodily consequences that often—
as with nicotine and alcohol, for example—develop only
after a long history of drug self-administration.
NEGATIVE REINFORCEMENT IN DRUG ADDICTION:
THE DEVIL IN THE DYSPHORIA (GEORGE F KOOB)
The notion of dependence on a drug, object, role, activity or any
other stimulus-source requires the crucial feature of negative
affect experienced in its absence. The degree of dependence can
be equated with the amount of this negative affect, which may
range from mild discomfort to extreme distress, or it may be
equated with the amount of difficulty or effort required to do
without the drug, object, etc. (Russell, 1976)
My view is that drug addiction, in contrast to recreational
use of drugs, involves not recruitment or sensitization
of reward but rather a drug-generated sensitization of
anti-reward: the ‘devil in the dysphoria.’ We have con-
ceptualized addiction as a three-stage cycle: binge/intoxica-

October 2011, Vol. 101, No. 10 SAMJSouth African Medical .docx

October 2011, Vol. 101, No. 10 SAMJSouth African Medical .docx

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October 2011, Vol. 101, No. 10 SAMJSouth African Medical .docx