Neurobiology of Addiction

Neurobiology of addiction
An integrative review
Aviel Goodman*
Minnesota Institute of Psychiatry, 1347 Summit Avenue, St. Paul, MN 55105, USA
Addiction neuroscience may well be our eras most dynamic
eld of scientic inquiry. The quality as well as quantity of
information that it generates seems almost to exceed the
capacity of our theories to organize and make coherent sense
of it. This article offers a framework that may be helpful in
organizing and integrating the wealth of information that is
the neurobiology of addiction. The cornerstone of this
framework is the addictive process, an underlying biopsycho-
logical process that addictive disorders are hypothesized to
share. The article begins by introducing the hypothesis that
psychoactive substance use disorders, bulimia nervosa (from
here on, bulimia), pathological gambling, and sexual addiction
share an underlying biopsychological process. Research
ndings are demonstrated to accord with empirically testable
predictions that were generated from the hypothesis, thereby
conrming it. Denitions are then offered for the key terms,
addiction and addictive process. The addictive process is brought
into focus as an interactionof impairments in three functional
systems: motivation-reward, affect regulation, and behavioral
inhibition. The review itself then follows, in which the
literature that addresses the neurobiology of addiction is
selectively organized according to the three functional
systems that constitute the addictive process. The review is
directed toward identifying candidate neurochemical sub-
strates for the impairments in motivation-reward, affect
regulation, and behavioral inhibition that could contribute
to an addictive process.
1. Addictive disorders
1.1. A shared underlying process
In the course of my work with individuals who suffered from
psychoactive substance use disorders, bulimia, pathological
gambling, or sexual addiction, I noticed that these conditions
shared a number of characteristic clinical features. These
included: (1) course of illness the disorder typically begins in
b i oc he mi c a l p ha r ma c ol o gy 7 5 ( 2 0 0 8 ) 2 6 6 3 2 2
a r t i c l e i n f o
Article history:
Received 8 May 2007
Accepted 23 July 2007
Keywords:
Addiction
Neurobiology
Neuroscience
Substance abuse
Bulimia
Gambling
a b s t r a c t
Evidence that psychoactive substance use disorders, bulimia nervosa, pathological gam-
bling, and sexual addiction share an underlying biopsychological process is summarized.
Denitions are offered for addiction and addictive process, the latter being the proposed
designation for the underlying biopsychological process that addictive disorders are
hypothesized to share. The addictive process is introduced as an interaction of impairments
in three functional systems: motivation-reward, affect regulation, and behavioral inhibi-
tion. An integrative review of the literature that addresses the neurobiology of addiction is
then presented, organized according to the three functional systems that constitute the
addictive process. The review is directed toward identifying candidate neurochemical
substrates for the impairments in motivation-reward, affect regulation, and behavioral
inhibition that could contribute to an addictive process.
# 2007 Elsevier Inc. All rights reserved.
* Tel.: +1 651 649 0847.
E-mail address: [email protected].
avai l abl e at www. sci encedi r ect . com
j our nal homepage: www. el sevi er . com/ l ocat e/ bi ochemphar m
0006-2952/$ see front matter # 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.bcp.2007.07.030
adolescence or early adulthood and follows a chronic course
with remissions and exacerbations; (2) behavioral features
narrowing of behavioral repertoire, continuation of the
behavior despite harmful consequences; (3) individuals
subjective experience of the condition sense of craving,
preoccupation, excitement during preparatory activity, mood-
altering effects of the behavior, sense of loss of control; (4)
progressive development of the condition craving, loss of
control, narrowing of behavioral repertoire, and harmfulness
of consequences all tending to increase as the duration of the
condition increases; (5) experience of tolerance as the
behavior is repeated, its potency to produce reinforcing effects
tends to diminish; (6) experience of withdrawal phenomena
psychological or physical discomfort when the behavior is
discontinued; (7) tendency to relapse i.e., to returnto harmful
patterns of behavior after a period of abstinence or control has
been achieved; (8) propensity for behavioral substitution
when the behavioral symptoms of the disorder have come
under control, tendency for addictive engagement in other
behaviors to emerge or intensify; (9) relationship between the
condition and other aspects of affected individuals lives for
example, neglect of other areas of life as the behavior assumes
priority; and (10) recurrent themes in the ways individuals
with these conditions relate to others and to themselves
including low self-esteem, self-centeredness, denial, rationa-
lization, and conicts over dependency and control. In
addition, I noticed that among my patients who suffered
from psychoactive substance use disorders, bulimia, patho-
logical gambling, or sexual addiction, more were comorbid
with at least one of the other three conditions and more
reported relatives with at least one of the other three than
chance would have predicted. On the basis of the clinical
features that these four conditions shared, as well as
similarities in their diagnostic criteria, I provisionally identi-
ed them as addictive disorders (denition to follow). My
observations further led me to speculate that the four
conditions and, by extension, addictive disorders in general
had something important in common. In 1990, I [1] proposed
the following hypothesis:
A hypothesis may be submitted, the gist of which is that
similar patterns in behavioral manifestations of the
various addictive disorders. . .reect similarities in some
set of personality and/or biological variables, which may or
may not be measurable by instruments currently available.
In other words, addictive disorders would be most
accurately described, not as a variety of addictions, but
as a basic underlying addictive process, which may be
expressed in one or more of various behavioral manifesta-
tions.
In brief, the hypothesis is that addictive disorders share an
underlying biopsychological process. From this hypothesis, a
number of empirically testable predictions can be generated:
(1) A person who has been diagnosed with an addictive
disorder is at a signicantly higher risk than is the general
population to develop (or to have developed), at some point
in his or her life, one or more of the other addictive
disorders.
(2) Biological relatives of an individual who has been
diagnosed with an addictive disorder are at signicantly
higher risk than is the general population to develop (or to
have developed), at some point intheir lives, one or more of
the other addictive disorders.
(3) Symptoms of the various addictive disorders respond
similarly to at least one major class of psychiatric
medications.
(4) Results of at least one major class of empirically validated
psychological tests are similar for individuals who have
been diagnosed with any one of the addictive disorders.
(5) Addictive disorders have in common one or more
identiable patterns of neurobiological activity, structure,
and development.
(6) Individuals who have been or who will be diagnosed with
an addictive disorder tend to exhibit one or more other
observable manifestations of biopsychological pathology,
such as symptoms of another psychiatric disorder or
dysfunctional behavior patterns, prior to the onset of the
addictive disorder.
These predictions enable scientic assessment of the
validity of the hypothesis that addictive disorders share an
underlying biopsychological process. To the extent that the
ndings of research accord with the predictions, the hypoth-
esis is conrmed (factoring in that the predictions vary in
salience). To the extent that they do not accord the predic-
tions, the hypothesis is disconrmed. Of course, conrmation
or disconrmation is relative to the data that currently are
available particularly in a eld as dynamic as neuroscience,
where potentially signicant data emerge with astonishing
frequency.
A wealth of published research ndings are relevant to
assessing the accuracy of the six aforementioned predictions,
and hence the validity of the hypothesis fromwhichthey were
generated. Addictive disorders that have been the subjects of
enough research to be considered in the validation process
include psychoactive substance use disorders, bulimia,
pathological gambling, and sexual addiction. Findings that
are relevant to the six predictions lifetime comorbidity,
family history, response to medications, psychometric stu-
dies, neuroscience research, and temporal/predictive relation-
ships will now be briey reviewed.
1.1.1. Lifetime comorbidity
Epidemiological and clinical research ndings indicate that a
person who has been diagnosed with psychoactive substance
dependence with respect to one type of substance (including
ethanol) is at a signicantly higher risk than is the general
population for dependence on (i.e., addictive use of) one or
more other psychoactive substances at some point in his or
her life [29]. More broadly, research ndings indicate that a
person who has been diagnosed with psychoactive substance
dependence, bulimia, pathological gambling, or sexual addic-
tion is at a signicantly higher risk than is the general
population to develop (or to have developed), at some point in
his or her life, one of the other disorders. A person who has
been diagnosed with bulimia is at a signicantly higher risk
than is the general population to develop (or to have
developed), at some point in his or her life, a psychoactive
b i oc he mi c a l p ha r ma c ol o gy 7 5 ( 2 0 0 8 ) 2 6 6 3 2 2 267
substance dependence [1032], and vice versa [3337]. A
person who has been diagnosed with pathological gambling
is at a signicantly higher risk thanis the general populationto
develop (or to have developed), at some point in his or her life,
a psychoactive substance dependence [3,3557], and vice versa
[3,5867]. A person who has been diagnosed with sexual
addiction is at a signicantly higher risk than is the general
his or her life, a psychoactive substance addiction [6876], and
vice versa [77,78]. A person who has been diagnosed with
pathological gambling is at a signicantly higher risk than is
the general population to develop (or to have developed), at
some point in his or her life, sexual addiction [45,79], and vice
versa [71]. And a person who has been diagnosed with sexual
addiction is at a signicantly higher risk than is the general
his or her life, an eating disorder or pathological gambling or
both [68,73,75,76].
Studies have found that these four conditions psychoac-
tive substance dependence, bulimia, pathological gambling,
and sexual addiction are associated also with affective
disorders, anxiety disorders, attention decit disorder, and
personality disorders at frequencies that are higher than are
their frequencies in the general population. Affective dis-
orders, primarily major depression, have a signicant degree
of comorbidity with ethanol dependence [334,3544,8083],
other psychoactive substance use disorders [2,4,5,8488],
bulimia [15,16,32,8991], pathological gambling [40,41,44,45,
51,9294,51,9597], and sexual addiction (paraphilic disorders
in most of these studies) [69,7176,98101]. Anxiety disorders
have a signicant degree of comorbidity with ethanol
dependence [2,79,80], other psychoactive substance depen-
dence [3,4,85,86,88], bulimia [16,32,89,102,103], pathological
gambling [42,44,47,50,96], and sexual addiction (paraphilic
disorders in most of these studies) [29,71,7278,98,100,104].
Attention decit disorder has a signicant degree of comor-
bidity with ethanol dependence [105107], other psychoactive
substance dependence [108,109], bulimia [32], pathological
gambling [97,107,110,111], and sexual addiction (paraphilic
disorders in most of these studies) [74,112114]. And person-
ality disorders have a signicant degree of comorbidity with
ethanol dependence [2,13,115117], other psychoactive sub-
stance dependence [3,85,115118], bulimia [32,119,120], patho-
logical gambling [47,97,111,121123], and sexual addiction
[73,77,100,124126].
1.1.2. Family history
Family history studies indicate that biological relatives of an
individual who has been diagnosed with psychoactive sub-
stance dependence, bulimia, pathological gambling, or sexual
addiction are at signicantly higher risk than is the general
their lives, one of the other disorders. First-degree relatives of
a person who has been diagnosed with psychoactive sub-
stance dependence are at a signicantly higher risk than is the
general population for pathological gambling [41,43,44,
120,129]. First-degree relatives of a person who has been
diagnosedwithbulimia are at a signicantly higher risk thanis
the general population for psychoactive substance depen-
dence [12,1517,34,127,128]. First-degree relatives of an
individual who has been diagnosed with pathological gam-
bling are at a signicantly higher risk than is the general
population for compulsive overeating [129] and for psychoac-
tive substance dependence [41,44,129,130]. And rst-degree
relatives of a person who has been diagnosed with sexual
addiction are at a signicantly higher risk than is the general
population for psychoactive substance dependence, for an
eating disorder, and for pathological gambling [69].
1.1.3. Response to medications
Research indicates that symptoms of the conditions that we
are considering respond similarly to a number of psychiatric
medications. Antidepressants, particularly those that affect
the serotonin system, have been found to reduce craving and/
or symptomatic behavior in ethanol dependence [131141].
1
other psychoactive substance dependence [141149], bulimia
[150157], pathological gambling [154161], and sexual addic-
tion [69,101,104,162170]. Opioid antagonists, most often
naltrexone, have been found to be effective in treating ethanol
dependence [171177], other nicotine/tobacco dependence
[178,179], pathological gambling [180183], and sexual addic-
tion [184,185]. Studies have supported the efcacy of stabi-
lizers, primarily topiramate, in the treatment of ethanol
dependence [186188], cocaine dependence [189], bulimia
[190193], pathological gambling [194197], and sexual addic-
tion [198200].
1.1.4. Psychometric studies
Similar patterns of results have been reported for alcoholics,
drug abusers, bulimics, and pathological gamblers on the
Minnesota Multiphasic Personality Inventory (MMPI) and on
the MacAndrew Alcoholism Scale. Research with the MMPI
has demonstrated similar proles for alcoholics and heroin
addicts [reviewed in 201], for women with ethanol or other
drug abuse problems and women with bulimia (who have no
history of substance abuse) [202], and for alcoholics and
nonalcoholic pathological gamblers [203,204]. Using the
MacAndrew Alcoholism Scale, researchers have found the
same range of scores for problem drinkers, heroin addicts,
massively obese individuals, and smokers [205207]. In a
comprehensive review, Sutker and Archer [208] concluded
that alcoholics, opiate addicts, and abusers of other illicit
drugs share commonconstellations of MMPI features; but they
noted that alcoholics, as abusers of a socially sanctioned drug,
differ from abusers of illicit drugs on dimensions of social
nonconformity and neurotic symptomatology. Since MMPI
proles for these groups of patients are not homogeneous,
1
While Cornelius et al. [139] found that treatment of alcoholism
with antidepressants is effective only in the context of comorbid
depression or anxiety, the studies that are cited here specically
excluded subjects who had any (axis I) psychiatric diagnosis other
than alcohol abuse/dependence. Nonetheless, I agree with Corne-
lius et al. with the caveat that the comorbid depression or
anxiety do not always meet the criteria for DSM diagnosis. As I
discuss in the next section, I believe that some kind of affective
dysregulation is an underlying component of all addictive disor-
ders. However, the affective and/or anxiety symptoms are often
chronic, unconsciously excluded from the alcoholics awareness,
and difcult to dissect out of the alcoholics personality, so they
may tend to y under the average clinicians radar.
b i o c he mi c a l p ha r ma c o l og y 7 5 ( 2 0 0 8 ) 2 6 6 3 2 2 268
some investigators have attempted to delineate homogeneous
MMPI prole subgroups with the help of multivariate cluster
analysis. Almost all studies of this nature have been
conducted with alcoholics. A review of these studies [208]
found that they consistently delineated two major subtypes or
clusters, a neurotic subtype and a sociopathic subtype. Similar
delineations of two major subtypes or groups of subtypes were
found in one study of opiate addicts [209] and in two studies of
pathological gamblers [204,210].
Assessments of eld dependence have yielded similar
results of greater eld dependence (poorer performance onthe
Rod-and-Frame Test) for alcoholics [reviewed in 201], for
heroin addicts [211], and for obese individuals [212,213]. A
related condition, overdependence on external cues and
impaired ability to recognize or correctly to interpret internal
cues, has been found to be associated with both alcoholism
[213,214] and obesity [213,215].
1.1.5. Neuroscience research
Research in the areas of clinical phenomenology, lifetime
comorbidity, family history, response to medications, and
psychometric studies has provided grounds for inferring that
psychoactive substance dependence, bulimia, pathological
gambling, and sexual addiction share an underlying biopsy-
chological process. Neuroscience research has accepted the
challenge of this inferred underlying process by investigating
it directly.
To set the stage, studies with pairs of twins have yielded
evidence for a shared or common vulnerability that underlies
the abuse of psychoactive substances, regardless of the type of
substance [216218]. These studies found that the shared
vulnerability comprised both genetically determined factors
and environmentally determined factors. Other studies either
did not examine the environmental component or found it to
be more substance-specic, while still concluding that most of
the inherited predisposition to abuse different psychoactive
substances converges in a shared or substance-nonspecic
liability [reviewed in 219221].
Neuroscience research has led beyond demonstrating a
shared vulnerability that underlies the abuse of psychoactive
substances toward delineating the neurobiological processes
that constitute this vulnerability. Among those mentioned are
dysregulated mesolimbic DA circuits [222224], reduction in
DA D
2
receptors [224229], abnormalities in the orbitofrontal
cortex and the anterior cyngulate gyrus [228,230232],
abnormalities in the ventromedial prefrontal cortex [233
235], genetic variants of cannabinoid receptor 1 (CB
1
/Cnr1)
[236,237], up-regulation of brain-derived neurotrophic factor
(BDNF) [238], and impaired leptin activity [228,239]. This
research also has expanded the realm of this shared
vulnerability to include pathological gambling and pathologi-
cal use of the natural rewards food and sex, as well as
psychoactive substance abuse [227,231,239248].
1.1.6. Temporal/predictive relationships
Correlations between behavioral syndromes and patterns of
psychometric or neuroscience ndings raise questions about
their causal relationships. Do biological and social conse-
quences of the behavioral syndromes cause the abnormalities
of psychological and neurobiological functioning that are
documented in the research ndings? Or do the abnormalities
documented in the research ndings predispose to develop-
ment of the behavioral syndromes? While empirical research
does not provide causal information, it can illuminate
temporal and predictive relationships from which causal
relationships may be inferred.
Archival studies found elevations in the MMPI and
MacAndrew scale scores of young individuals who later
became abusers of psychoactive substances to be similar to
the score elevations of psychoactive substance abusers. The
results for subjects who were tested again at the time of
substance abuse treatment correlated well with their pre-
morbid test results [249251]. In the case of eld dependence,
early studies determined that this tendency antedated the
onset of drinking [252,253]. Anumber of archival, longitudinal,
and prospective studies have found several premorbid
personality traits to be associated with the later development
of psychoactive substance abuse, including: unconvention-
ality or nonconformity, rejection of societal values, alienation,
social anxiety, pessimism, depression, sensation-seeking,
impulsivity, extraversion, aggressiveness, emphasis on inde-
pendence, and labile or erratic mood [105,249,254289]. A
recent prospective population-based study [55] found that
subjects with a diagnosis of past-year problem gambling,
ethanol dependence, cannabis dependence, or nicotine
dependence at age 21 years were more characterized by
anxiety, alienation, low stress tolerance, anger or aggressive-
ness, impulsivity, risk-taking, and nonconformity measured
at age 18 years than were control subjects who did not have a
past-year addictive disorder at age 21 years. Vanyukovs
review of research up to 2003 [220] concluded that variation in
the liability to substance use disorder is shared in common
with personality phenotypic variation that predates the
initiation of substance use.
Similar questions about causal relationships have arisen
around ndings of lifetime comorbidity between the beha-
viorally denedsyndromes that we have beenconsidering and
other psychiatric disorders. Retrospective epidemiologic sur-
veys have consistently found that in respondents with
comorbid substance use disorders and other psychiatric
disorders, the onset of the other psychiatric disorders is
typically 510 years earlier than is the onset of the substance
use disorders [290292,87,293,86]. The WHO International
Consortium in Psychiatric Epidemiology found signicant
predictive associations (odds ratios greater than 1.0 and 87%
statistically signicant at the .05 level) between temporally
primary mental disorders and the subsequent rst onset of
psychoactive substance use, problems among users, and
dependence among problem users [294,295]. The results of
prospective studies up to 2004 [reviewed in 220, 296] similarly
supported the temporal and predictive primacy of anxiety,
mood, and attention decit disorders when comorbid with
psychoactive substance abuse. Subsequent studies [297299]
found that decits in affect and self-regulatory functioning
usually precede and increase the risk for development of
substance use problems, though the data are more robust for
anxiety disorders than they are for depression.
Studies of temporal and predictive relationships between
bulimia, pathological gambling, or sexual addiction and other
psychiatric disorders are still scarce. A few studies found that
anxiety disorders that were comorbid with bulimia usually
began in childhood before the onset of the eating disorder
[108,300,301], and a twin study identied a common genetic
factor that inuences liability to anxiety, depression, and
eating disorder symptoms [302]. One epidemiologic study with
pathological gambling found that among problem gamblers
with comorbid depression or anxiety, onset of the depression
or anxiety usually preceded onset of gambling [51].
1.1.7. What to conclude?
The preceding blitz-review indicates that the ndings of
scientic research accord with each of the predictions that
were generated from the hypothesis that addictive disorders
share an underlying biopsychological process. The hypothesis
is thereby conrmed. In accord with this conrmation,
Krueger and colleagues [303,304] proposed that co-occurrence
of common psychiatric disorders at greater than chance rates
suggests that the disorders are indicators of latent factors or
hypothetical core psychopathological processes that underlie
putatively separate conditions. The foregoing reviewventured
beyond comorbidity data to include a range of research that
provides substantial support for the hypothesis that addictive
disorders have in common an underlying biopsychological
process. The discussion of temporal and predictive relation-
ships then indicated that, for the most part, the abnormalities
documented in the research ndings are temporally primary
to and predictive of the behavioral syndromes that we have
been considering. From this we can infer that the underlying
biopsychological process that these conditions share precedes
their onset, and is not simply a consequence of the behavior or
life-style that characterizes them.
Our next step is to begin mining the neurobiology research
literature for ore that can then be sifted, rened, and
eventually fashioned into a neurobiological theory of the
process that underlies addiction. But before we proceed any
further, we need to dene our key terms.
1.2. Denitions
1.2.1. Addiction (or addictive disorder)
Presenting a theory of addiction without a clear and mean-
ingful denition of the term is a recipe for misunderstanding.
The denition is a matter of controversy, and DSM-IV [305]
does not employ the term at all. However, we can begin to
formulate a denition by identifying the key features of drug
addiction (in DSM-IV, psychoactive substance dependence),
the paradigm of addictive disorders.
We nowrecognize that neither tolerance nor withdrawal is
necessary or sufcient for a diagnosis of drug addiction [305].
These processes reect the natural adaptive responses of our
bodies cells to a changed chemical environment, regardless of
whether the chemicals had been used addictively. Extensive
exploration has led me to conclude that the characteristics
that are both necessary and sufcient for identifying a pattern
of drug use as drug addictionare (1) recurrent failure to control
the use of one or more drugs, and (2) continuation of drug use
despite signicant harmful consequences. (Recurrent failure
to control means not that addicted individuals invariably lose
control when they use drugs, but that their predictions that
they would remainincontrol of their drug use have repeatedly
proved to be unreliable.)
These key features distinguish drug addiction from drug
use that does not constitute addiction. However, they do not
distinguish addictive behavior from compulsive behavior or
from impulsive behavior. These latter distinctions depend on
the behaviors motivational functions. Compulsive behavior
functions to reduce anxiety or other painful affects, but by
denition it does not produce pleasure or gratication [305]. It
is motivated by negative reinforcement (i.e., the alleviation of
aversive stimulus conditions). Impulsive behavior functions to
produce pleasure or gratication but not to reduce painful
affects. It is motivated by positive reinforcement. Finally,
addictive behavior functions both to produce pleasure and to
reduce painful affects. It is motivated by both positive and
negative reinforcement.
When we combine this distinctive dual motivational
function of addictive behavior with the key features that
distinguishdrug addictionfromordinary drug use, we arrive at
a workable, behaviorally nonspecic denition of addiction:
addiction is a condition in which a behavior that can function both to
produce pleasure and to reduce painful affects is employed in a
pattern that is characterized by two key features: (1) recurrent failure
to control the behavior, and (2) continuation of the behavior despite
signicant harmful consequences.
1.2.2. Addictive process
The addictive process is the term by which I propose that we
designate the underlying biopsychological process that addic-
tive disorders are hypothesized to share. It can be dened
operationally as an enduring, inordinately strong tendency to
engage in some form of pleasure-producing behavior in a
pattern that is characterized by impaired control and
continuation despite signicant harmful consequences. The
class of addictive disorders includes psychoactive substance
addiction, bulimia, pathological gambling, shopping or buying
addiction,
2
sexual addiction, and other enduring conditions in
which a behavior that can function both to produce pleasure
and to reduce painful affects is employed in a pattern that is
characterized by two key features: (1) recurrent failure to
control the behavior, and (2) continuation of the behavior
despite signicant harmful consequences. When we talk
about addictive disorders as a group, what we are talking
about is not a collection of distinct disorders, but an under-
lying process that can be expressed in one or more of various
behavioral manifestations.
Thus, we can recognize that two sets of factors shape
the development of an addictive disorder: those that concern
the underlying addictive process, and those that relate to the
selection of a particular substance or behavior as the one that
is preferredfor addictive use. The following discussionfocuses
on the former, which is the more important both theoretically
and practically.
2
Addiction or addictive disorder is a more suitable designation
for this condition than is compulsion or compulsive disorder,
since the symptomatic behavior usually tends to be associated
with pleasure or gratication as well as alleviation of anxiety or
other affective discomfort.
2. The addictive process
In the course of reviewing evidence that psychoactive
substance use disorders, bulimia, pathological gambling,
and sexual addiction share an underlying biopsychological
process, we noted that neuroscience research has demon-
strated that a shared vulnerability underlies the abuse of
psychoactive substances, has begun to delineate the neuro-
biological processes that constitute this vulnerability, and has
expanded the realm of this shared vulnerability to include
pathological gambling and pathological use of food and sex, as
well as psychoactive substance abuse. These developments
introduce us to the possibility of formulating a neurobiological
theory of the addictive process. We begin the project of
actualizing this possibility with a comprehensive but selective
reviewof the neurobiology literature, insearchof rawmaterial
for such a theory. The selection process is guided by two
principles, generality and specicity. To be included in this
review, a researchnding or idea must be relevant to addictive
disorders in general, not just to a particular psychoactive
substance or behavior. Findings and ideas that concern a
particular psychoactive substance or behavior and do not
generalize to the rest may inuence which substance or
behavior a person who is predisposed to developing an
addictive disorder (by virtue of an addictive process) is most
inclined to use addictively, but they are unlikely to participate
signicantly in the genesis of that predisposition. Inclusion in
this reviewadditionally requires that a researchnding or idea
be specic to addictive patterns of using a substance or
engaging ina behavioras distinct frombeing applicable to all
instances of a behavior, regardless of whether they instantiate
an addictive disorder. In other words, the object of our quest is
not the neurobiology of what makes cocaine or sexpleasurable
for people in general, but the neurobiology of what makes the
drive for cocaine or sex so much more inexorable for a person
who uses it addictively.
The addictive process can be understood to involve
impairments in three functional systems: motivation-reward,
affect regulation, and behavioral inhibition.
3
Impaired moti-
vation-reward exposes addicts to unsatised states of irritable
tension, emptiness, and restless anhedonia. In the context of
aberrant motivation-reward function, behaviors that are
associated with activation of the reward system are more
strongly reinforced (via both positive and negative reinforce-
ment) than they otherwise would have been. Impaired affect
regulation renders addicts chronically vulnerable to painful
affects and emotional instability. In the context of impaired
affect regulation, behaviors that are associated with escape
from or avoidance of painful affects are more strongly
reinforced (via negative reinforcement) than they otherwise
wouldhave been. Impairedbehavioral inhibitionincreases the
likelihood that urges for some form of reinforcement
(negative, positive, or both) in the short term will override
consideration of longer termconsequences, both negative and
positive. When motivation-reward and affect regulation are
impaired, impaired behavioral inhibition means that urges to
engage in behaviors that are associated with both (a)
activation of the reward system, and (b) escape from or
avoidance of painful affects, are extraordinarily difcult to
resist, despite the harmful consequences that they might
entail.
We now embark on a quest to identify candidate
neurochemical substrates for the impairments in motiva-
tion-reward, affect regulation, and behavioral inhibition that
could contribute to an addictive process. (Candidate neuroa-
natomical substrates for these impairments are considered in
a separate publication, as are genetic and environmental
factors that shape the development of an addictive process.)
Our initial assumption is that no single factor is either
necessary or sufcient, and that an addictive process can
result from any of a variety of multi-factor combinations. The
addictive process that characterizes a person is the unique
outcome of individual genetic and environmental inuences.
But among the array of uniquenesses, a good set of theories
will enable us to recognize some patterns.
2.1. Aberrant motivation-reward
2.1.1. Dopamine (DA)
Administering any drug of abuse [306323] or engaging in
eating (especially sweets) [324328], gambling [329,330], or
sexual behavior [330334] is associated with increased
intrasynaptic levels of dopamine (DA) in the nucleus accum-
bens (NAc). Accumbal DA was initially thought to be the
neurobiological correlate of reward or pleasure. However,
recent research has claried DAs function in signaling the
incentive salience of events (including rewarding, aversive,
novel, and unexpected stimuli), in driving motivated behavior,
in predicting reward or non-reward, and in facilitating
consolidation of memory for salient events [335349].
Five DA receptors have been identied, all of which are G
protein-coupled. They can be classied into two families: D
1
and D
5
receptors that stimulate adenylate cyclase to produce
cyclic AMP; and D
2
, D
3
, and D
4
receptors that inhibit the
production of cyclic AMP [350]. Most D
1
and D
5
receptors are
located postsynaptically, while most D
2
, D
3
, and D
4
receptors
are located presynaptically [351353]. The functions of D
1
, D
2
,
and D
3
receptors primarily concern motivation and reward,
while D
4
and D
5
receptors are more involved with behavioral
inhibition (and consequently will be discussed in the Section
2.3).
2.1.2. DA D
1
receptors
Activation of DA D
1
receptors has been found to be associated
with ethanol reward [354], psychostimulant reward [355,356],
foodreward[357], cocaine-inducedlocomotor activity[355,358],
reinstatement of cue-induced cocaine-seeking behavior
[359,360], reinstatement of extinguished cocaine-conditioned
place preference [356], and enhancement of food palatability
[361]. Activation of D
1
receptors has been found also to be
critically involved in enduring cell-surface and intracellular
3
At this point, motivation-reward, affect regulation, and beha-
vioral inhibition are heuristic constructs that provide an intui-
tively meaningful framework within which relevant research
ndings may be organized. As abstractions from the nonlinear
system of an organisms neurobiology, they are more clearly
delineated from one another than are the processes to which they
refer. The organization of research ndings that this framework
enables can be expected to facilitate the eventual formulation of
operational denitions for these terms.
changes that follow administration of psychostimulants,
other drugs of abuse, and palatable food. Changes at the cell
surface that are associated with activation of D
1
receptors
include psychostimulant-induced externalization of a-amino-
3-hydroxy-5-methylisoxazole-4-propionic acid receptors
(AMPARs) with promotion of long-term potentiation, which
facilitates reward-related learning [362], and dendritic remo-
deling of medium spiny neurons in the NAc, an adaptive
response to chronic cocaine exposure that is linked to addictive
patterns of behavior [363,364]. Intracellular changes that are
triggered by activation of D
1
receptors include induction of c-
Fos, FosB, Fra-2 and JunB by acute cocaine exposure, induction
of DFosB by repeated cocaine administration in both the NAc
and caudate-putamen (CPu), and cocaine-induced expression
of olfactory-specic G protein a (Gaolf), b-catenin, and BDNF in
the NAc and CPu [364366]. The processes that are involved in
the dendritic remodeling of medium spiny neurons are
integrated by the c-Fos that has been induced by activation
of D
1
receptors [364]. Zhang et al. [366] demonstrated that
cocaine-induced expression of Fos family genes, including c-
Fos, FosB, and Fra-2, is mediated by activation (via phosphor-
ylation) of extracellular signal-regulated kinase (ERK), which in
turn is mediated by D
1
receptors. Valjent et al. [367] found that
activation of ERK is induced not only by administration of
cocaine, but also by administration of morphine, nicotine, or
tetrahydrocannabinol (THC). Activation of D
1
receptors by
administration of ethanol [368], cocaine [369], and palatable
food [370] also results in phosphorylation at threonine-34 (T35)
of the intracellular messenger DARPP-32 (dopamine and cyclic
3
0
, 5
0
adenosine monophosphate-regulated phosphoprotein), a
process that Zachariou et al. [369,371] found to be a critical
mediator of cocaines rewarding effects.
The foregoing ndings provide valuable information about
the relationshipbetweenDAD
1
receptors andreward, but they
do not necessarily enhance our understanding of addiction.
The latter depends less on knowing what makes a particular
substance or behavior rewarding, than it does on knowing
what makes some people more susceptible than are others to
developing addictive patterns of using a rewarding substance
or engaging in a rewarding behavior. So how might D
1
receptors be involved in an addictive process? One possibility
is suggested by Haney et al.s [372] ndings that maintenance
administration of the selective D
1
antagonist ecopipam to
human subjects enhanced both self-administration and
subjective effects of cocaine, compared to maintenance on
placebo. These ndings are consistent with the results of
preclinical studies in which doses of cocaine that had been
maintaining relatively low levels of self-administration
maintained higher levels following chronic exposure to a D
1
antagonist [373376]. These behavioral shifts were associated
with an increased density of D
1
receptors [377379] and
enhanced D
1
receptor sensitivity within the NAc [380].
Considered together, these data suggest that maintenance
administration of a D
1
antagonist results in D
1
receptor
supersensitivity, which increases the reinforcing and sub-
jective effects of cocaine. Since the inuence of D
1
receptor
supersensitivity on the reward effects of cocaine is almost
certainly mediated by the increase in intrasynaptic DA that
follows cocaine administration, D
1
receptor supersensitivity is
likely to have the same inuence onany substance or behavior
that increases the intrasynaptic availability of DAwhich
includes every substance and behavior that is used addic-
tively. Thus couldD
1
receptor supersensitivity, however it may
develop, contribute to an addictive process.
2.1.3. DA D
2
receptors
Preclinical studies in which D
2
agonists or antagonists were
administered have yielded a complex array of results.
Administration of the D
2
/D
3
agonist quinpirole was reported
to eliminate rats preference for a highly palatable chocolate
food [361], to block expression of an established cocaine-
conditioned place preference (CPP), and to induce place
aversions to the cocaine-paired side of the conditioning
apparatus following extinction of the established cocaine
preference [356]. However, it was reported also to evoke
reinstatement of self-administration after extinction in both
cocaine-trained and heroin-trained rats [381]. The D
2
/D
3
partial agonist terguride was found to reduce self-adminis-
tration of cocaine and of food [382]. Administration of D
2
receptor antagonists was reported to reduce ethanol self-
administration [383], to inhibit reinstatement of cue-induced
cocaine-seeking behavior [384], and, in the case of raclopride,
to potentiate reinstatement of cue-induced cocaine-seeking
behavior with a low dose and to attenuate it with a high dose
[359]. According to a model that was presented by Welter et al.
[385], D
2
receptors tonically inhibit an inhibitory signaling
pathway that decreases the cocaine-induced locomotion,
blocks the c-Fos induction that cocaine typically triggers,
and attenuates cocaine-induced CPP. To the extent that D
2
receptor activity decreases, the inhibitory pathway is released
to block these characteristic responses to cocaine.
In a more direct and readily interpretable vein, clinical
studies have indicated an associationbetweenalcoholismand
decreased D
2
receptors [386388]. Positron emission tomo-
graphy (PET) and single photon emission computed tomo-
graphy (SPECT) studies of addictive users of ethanol, cocaine,
methamphetamine, andheroinhave revealedreductions of D
2
receptor density in the ventral striatum that persist long after
detoxication [389392]. Studies with pathologically obese
subjects found reductions in striatal D
2
receptors that were
similar to those observed in studies with drug addicts, and
additionally found an inverse relationship between the
subjects body mass index and their D
2
receptor levels
[228,393]. An initial hypothesis that low levels of D
2
receptors
predispose subjects to search for psychoactive substances as a
means to compensate for the consequent decrease in reward
circuit activation [224,394,395] was expanded, in response to
the studies with obese subjects, by replacing psychoactive
substances with the more general term, reinforcers [396].
This hypothesis has been supported both by preclinical
research and by research with nonclinical populations. Rats
that were high responders to novelty as measured by locomo-
tion in an open eld and thus were more likely to acquire
amphetamine self-administration compared to low-respond-
ing rats [397] were found to have lower D
2
receptor levels in the
NAc [398], and an inbred ethanol-preferring strain of rats was
found to have lower D
2
receptor binding than did ethanol-
nonpreferring rats [399402]. Virally mediated overexpression
of D
2
receptors was associated with marked reductions in
ethanol preference and intake in both ethanol-preferring and
ethanol-nonpreferring rats, which reverted to status quo ante
as theD
2
receptor densityreturnedtobaseline[402,403]. Astudy
with rhesus macaques found that baseline D
2
receptor
availability was negatively correlated with rates of cocaine
self-administration [404]. And mice that showed an increased
propensity to ethanol sensitization were found to have higher
levels of D
2
receptor binding in localized brain areas than did
mice that showed less propensity to sensitization [405]. Mean-
while, Yoder et al. [406] reported a study in which a low (sub-
intoxicating) doseof ethanol was administeredtonon-addicted
human subjects. They found that baseline availability of D
2
receptors in the left NAc was correlated with peak perceived
intoxication and marginally correlated with peak perceived
high. The moreD
2
receptors that were available for binding in
the sober state, the more likely was the subject to feel
intoxicated and high from a low dose of ethanol. The
authors speculated that individuals with fewer D
2
receptors
would require larger quantities of ethanol to experience the
same subjective high. Similarly, Volkowet al. [407,408] reported
that baseline measures of striatal D
2
receptors in non-addicted
human subjects predicted their subjective responses to the
reinforcing effects of intravenous methylphenidate (MP).
Subjects who described MP as pleasant had signicantly lower
levels of D
2
receptors than did subjects who described it as
unpleasant. The authors hypothesized that every persons
brain has an optimal range of D
2
stimulation by MP that is
experienced as pleasant, below which administration of MP is
perceived as neutral or insufcient, and above which admin-
istrationof thedrugisexperiencedas aversive. Theauthors also
noted that subjects who reported the effects of MP as pleasant,
as do most cocaine abusers [409], had D
2
receptor levels similar
to those that were previously reported to characterize cocaine
abusers [410,411]. They interpreted these results as suggesting
that low D
2
receptor levels in cocaine abusers may have
antedated their use of cocaine and may have contributed to
their shift from cocaine use to cocaine addiction.
While consideration of genetic factors that shape the
development of an addictive process is in general being
deferred to another publication, no discussion of the relation-
ship between DA D
2
receptors and addiction would be
complete without at least mentioning the ndings that
concern associations between the Al allele of the D
2
receptor
gene Taq1A polymorphism and alcoholism [412417], cocaine
addiction [418], psychostimulant addiction [419], cigarette
smoking [420,421], pathological gambling [422424], and
exaggerated reward value of food [425,426]. Interestingly, a
number of studies have found that human subjects who carry
the Al allele of the D
2
receptor gene Taq1Apolymorphismhave
signicantly reduced D
2
receptor density [427432].
2.1.4. DA D
3
receptors
Research with DA D
3
receptors is a relatively recent
phenomenon. While ndings that D
3
receptors are located
primarily in limbic regions led to speculation that D
3
receptors might be involved in addiction, their structural
similarity to D
2
receptors made them elusive targets for
molecular sharpshooters. Only when new compounds with
high selectivity for central D
3
receptors were synthesized and
characterized was research with these receptors able to
proceed [433].
The era of addiction research with D
3
receptors was
launched by the publication in 1999 of Pilla et al.s [434] report
that BP 897, a D
3
antagonist [435], inhibited cue-induced
reinstatement of drug-seeking behavior by cocaine-trained
mice that had undergone response extinction. These ndings
were greeted by a urry of optimistic response [436438], and
were later extended to rats and rhesus monkeys [439441].
Other studies found that BP 897 blocked the expression (but
not the acquisition) of amphetamine-conditioned activity
[442,443], reduced both cue-induced ethanol-seeking behavior
and relapse-like drinking [444], and inhibited nicotine-condi-
tioned locomotor responses [445]. Another selective D
3
antagonist, SB-277011-A, was found to block reinstatement
of cocaine-seeking behavior that had been triggered by
cocaine-priming [446], to attenuate cue-induced reinstate-
ment of cocaine-seeking [384,441,447], to block stress-induced
reinstatement of cocaine-seeking [448], and to lower the
amount of work that rats would perform for a given dose of
cocaine while raising the lower limit of the cocaine dose that
would sustain a given amount of work [449]. SB-277011-A
similarly was found to reduce oral self-administration of
ethanol [444,450,451], cue-induced reinstatement of ethanol-
seeking behavior [444,450], nicotine self-administration [452],
reinstatement of nicotine-seeking behavior [453], nicotine-
induced CPP [454], and the acquisition and expression of
heroin-induced CPP [455]. The D
3
receptor antagonist NGB
2904 was found to inhibit cue-induced reinstatement of drug-
seeking behavior by cocaine-trained rats [441]. Interestingly,
SB-277011-Awas found to potentiate the pharmacological MRI
response to D-amphetamine [456], and NGB 2904 was found to
enhance amphetamine-stimulated locomotion in wild-type
mice but to have no measurable effect in mice that had been
genetically modied so as not to develop D
3
receptors (D
3
receptor knockout mice) [457], effects that intuitively seem to
contradict the other D
3
receptor antagonist ndings. However,
since NGB 2904 by itself stimulated spontaneous locomotion
in wild-type mice while having no measurable effect in D
3
receptor knockout mice [457], the effects of SB-277011-A and
NGB 2904 on response to amphetamine may have pertained
more to amphetamines stimulant effect on locomotion than
to its reinforcing or addictive properties.
Addiction-related research with D
3
receptors that does not
involve antagonists has been relatively rare. In a study that
demonstratedthe role of DAD
1
receptors inactivating ERKand
inducing c-Fos in response to acute cocaine administration,
Zhang et al. [366] also showed that D
3
receptors have opposite
effects on the same intracellular systems. Meanwhile, Boyce-
Rustay and Risinger [458] found no difference between D
3
knockout and C57BL/6J mice in ethanol CPP, in two-bottle
drinking preference, or in operant ethanol self-administra-
tion, from which they inferred that elimination of D
3
receptor
function has little inuence on ethanol reward or intake. The
apparent discrepancy between this nding and those that
were reviewed in the preceding paragraph probably reects
the difference between acute inactivation of a functioning
receptor system and congenital absence of a receptor system,
for which the postnatal plasticity of the mammalian brain can
to some extent compensate.
The opposite effects of D
1
and D
3
receptors on ERK and c-
Fos, as well as ondynorphin, neogenin, andsynaptotagminVII
[366], may suggest that D
3
receptors potential involvement in
an addictive process would similarly be opposite to that of D
1
receptorsi.e., that an addictive process could be facilitated
by D
3
hyposensitivity. However, D
3
receptor antagonists
inhibit processes that are associated with addiction, which
suggests that an addictive process could be potentiated by D
3
receptor supersensitivity.
2.1.5. Serotonin (5-HT)
Serotonin (5-hydroxytryptamine, or 5-HT) activity is associated
with behavioral inhibition [459,460], emotional stabilization
[461], appetite modulation [462], sensory reactivity [463,464],
pain sensitivity [464,465], and sleep, sexual behavior, and
cognitive function [466,467]. At least 14 subtypes of 5-HT
receptors have been cloned and identied. The 5-HT
1
class is
inhibitory both pre- and post-synaptically, and reduces
adenylate cyclase activity via Gi activation. The excitatory 5-
HT
2
class is predominantly postsynaptic, and activates phos-
pholipase C via Go. The 5-HT
3
receptor exerts its excitatory
effects byacting as anionchannel. Andthe 5-HT
4
, 5-HT
5
, and5-
HT
6
classes all activate adenylate cyclase via Gs [468].
Serotonin does not directly participate in motivation-
reward, but exerts inuence through its effects on the DA
system. Application of 5-HT onto dopaminergic neurons from
the VTA increased their ring rate in vitro, an effect that was
attributed to action of 5-HT on 5-HT
2
receptors [469]. However,
increased release of DA in the NAc (presumably of VTA origin)
that was elicited by electronic stimulation of the dorsal raphe
nucleus (DRN) in vivo was counteracted by the selective 5-HT
3
antagonists ondansetron and (S)-zacopride [470].
In a study with pathological gamblers, Pallanti et al. [471]
found that direct postsynaptic serotonergic receptor stimula-
tion with meta-chlorophenylpiperazine (m-CPP), a mixed
serotonergic agonist with highest afnity for 5-HT
2C
receptors,
elicited an enhanced prolactin response that the authors
interpreted as a hypersensitive postsynaptic serotonergic
function. In addition, the pathological gambling subjects
reported that the high sensation that they experienced in
response to m-CPP was similar to the one that they
experienced while gambling, a result reminiscent of alcoholic
subjects reports that their m-CPP-induced experience was
comparable to their experience with ethanol. The authors
speculated that increased sensitivity to 5-HT stimulation,
shared by the other addictive diseases, could be a vulnerability
factor for addiction.
The most well researched and apparently most signicant
component of the serotonergic system that inuences
motivation-reward is the 5-HT
1B
receptor, a G
i
-coupled
receptor that can be located on the axon terminals of many
types of neuron. Axon terminals of g-aminobutyric acid
(GABA) neurons that project from the NAc shell to the VTA
contain 5-HT
1B
receptors that, when activated, inhibit GABA
release. Since GABA that is released in the VTA inhibits local
dopaminergic neurons, inhibition of GABA release disinhibits
the mesolimbic dopaminergic neurons and thus potentiates
the DA-increasing effects of cocaine [472475] and of other
rewarding (or salient) substances and behaviors. Up-regula-
tion of 5-HT
1B
receptors on the axon terminals of NAc shell
GABAergic neurons could then contribute to a persons
vulnerability to developing an addictive disorder.
A study that was designed to measure the effect of chronic
cocaine injections on 5-HT
1B
mRNA expression in the NAc
shell [476] found that the latter was increased not only in rats
that received cocaine but also in control rats that received
injections of vehicleand interestingly, only in those control
rats that were housed with cocaine-treated rats. The authors
interpreted this unexpected nding to have been mediated by
social stress that the control rats experienced through
interaction with their cocaine-treated cagemates.
2.1.6. Norepinephrine (NE)
Norepinephrine (NE) is both a neurotransmitter that is
produced primarily by the locus coeruleus (LC) in the brain
stem, and a hormone that is produced by the adrenal medulla.
It is synthesized from DA by the action of the enzyme
dopamine beta hydroxylase (DBH). NE as well as epinephrine
(adrenalin) is a ligand for adrenergic receptors (adrenocep-
tors), G protein-coupled receptors that can be either a-
adrenergic or b-adrenergic. The group of a-adrenoceptors
contains two subgoups, a
1
anda
2
, eachof whichhas three sub-
subgroups: a
1A
, a
1B
, and a
1D
; and a
2A
, a
2B
, and a
2C
. The group of
b-adrenoceptors contains three subgoups, b
1
, b
2
, and b
3
. The
brain noradrenergic system consists of two main ascending
projections: the dorsal noradrenergic bundle (DNB), which
originates in the LC and projects to the hippocampus,
cerebellum, and forebrain; and the ventral noradrenergic
bundle (VNB), which arises in a number of nuclei of the pons
and medulla and projects to the hypothalamus, midbrain, and
extended amygdala [477].
Evidence for the involvement of NE in motivation-reward
has emerged from studies of self-administration, CPP,
reinstatement, and locomotor activation. Ethanol self-admin-
istration was found to be attenuated by lofexidine, an agonist
at the a
2A
autoreceptor that reduces NE transmission, and to
be enhanced by blockade of this receptor [478]. While wild-
type mice readily self-administer cocaine or morphine orally,
a
1B
knockout mice were found not to do so [479]. NE
transporter (NET) knockout mice lack the reuptake function
that terminates the action of NE and consequently have
elevated levels of extracellular NE. Such mice have been
reported to self-administer cocaine at an average rate that is
four times that of wild-type mice, suggesting that a chronic
NET deciency decreases the reinforcing properties of cocaine
[480]. Chronically elevated NE levels could conceivably
dysregulate the dopaminergic brain reward system, perhaps
via downregulation of presynaptic DA transmission or via
postsynaptic D
2
/D
3
supersensitivity [481].
Establishment of CPP for opiates seems to require intact
noradrenergic function. Clonidine, an a
2A
agonist that
decreases NE release by activating inhibitory autoreceptors,
was reported to disrupt the establishment of heroin CPP in
rats, presumably by inhibiting NE release [482]. Morphine CPP
in mice was shown to be attenuated by either clonidine or
prazosin (an a
1A
antagonist) and to be increased by yohimbine
(ana
2A
antagonist) [483,484]. Furthermore, bothDBHknockout
mice, which are incapable of producing NE, and a
1A
knockout
mice failed to express a CPP over a wide range of morphine
doses [479,485].
Noradrenergic function appears to be critical also in stress-
induced reinstatement of drug-seeking for multiple classes of
abused drugs. Administration of a
2A
agonists has been found
to attenuate stress-induced reinstatement of ethanol-seeking
behavior [486], cocaine-seeking behavior [487,488], and her-
oin-seeking behavior [489,490]. DBH inhibitors that block NE
synthesis were shown to attenuate reinstatement of amphe-
tamine self-administration and opiate self-administration
[491]. Conversely, blockade of a
2A
autoreceptors with either
yohimbine or RS-79948 was reported to reinstate cocaine-
seeking in the absence of any stressors [492]. In addition, the
reinforcing properties of morphine, as reected in the CPP
paradigm, seem to depend on NE. Chronic treatment with
venlafaxine, a dual NE/5-HT reuptake inhibitor, was reported
to attenuate the reacquisition of morphine CPP by a priming
injection of morphine [493]. And selective depletion of medial
prefrontal cortex (PFC) noradrenergic afferents was found to
abolish the reinstatement of an extinguished morphine CPP
that had been produced by a priming injection of morphine
[494], as well as the reinstatement of an extinguished
amphetamine CPP that had been produced by a priming
injection of amphetamine [495].
Finally, locomotor activation that is induced by psychos-
timulants or by opiates seems to involve and in some
instances to depend on NE. Administration of prazosin, either
systemically or directly into the PFC, has been found to
attenuate the acute locomotor responses and sensitization
that are produced by psychostimulants [479,496503] or by
morphine [479,496,504]. The locomotor activation that is
induced by morphine was shown to be decreased also by
the nonspecic a-adrenergic antagonist, phenoxybenzamine
[505,506] and by pre-treatment with FLA-63, a DBH inhibitor
[506]. LC lesions were found to attenuate amphetamine-
induced locomotion [507], while the locomotor response to
psychostimulants was reported to be amplied by blockade of
a
2A
inhibitory autoreceptors, which increases levels of extra-
cellular NE [508], and by the non-selective b-adrenergic
antagonist propranolol [509]. Additional evidence for NE
mediation of drug-induced locomotion comes from studies
in which NE function was modied genetically. a
1B
knockout
mice were found to be refractory to both psychostimulant-
induced and morphine-induced locomotor activity and sensi-
tization [479,496,500]. DBH knockout mice have been reported
not to develop morphine-induced locomotion, a decit that is
partially reversed by pharmacological restoration of NE or by
viral-mediated reexpression of DBH in the DNB or VNB [485].
Finally, genetic ablation of the NET was found to increase the
locomotor response to psychostimulants [481].
Weinshenker and colleagues [510] demonstrated that DBH
knockout mice were hypersensitive to the rewarding and
locomotor effects of amphetamine. Further work with DBH
knockout mice [511] found that they were at least as
hypersensitive to the aversive effects of cocaine and amphe-
tamine as they were to their rewarding effects. They even
developed conditioned place aversion to cocaine, which
control mice could not be convinced to do. Other studies
have reported that DBH knockout mice are hypersensitive to
the aversive effects of ethanol [512] and that mice that
specically lack NE in the PFC showa similar place aversion to
amphetamine [495]. These ndings can be understood in light
of the relationship between the NE and DA systems. The LC
noradrenergic system regulates the activity of the ascending
DA pathways [496,513]. They meet in the VTA, where
noradrenergic neurons modulate the DA cell ring pattern
via excitatory postsynaptic a
1
-adrenoceptors [514]. The LC
noradrenergic system also regulates the mesencephalic
dopaminergic system indirectly, via the PFC. DA release in
the PFC is regulated by local noradrenergic nerve terminals
[515], and electrical stimulation of the LC neurons increases
bothextracellular DAand NE inthe PFC[516]. WhenNE release
is blocked, DArelease is similarly attenuated. If the NE block is
chronic, the DA system gradually compensates by up-
regulating high-afnity state postsynaptic DA receptors (i.e.,
increasing their density) by a factor of 36 [517]. This process
results in hypersensitivity to psychostimulants and to any
other substance (or behavior) that increases intrasynaptic DA
levels.
In the course of a comprehensive reviewof the role of NE in
drug addiction, Weinshenker and Schroeder [517], reassessed
the operation of disulramfromthe perspective of its function
as a potent inhibitor of DBH. While the aversiveness of ethanol
after disulram administration had traditionally been attrib-
uted to the accumulation of acetaldehyde that results from
disulrams inhibition of the enzyme acetaldehyde dehydro-
genase, such an explanation could not account for the
effectiveness of disulram in treating cocaine addiction when
ethanol abuse is not comorbid [518520]. Amit et al. [521]
compared the efcacy of disulram in decreasing ethanol
intake with that of calcium carbamide and of FLA-63, and also
assessed the effect that each of these compounds had on
acetaldehyde levels following ethanol injection. Administra-
tion of disulram and FLA-63, both DBH inhibitors, signi-
cantly reduced ethanol intake. Calciumcarbamide, which had
the greatest effect on acetaldehyde levels following ethanol
injection, had the least effect on ethanol intake. FLA-63 had
the least effect on acetaldehyde levels, but was the most
potent suppressor of ethanol intake.
These research ndings suggest that potential contributors
to an addictive process could include blockade, hyposensitiv-
ity, or excessive downregulation of a
2A
autoreceptors, and
chronic deciency or malfunction of NE transporters. The
central factor in a potential relationship between the
noradrenergic system and addiction seems to be an increased
level of extracellular NE and its effects on the dopaminergic
system. The most frequent and signicant cause (or correlate)
of increased levels of extracellular NE is stress. The relation-
ship between the noradrenergic system, stress, and the
addictive process will be addressed in Section 2.2.
2.1.7. Endorphins and opioid receptors
Administering opiate drugs directly stimulates opioid recep-
tors in the brain [522]. Administering any other drug of abuse
[519528] or engaging in eating (especially sweets) [226,244,
529533], gambling [329], or sexual behavior [331,534,535] is
associated with the release of endogenous opioids. Studies
that measured m opioid receptors in cocaine abusers showed
signicant increases in receptor availability that were inter-
preted to reect decreased endogenous opioid release [536].
CSF b-endorphin levels in bulimic subjects were found to be
lower than in controls [537]. Low baseline levels of b-
endorphin and consequent m opioid receptor hypersensitivity
would constitute a vulnerability to addictive engagement in
any behavior that results in stimulation of m opioid receptors.
However, these cross-sectional studies do not address the
question of whether the decreased b-endorphin levels and
increased m opioid receptor availability preceded or developed
subsequent to the onset of the subjects disorders.
2.1.8. Dynorphin
Dynorphin is an endogenous opioid peptide that functions as
an agonist at k opioid receptors. Dopaminergic VTA neurons
that project to the NAc contain k opioid receptors on
presynaptic axon terminals in the NAc and also on cell bodies
and dendrites in the VTA. Action of dynorphin on these k
opioid receptors inhibits the release of DA, thus attenuating
the reward-salience effects of substances and behaviors that
can be used addictively, and moreover generating dysphoria
[538540]. Dynorphin expression is induced in the NAc and
related striatal regions after exposure to drugs of abuse, an
effect that seems to be mediated by the gene transcription
factor CREB (cAMP response element binding protein) [540].
Drugs of abuse also induce the transcription factor DFosB,
which targets the gene that encodes dynorphin and decreases
its expression [541]. Variations in CREB, DFosB, or the balance
between them that result in decreased dynorphin expression
could contribute to an addictive process.
2.1.9. g-Aminobutyric acid (GABA)
g-Aminobutyric acid (GABA) is the chief inhibitory neuro-
transmitter in the central nervous system. Three classes of
GABA receptors have been identied: GABA
A
, GABA
B
, and
GABA
C
. GABA
A
and GABA
C
receptors are ionotropic receptors
(ligand-gated ion channels). The binding of a GABA molecule
to a GABA
A
or GABA
C
receptor directly triggers the opening of a
chloride ion-selective pore that allows intracellular and
extracellular chloride to equilibrate, thereby hyperpolarizing
the neuron and inhibiting its ring [542,543]. In addition to an
active binding site at which GABA binds, GABA
A
receptors
have specic allosteric sites that bind benzodiazepines,
barbiturates, ethanol, picrotoxin, neuroactive steroids, fur-
osemide, and inhalation anesthetics [544]. GABA
C
receptors
seem to be variants of GABA
A
receptors that are insensitive to
the typical allosteric modulators of GABA
A
receptors. GABA
B
receptors are metabotropic (G protein-coupled) receptors that
can open transmembrane potassium channels, suppress
calciumchannels, and reduce the activity of adenylate cyclase
[545547]. They too exert inhibitory effects when activated.
2.1.10. GABA
A
receptors
GABA
A
receptor antagonists that bind at or near the active site,
such as picrotoxin and bicuculline, have been found to reduce
self-administration of ethanol [548552] and cocaine [553].
Nowak et al. [550] reported that microinjections of picrotoxin
or of bicuculline into the VTA resulted in decreases in ethanol
consumption, but that microinjections in regions outside the
VTA failed to decrease ethanol intake. This neuroanatomical
specicity could reect the VTAs role in the dopaminergic
reward system. VTA dopaminergic neurons that project to the
NAc are under tonic inhibitory control mediated by GABA
A
receptors, and injections of picrotoxin into the VTA were
found to increase DA release in the NAc [554]. Nowak et al.
[550] hypothesized that GABA
A
antagonists, by producing
effects on the VTA DA system similar to those of ethanol, may
enable the animal to obtain the same rewarding effects while
consuming less ethanol. Consistent with this hypothesis,
administration of picrotoxin or of bicuculline during acquisi-
tion of ethanol-induced CPP was found to increase the
magnitude of ethanol-induced CPP relative to ndings for
vehicle-treated controls [555], and simultaneous microinfu-
sion of the D
2
antagonist eticlopride into the VTA and the
GABA
A
receptor antagonist SR 95531 into either the bed
nucleus of the stria terminalis (BNST) or NAc was found to
completely attenuate the reduction in ethanol self-adminis-
tration that was observed with eticlopride alone [383].
Partial inverse agonists that bindat the benzodiazepine site
on the GABA
A
receptor also have been reported to reduce
ethanol self-administration [551,552,556566]. June et al. [561]
found that microinfusions of b-carboline-3-carboxylate-t-
butyl ester (bCCt) into the ventral pallidum (VP) produced
marked reductions in ethanol-reinforced behaviors, but that
no effects on ethanol-reinforced behaviors were observed
following infusion into the NAc or the CPu. The VP has been
found to play a role in regulating the rewarding properties of
both psychostimulant and opioid drugs [567572]. It has been
reported to code the normal hedonic impact of rewards in
general [573], and it is in a good position to do so, since it
receives efferent projections from the NAc [574,575], serves as
a centripetal nal common output path for mesocorticolimbic
circuits [576578], and sends projections to other reward
structures such as the amygdala [579,580], orbitofrontal and
insular cortex [578,581], VTA, and parabrachial nucleus
[575,582586]. Whether the VPs role with respect to GABA
A
receptor partial inverse agonists is analogous to that of the
VTAwith respect to GABA
A
receptor antagonists remains to be
hypothesized.
The effects of GABA
A
agonists on ethanol self-administra-
tion have been less consistent than have those of GABA
A
antagonists. The selective GABA
A
agonist muscimol was
found to decrease operant self-administration of ethanol
when injected intraperitoneally [551] or into the NAc [587].
When it was injected into the central nucleus of the amygdala,
it was found to decrease self-administration in dependent but
not nondependent rats [546]. Conversely, when it was injected
into the dorsal, but not the median, raphe nucleus it was found
to enhance ethanol self-administration[588]. Petry [563] found
that the effect of the benzodiazepine agonist chlordiazepoxide
dependedonthe dose administered: the lowest dose increased
ethanol self-administration, an intermediate dose had no
effect, and the highest dose decreased ethanol self-adminis-
tration. That GABA
A
agonists produce both increases and
decreases in ethanol self-administration could conceivably be
explained by a combination of neuroanatomical specicity
and the diversity in subunit composition of GABA
A
receptors
[589].
These ndings with GABA
A
receptor antagonists and
agonists could lead to speculation that a deciency or
hyposensitivity of GABA
A
receptors in the VTA or in the VP,
or perhaps an excess or supersensitivity of GABA
A
receptors in
the dorsal raphe, could contribute to an addictive process. A
couple of other studies are more directly relevant to potential
relationships between GABA
A
receptors and the addictive
process.
Tyndale and Tomkins [590] trained rats to self-administer
ethanol, and 8 weeks later assessed the levels of GABA
A
receptor mRNAin various regions of their brains. Compared to
rats that were in the lowest 15th percentile of ethanol self-
administration (LES), the rats that were in the highest 15th
percentile (HES) had signicantly higher GABA
A
receptor
mRNA levels in the dorsal raphe, medial raphe, cerebellum,
and hippocampus. The authors noted that the GABA
A
receptor
differences between the two groups either reected the
groups different pre-existing propensities to consume etha-
nol or were caused by their differing ethanol exposure, adding
that they believed that the differences were part of the cause
or at least existed prior to exposure to ethanol. Their position
has been supported by more recent research that demon-
strated that long-term ethanol consumption leads to sig-
nicant decreases in expression of GABA
A
receptor mRNA
[591593]. So to whatever extent the GABA
A
receptor mRNA
levels in Tyndale and Tomkinss [590] HES rats were affected
by higher levels of ethanol consumption, the effect would
have been in the direction of lowering their mRNA levels
relative to LES rats, whereas the study found the HES rats
mRNA levels to be higher than those of the LES rats. Thus,
elevated GABA
A
receptor mRNA levels in the dorsal raphe,
medial raphe, cerebellum, or hippocampus, most likely
associated with an increased density of GABA
A
receptors,
may predispose to the development of an addictive process.
In a fascinating study, Laviolette et al. [594] proposed that a
discrete population of GABA
A
receptors on non-dopaminergic
neurons in the VTA that tonically inhibit VTA dopaminergic
neurons serves as a potential addiction switching mechanism
by gating reward transmission through one of two neural
motivational systems, either a dopamine-independent system
or a dopaminergic system. And they demonstrated that in the
latter, the functional conductance properties of the rat VTA
GABA
A
receptor switch from an inhibitory to an excitatory
signaling mode. In opiate-nave animals, animals that have
received chronic opiate exposure but not withdrawal, and
animals that have completed and recovered from opiate
withdrawal, opiates can produce their acute rewarding effects
through a DA-independent system that is mediated through
brainstem reward circuits [595597]. On the other hand, in
animals that are in a state of opiate withdrawal, the
motivational effects of opiates are dependent on the meso-
limbic DA system [596,598600]. Laviolette et al. [594] refer-
enced the suggestion by Robinson and Berridge [335,344] that
DA transmission mediates a drug wanting or craving signal,
independently of the acute rewarding properties of opiates.
This suggestion makes particular sense in light of the opiate
withdrawal states mix of strongly aversive stimuli that are
relieved by administration of opiates. Such negative reinfor-
cement motivation is incentively salient and thus suitable for
DA signaling, while not depending at all on reward. While
Laviolette et al. [594] focused on opiate state specically, the
difference between animals in opiate withdrawal and animals
not in opiate withdrawal as the determinant of whether VTA
GABA
A
receptors are in an inhibitory or an excitatory mode, I
believe that the scope of their ndings is deeper and more far-
reaching than opiate states. Neurobiologically, the state of
opiate withdrawal is very similar to a state of acute stress. Both
involve activation of the hypothalamicpituitaryadrenal
(HPA) axis and dysregulation of the noradrenergic system.
My hypothesis is that the component of the opiate withdrawal
state that determined the VTA GABA
A
receptor switch from
inhibitory to excitatory in Laviolette et al.s study [594] is one
that they share with the state of acute stress. The signicance
for addiction of the VTA GABA
A
receptor inhibitory-excitatory
switch remains to be elucidated, but I believe that it also will
enhance our understanding of how recurrent acute stress can
potentiate an addictive process.
2.1.11. GABA
B
receptors
In preclinical research, the GABA
B
receptor agonist baclofen
has been found to attenuate self-administration of cocaine
[601604], heroin [605,606], ethanol [607], nicotine [608610],
and d-amphetamine [611]. It has been found also to reduce
reinstatement of cocaine self-administration [612], to reduce
reinstatement of heroin self-administration [613], and to
decrease stimulus-maintained responding for either cocaine
or heroin [614]. The highly selective GABA
B
receptor agonist
CGP 44532 reduced cocaine-induced enhancement of brain
stimulation reward (BSR) [615], and the positive allosteric
modulator of GABA
B
receptors CGP 7930 reduced operant self-
administration of ethanol in ethanol-preferring rats [616].
Preliminary clinical studies have demonstrated that
administration of baclofen reduces craving for both cocaine
and ethanol in addicted patients [617619]. Additionally,
baclofen has been reported to attenuate the limbic cortical
activation induced in cocaine addicts by conditioned stimuli
that previously had been paired with cocaine use [602,620].
Baclofen and other GABA
B
agonists are understood to
attenuate the reinforcing effects of abusable psychotropics
through modulation of DA transmission from the VTA to the
NAc, and perhaps also to the PFC [606,621]. Their targets are
inhibitory GABA
B
receptors that are located on the cell bodies
of VTA dopaminergic neurons [622624] and that, when
stimulated, hyperpolarize the membrane potential and
decrease the ring rate of these neurons [625,626]. Both
GABA
B
agonists and GABA
B
antagonists can increase BSR
thresholds, whichsuggests a complex interactionbetweenthe
reward system and GABA function, possibly reecting
differential effects at pre- and post-synaptic receptors [627].
The endogenous ligand for the GABA
B
receptors that are
located on VTA DA neurons (i.e., GABA) is tonically produced
by local VTAGABAergic interneurons. Inadequate or abnormal
functioning of these GABA neurons could disinhibit the
dopaminergic neurons, free them to respond more enthu-
siastically when stimulated, and thus intensify the reinforcing
effects of substances and behaviors that can be used
addictively.
2.1.12. Endocannabinoids and cannabinoid receptors
At the current time, there are two known cannabinoid
receptor subtypes: cannabinoid-type 1 (CB
1
), which are widely
expressed throughout the peripheral and central nervous
systems, and cannabinoid-type 2 (CB
2
), which show high
levels of expression within the immune and enteric nervous
systems as well as in glial cells of the CNS. Both are coupled to
inhibitory Gi/Go proteins. The majority of neuronal CB
1
receptors appear to be expressed pre-synaptically. Endogen-
ous cannabinoids or endocannabinoids (eCBs) appear to
function as retrograde neurotransmitters. Upon release from
postsynaptic neurons via membrane depolarization, they
migrate back to an adjacent presynaptic membrane and
activate presynaptic CB
1
receptors, which then inhibit
neurotransmitter release [223,724]. Two major classes of eCBs
have been identied thus far, exemplied by anandamide and
2-arachidonoyl glycerol [628631]. The eCB system is under-
stood to reinforce both the motivation and the reward
functions of the mesolimbic DA system in its regulation of
eating behavior [632].
Dopaminergic terminals lack cannabinoid receptors [633].
Nonetheless, genetic elimination of CB
1
receptors (CB
1
knock-
out mice, CB
1
1/) abolished DA release in the NAc in
response to morphine [634] and ethanol [635], and the
cannabinoid CB
1
receptor blocker rimonabant curtailed DA
responses to administration of nicotine, ethanol, and cocaine
[636]. The likely anatomical locus for the CB
1
receptors that
made the critical difference in these studies is the presynaptic
terminals of VTA GABAergic neurons that synapse onto VTA
dopaminergic neurons and modulate their activity. Under
ordinary circumstances, eCBs that had been launched by VTA
dopaminergic neurons would drift over to activate the
presynaptic CB
1
receptors that mediate the inhibition of GABA
release, thereby decreasing the GABA-mediated inhibition of
DA release. Inactivation or elimination of the CB
1
receptors
interrupts this process and thus attenuates the DA responses
to administration of psychoactive substances and to any other
behavior that is associated withDArelease inthe NAc. Genetic
variants of cannabinoid CB
1
receptors have been identied as
probable factors in a persons vulnerability to develop an
addictive disorder, especially one that involves consumption
of food or of psychoactive substances [236,237].
2.1.13. Cyclic AMP response element binding protein (CREB)
Cyclic AMP response element binding protein (CREB) is a
transcription factor that mediates effects of the cAMP second
messenger pathway on gene expression. Once CREB has been
phosphorylated by proteinkinase A(a proteinkinase activated
by cAMP) or another protein kinase, it forms dimers that bind
to specic CRE (cAMP response element) sites on target genes
andinteract withthe basal transcriptional complex to regulate
gene transcription [637].
Administration of psychostimulant and opiate drugs
induces the phosphorylation and activation of CREB in several
reward-related regions [638643]. The induction of CREB
activity appears to become greater and more persistent with
repeated drug exposures [644]. In the NAc, the ability of
psychostimulants to induce CREB is mediated via activation of
the DA D
1
receptor [638,639]. Cocaine increases cAMP-PKA
signaling in the NAc, which directly decreases medium spiny
neuron (MSN) excitability, while also activating CREB. CREB
increases MSN excitability and thus counterbalances the
magnitude of the cocaine-induced decrease [645]. Increased
CREB function in the NAc decreases an animals sensitivity to
the rewarding effects of cocaine, morphine, or sucrose, while
reduction in CREB activity produces opposite effects [646,647].
Chronic administration of cocaine or other stimulants
induces dynorphin expression in the NAc, and this induction
is dependent on CREB [639,646]. Dynorphin activates k opioid
receptors on VTA dopaminergic neurons to decrease DA
release in the NAc and thus to dampen the reward-reinforce-
ment process [648]. At least some of the CREB-related decrease
in the rewarding properties of drugs is mediated by the
induction of prodynorphin mRNA, which encodes dynorphin
[639].
Exposure of an animal to aversive stimuli activates CREB in
the NAc in muchthe same way as do drugs of abuse. Following
the parallel, researchers foundthat increasedCREBfunctionin
the NAc decreased an animals responsiveness to a variety of
aversive or negative emotional stimuli, including stressful,
anxiogenic, and nociceptive events; and that decreased CREB
function in this region increased the animals sensitivity to
these conditions [647,649]. Activation of CREB in the NAc
appears to result from exposure to stimuli of high hedonic-
emotional charge, whether they are rewarding or aversive.
And it appears to mediate a behavioral state that is
characterized by reduced sensitivity to hedonic-emotional
stimuli in general, again regardless of their valence [637]. This
behavioral state resembles the syndromes of anhedonia and
emotional numbing that can characterize depression, post-
traumatic stress disorder (PTSD), and some forms of drug
withdrawal [650].
2.1.14. DFosB
DFosB is a member of the Fos family of transcription factors.
These proteins dimerize with a Jun family member to form
activator protein-1 (AP-1) transcription factor complexes,
which bind to AP-1 sites within the regulatory regions of
certain genes [637].
DFosB is induced by virtually all drugs of abuse, including
psychostimulants, opiates, ethanol, and nicotine, among
others [651655]. DFosB also is induced by repetition of
naturally rewarding behavior, such as wheel running or
sucrose drinking [541,656], and by several forms of chronic
stress [657,658]. Interestingly, levels of stress-related DFosB
induction negatively correlate with the degree to which the
animals develop learned helplessness, suggesting that induc-
tion of DFosB represents an adaptive, active coping mechan-
ism that opposes the development of learned helplessness
[657]. And DFosB is induced by the chronic administration of
pharmaceutical antidepressants [651].
Inducible transgenic mice that overexpressed DFosB within
the NAc and dorsal striatum showed increased sensitivity to
the behavioral effects of cocaine, enhanced incentive motiva-
tion for cocaine, increased sensitivity to the behavioral effects
of morphine, and greater responsiveness to naturally reinfor-
cing behaviors, such as running and eating [539,540,637].
Nestler, the author of these studies, interpreted their ndings
to suggest that DFosB could be part of a sustained molecular
switch that functions rst to induce and later to maintain a
state of heightened incentive motivation toward reinforced
behaviors.
DFosB appears to be the antithesis of CREB. While CREB
activation mediates a state of reduced reward and reduced
emotional reactivity, DFosB accumulation mediates a state of
heightened drug sensitivity and increased drive for rewarding
behavior. Drug-induced activation of CREB in the NAc
dissipates within a few days of coming off the drug, while
DFosB increases over time and persists in the brain for up to 2
months [659].
At one time, DFosB may have seemed to epitomize the
argument that drug addiction is caused by drug use. DFosB is
induced by drug use, it increases sensitivity to and drive for
drugs, and its extended duration of action could account for
abstinent addicts vulnerability to relapse. However, as Nestler
noted [539], DFosB does not last long enough to underlie the
near-permanent predispositions that are seen in many
addicted individuals. He suggested that variations in the
genes encoding DFosB could contribute to the genetic risk for
addiction: for example, an individual with a gene that
expresses DFosB at high levels might be more prone to
addiction [660]. Another means by which levels of DFosB could
increase andthus contribute to anaddictive process is through
its induction by chronic stress [658,657].
2.1.15. Dopamine and cAMP-regulated phosphoprotein
(DARPP-32)
The dopamine and cAMP-regulated phosphoprotein (DARPP-
32) is a key regulator of kinase-phosphatase signaling
cascades that is found in dopaminergically innervated areas
of the brain. cAMP that has been generated by activation of D
1
receptors activates protein kinase A (PKA), which phosphor-
ylates DARPP-32 at the threonine-34 site (T34) [661,662]. When
DARPP-32 is phosphorylated at this site, it acts as an inhibitor
of protein phosphatase-1 (PP-1) [663], thereby maintaining the
phosphorylation state of various neuronal proteins. DARPP-32
can be phosphorylated also at the threonine-75 site (T75) by
cyclin-dependent kinase 5. DARPP-32 that has been phos-
phorylated at this site inhibits PKA activity, resulting in
reduced efcacy of DA signaling [664]. In this way, DARPP-32
acts as a bidirectional signaling protein that regulates protein
phosphorylation and dephosphorylation via PKA and PP-1.
The phosphorylation state of DARPP-32 is inuenced also by
the phosphatases, calcineurin (dephosphorylates T34) and
protein phosphatase 2A (dephosphorylates T75) [665].
DARPP-32 knockout mice were found to have heightened
substance P-like immunoreactivity and not to show the
characteristic increase in DFosB after repeated cocaine
administration [666]. They also were reported to have reduced
cocaine CPP [371], suggesting that a DARPP-32 decit can
decrease the rewarding properties of cocaine. Zachariou et al.
[369] used a mutation of T34 to demonstrate that phosphor-
ylation at T34 of DARPP-32 is a necessary mediator of cocaine-
induced place conditioning, locomotor activity, and sensitiza-
tion. The T34 mutationalso diminished the induction of DFosB
in the ventral striatum by chronic cocaine administration.
Donohue et al. [667] reported that transgenic mice that
overexpress an ethanol-sensitive isoform of adenylate cyclase
(AC7) had higher basal levels of T34 DARPP-32 in the striatum
and amygdala than did wild-type mice, whereas basal levels of
T75 DARPP-32 did not differ between wild-type and transgenic
mice. Ethanol administrationwas foundtoincreaseT34DARPP-
32 in the NAc and amygdala (but not in the striatum) of wild-
type and transgenic mice, with a greater effect in the amygdala
of transgenic mice. It was found also to increase T75 DARPP-32
in the amygdala of the wild-type mice only, and in the NAc and
striatumof boththetransgenicandwild-typemice. Theauthors
concludedthat the effect of ethanol onthe balance of DARPP-32
phosphorylation, especially inthe amygdala, may contribute to
differential motivational effects of ethanol.
2.1.16. Neuropeptide Y (NPY)
Neuropeptide Y(NPY) is a36-aminoacidneuromodulator that
is expressed throughout the central nervous system [668].
Most of it derives from neurons in the arcuate nucleus (ARC)
of the hypothalamus, which project dorsally to the para-
ventricular nucleus (PVN) as well as to other hypothalamic
and extrahypothalamic nuclei [669]. NPY is involved with a
diverse set of biological functions that include integration of
emotional behavior [670,671], control of food intake [672,673],
neuronal development [674,675], circadian rhythms [676
679], pain modulation [680,681], and reproduction [682,683].
NPY acts through at least ve receptor subtypes the Y1, Y2,
Y4, Y5, and Y6 receptors all of which couple to G proteins
that inhibit the production of cyclic adenosine monopho-
sphate [684]. Y5 receptors are present at signicant levels in
the PVN, ARC, thalamus, and amygdala, which suggests the
presence of functional hypothalamiclimbic neural circuits
[685].
A number of studies found that administration of NPY
[686,687] reduces ethanol consumptioninethanol-preferring P
rats and high ethanol-drinking HAD rats, but not in ethanol-
nonpreferring NP rats, low-ethanol-drinking LAD rats, or
nonselected rats. However, other studies found that admin-
istration of NPY increases [688,689] and of NPY antagonist
decreases [690693] ethanol self-administration. Schroeder
et al. [694] suggested that these discrepant ndings could be
reconciled with the recognition that the nature of NPYs
inuence on ethanol intake is brain region dependent.
Research indicating that NPY increases ethanol intake infused
the peptide directly into the PVN, where it functions as an
orexigenic agent [688,689]. Meanwhile, research indicating
that NPY decreases ethanol intake administered it via
intracerebroventricular infusion [686,687].
Other research speaks with a more unied voice about
NPYs role in modulating ethanol consumption. Mice that
overexpress NPY consume less ethanol than wild-type
controls, while transgenic mice that lack NPY (NPY knockout
mice) consume more ethanol than wild-type controls [695].
Ethanol consumption is suppressed by blockade of either NPY
Y1 receptors [693] or NPY Y2 receptors [696,697], but elevated
in Y1 receptor null mutant mice [698]. And in humans, a
polymorphism in NPY (Leu7Pro) was signicantly associated
with addiction in European American and Finnish alcoholics,
both exhibiting an increased frequency of the Pro7 allele
compared with controls [699,700].
NPY is a highly potent activator of feeding behavior. When
administered into the PVN, it induces feeding in satiated
animals and it seems to selectively stimulate prodigious
carbohydrate intake [222]. Studies indicate that NPY and 5-
HTplay antagonistic roles inthe regulationof feeding [701,702],
and that NPYs stimulation of feeding is mediated via the
internal opioidsystem, sinceNPY-inducedfeedingisblockedby
the opioid antagonists naloxone and naltrexone [703]. NPYalso
hasbeenobservedtobindtonon-selectiveopiatereceptorswith
modest activity similar to that of the endogenous opioid leu-
enkephalin [704]. NPYs induction of feeding in satiated
animals, its involvement with the internal opioid system, its
antagonistic relationship with 5-HT, and its presence in
functional hypothalamiclimbic neural circuits suggest that it
could contribute to an addictive process.
2.1.17. Galanin
Galanin is a 29-amino acid neuropeptide that activates at least
three receptor subtypes coupled to Gi, Gq, or Go [705,706]. It is
synthesized inmany types of neuron, including brainstemNE-
producing cells of the LC and 5-HT-producing neurons of the
DRN. Cells that express galanin are concentrated in several
hypothalamic areas: the dorsomedial nucleus, PVN, perifor-
nical lateral hypothalamus (PLH) and ARC. They send out
dense projections throughout the hypothalamus as well as to
other parts of the limbic system, including the amygdala,
BNST, andhippocampus [707711]. Galaninserves a number of
disparate functions. It inhibits the ring of NE, 5-HT, and DA
neurons and reduces release of these neurotransmitters in
forebrain target regions [712]. It inhibits glucose-induced
insulin release and reduces levels of 5-HT, NE, and acetylcho-
line through the inhibition of adenylate cyclase and phos-
phatidyl inositol hydrolysis [713]. Galanin also is a potent
endogenous modulator of ring pattern in hypothalamic
neuroendocrine cells [714], a hypothalamic-hypophysiotropic
hormone that modulates the secretion and action of luteiniz-
ing hormone releasing hormone (LHRH) [715], and a regulator
of food intake [716,717].
Injection of galanin in the PVN at a dose known to induce
feeding has been found to potentiate intake of 4% ethanol,
even when food and water were available as sources of
calories and uid [718]. In rats that have been trained to drink
ethanol, galanin seems to stimulate the appetite for it
[718,719]. We can wonder whether a similar process would
occur with rats that have been trained to drink avored
solutions that have been paired with infusions of cocaine or
heroin.
Galanin has interesting relationships with the endogenous
opioid and dopamine systems that could contribute to its
involvement in an addictive process. Galanin has been found
to potentiate morphine analgesia [720]. Meanwhile, naloxone
has been found to block galanin-induced feeding [721,722] and
to decrease PVNgalanin mRNAin ethanol-drinking rats, while
having little or no effect on galanin mRNA in water-drinking
rats [723]. Another study found that injection of galanin into
the PVN of rats releases DA and inhibits acetylcholine release
in the NAc, an effect that occurs only in rats that previously
had demonstrated signicant increases in their feeding
behavior in response to galanin [724]. These ndings were
interpreted in one later study as indicating that ethanol
consumption induced by PVN injections of galanin may be
mediated through DA in the NAc [718], and in another as
indicating that galanin-induced overeating is associated with
DA release [723].
Studies have demonstrated that hypothalamic galanin
increases the consumption of a fat-rich diet [725,726] and,
conversely, that the consumption of fats can increase the
expression of galanin in hypothalamic nuclei [727,728].
Leibowitz et al. [723] commented that these ndings suggest
the operation of a positive feedback loop that could contribute
to overeating until the cycle is interrupted by postingestional
satiety signals [717,729]. Interestingly, Thiele et al. [730] and
Rada et al. [718] identied a similar positive feedback loop
between galanin and ethanol intake, since ethanol increases
galaninexpressionin the PVNand injection of galanin into the
PVN potentiates consumption of ethanol. A key difference
between the two positive feedback loops is that in the latter,
ethanol produces no satiety signal. (Actually, some sufferers of
bulimia and binge-eating disorder report that they do not
experience satiety signals after eating.).
2.1.18. Orexin
Orexins (or hypocretins) are neuropeptides that are synthe-
sized in neurons of the posterior and lateral hypothalamus
(LH). Neurons that synthesize the excitatory peptide hypo-
cretin also synthesize dynorphin, a peptide that usually is
inhibitory [731]. Orexin neurons that are located in posterior
hypothalamic areas are involved in regulating wakefulness,
thermogenesis, and energy expenditure, whereas those that
are located in the LH are involved in stimulation of appetitive
behaviors and in reward processing. Orexin A and orexin B are
produced by cleavage of a single precursor protein, and their
actions are mediated by two G protein-coupled receptors,
orexin receptor type 1 (OXR1) and orexin receptor type 2
(OXR2). OXR1 shows higher afnity for orexin A, while OXR2
shows equal afnity for both ligands [732]. Orexin neurons
receive input from the amygdala, basal forebrain cholinergic
neurons, GABAergic neurons in the preoptic area (POA), and
serotonergic neurons in the median/paramedian raphe nuclei.
During periods of wakefulness, emotional stimuli from the
limbic system and cholinergic inuences from the basal
forebrain stimulate orexin neurons to maintain the activity of
the monoaminergic system, while sleep-active neurons in the
POAinhibit themduring periods of sleep [733]. Orexinneurons
of the LH-perifornical area send widespread axonal efferents
to the LC, VTA, NAc, cortex, and midline thalamus, and to
other regions of the lateral and medial hypothalamus. They
also maintain local axonal collaterals that terminate on other
cells in the LH, including orexin cells and neurons that
synthesize melanin concentrating hormone (MCH), though
orexin neurons show little direct response to orexin [731].
Orexin A has been demonstrated to increase the ring rate
and in some cases to cause burst ring of VTA dopamine
neurons in rat brain slices [734]. Orexin neurons send
excitatory projections to the VTA and substantia nigra pars
compacta. Intra-VTA infusions of orexin A in vivo have been
found to increase extracellular DA levels in the PFC and in the
shell region of the NAc, but not in the NAc core [735,736].
Through their enhancement of midbrain dopaminergic
system activity, orexins can potentiate an increase in motor
activity and thereby reduce the threshold for emitting specic
(previously rewarded) behaviors [737].
Orexin neurons in the LH become activated by cues that
have been associated with consummatory rewards such as
food and drugs [738]. Several studies demonstrated orexin to
have a critical role in activating reward-seeking or appetitive
behavior in response to conditioned or discriminative stimuli.
Intracerebroventricular (icv) infusion of orexin was found to
evoke a dose-related reinstatement of extinguished cocaine
self-administration in rats, an effect that was prevented by
antagonists of receptors for NE or for corticotropin releasing
factor (CRF) [739]. The inference that orexins activation of
cocaine self-administration reinstatement is mediated via NE
and CRF is consistent with ndings that icv administration of
orexin A activates CRF-expressing neurons in the PVN and the
central nucleus of the amygdala (CeA) [740]. Antagonism of
orexin OXR1 receptors by the selective orexin Aantagonist SB-
334867 was found to reduce operant responding for ethanol
and also to abolish cue-induced reinstatement of ethanol-
seeking behavior in ethanol-preferring iP rats [741]. Harris
et al. [738] reported that the amount of Fos activation in LH
orexin neurons of animals that had been conditioned via CCP
protocol for morphine, cocaine, or food reward was correlated
with the intensity of their reward-seeking. They reported also
that microinjection of orexin into the VTAcaused a signicant
reinstatement response for morphine reward; that adminis-
tration of the orexin antagonist SB-334867 after morphine CPP
training produced a signicant reduction in preference
compared to animals that were given a vehicle injection; that
reinstatement of extinguished CPP by microinfusionof rPP (rat
pancreatic polypeptide, an agonist at NPY Y4 receptors on
orexin neurons) in the LH was similar to the reinstatement
produced by systemic morphine; and that reinstatement was
completely blocked by prior systemic administration of SB-
334867. Harris and Aston-Jones [742] concluded that both the
orexin neurons that originate in the perifornical and dor-
somedial hypothalamic areas (PFADMH) and those that
originate in the LHcan participate in drug relapse, but through
different processes. The PFADMH orexin system, which is
involved in regulating wakefulness and energy expenditure,
drives relapse through activation of stress systems (perhaps
involving CRF or NE), whereas the LH orexin system, which is
involved in reward processing, drives relapse through activa-
tion of brain circuits that are associated with reward learning
and reward-seeking behavior [742].
Neuroplasticity at VTA glutamatergic synapses that is
induced by drugs of abuse has been suggested to play an
important role in the behavioral consequences of in vivo drug
exposure [343,659,743]. A recent study by Borgland et al. [744]
demonstratedthat orexinAisacritical substrateinthisprocess.
Glutamatergic N-methyl-D-aspartate receptors (NMDARs) on
VTA DA neurons perform two major functions: they promote
burst ring[743,745], andtheyarenecessaryfor theinductionof
long-term potentiation [746,747]. Burst ring of VTA dopamine
neurons, which increases extracellular DA in the projection
areas more efciently than does a regularly spaced train of
action potentials [745,748], signals the occurrence of salient
stimuli and facilitates consolidation of the relevant memory
traces [749]. Long-term potentiation is an enduring decrease
in depolarization threshold that functionally strengthens
synapses and contributes to synaptic plasticity. Borgland
et al. [744] reported that in vitro application of orexin A
potentiates NMDAR responses in VTA dopamine neurons; that
the OXR1 receptor antagonist SB 334867 blocks induction of
cocaine-induced potentiation of excitatory inputs onto VTA
neurons; that orexin A causes late-phase increases in AMPAR-
mediated synaptic transmission; and that microinjection of SB
334867directlyintotheVTAblocks thedevelopment of cocaine-
induced locomotor sensitization. These data provide evidence
that orexin signaling pathways play an important role in the
drug-induced neural plasticity that contributes to cocaine
addictionand by inference, to other addictions as well.
2.1.19. Substance P (SP)
Substance P (SP) is the most common of the ve known
mammalian neurokinins (or tachykinins), the others of which
are neurokinin A (NKA), neurokinin B (NKB), neuropeptide K,
and neuropeptide a. Three G protein-coupled neurokinin
receptors have been identied NK-1, NK-2, and NK-3 for
which SP, NKA, and NKB have the highest binding afnity,
respectively, but all neurokinins bind to all three NK-Rs
[750,751]. SP is colocalized with other neurotransmitters and
has important neuromodulatory effects. Examples are colo-
calizations with 5-HT in the nuclei raphes, with DA in the
midbrain and striatum, with GABA and acetylcholine in the
cortex, and with CRH in the hypothalamus [752]. Examples for
direct neuromodulatory effects of SP are the regulation of
acetylcholine release in the human cortex [753] and the
modulation of noradrenergic neurotransmission in the LC
[754].
SP and the NK-1 receptor play a role in maintaining the
activity of mesocorticolimbic DA neurons, under both basal
and drug-induced conditions. Blockade of NK-1 receptors by
systemic injection of the NK-1 receptor antagonist CP-96345
decreased the number of spontaneously active DA neurons in
the VTA [755], and injection of a SP antibody into the NAc
produced increases in concentrations of DA and metabolites,
an effect consistent with intracellular accumulation and
metabolism of DA following decreases in DA release [756].
SP afferents have synaptic contacts with dopaminergic
neurons in the VTA [757], and SP is present in high
concentration in terminals close to the VTA dopaminergic
cell bodies [758,759]. Injection of SP directly into the VTA has
been found to increase the levels of DA and/or its metabolites
in the PFC and the NAc, suggesting that SP stimulates the
release of DA from mesocortical and mesolimbic DA neurons
[760762]. SP has been shown to preferentially activate
mesocortical DA neurons in a manner similar to acute
stressors such as mild footshock or restraint [763]. Further-
more, evidence suggests that the increased turnover of DA in
the PFC and the NAc in response to stress may be mediated by
SP. Increases in DA metabolism in the PFC in response to
footshock-stress can be blocked by a SP antibody in the VTA
[764]. These ndings suggest that not only does SP have a tonic
facilitatory inuence on mesocorticolimbic DA activity, it also
may contribute to the DA-dependent behavioral responses to
drugs. They also raise the possibility that the activation of
these DA neurons in response to stress may be mediated by
the endogenous SP system [765,766].
Injection of SP into the VTA has been shown to enhance
responding for conditioned reward, but not selectively for the
reward-paired lever [767]. Similarly, on a test of xed interval
responding, intra-VTA injection of SP was shown to increase
responding on the non-reinforced lever [768]. These ndings
suggest that activation of VTA cell bodies by SP or its analogue
produces increases in reward, but may also disrupt discrimi-
nation processes and thereby result in some degree of
response generalization [765].
The experimental literature consistently afrms that SP is
involvedinopiaterewardprocesses. Reward-relatedbehavioral
effects of morphine or heroin are substantially attenuated
when SPs favorite receptor, NK-1, is blocked by the antagonist
GR82334, ablated, or geneticallydeleted[766,769771]. However,
when we turn to consider the relationship between SP and
psychostimulants, the research results are mixed and perplex-
ing. Placenza et al. [766] reported a study in which icv
administration of the selective NK-1 receptor antagonist
GR82334hadnoeffect oncocaine-inducedlocomotor activation
or cocaine self-administration, though it had produced sig-
nicant increases in heroin self-administration and attenua-
tion of morphine-induced locomotion. Their results are
consistent with studies that found that genetic deletion of
the NK-1 receptor did not impair the reinforcing effects of
cocaine [769,770]; that ablation of NK-1 receptors in the
amygdala did not block cocaine-induced CPP [771]; and that
icv injections of NK-1 receptor antagonists had no effect on the
reinstatement of cocaine seeking induced by a priming
injection of cocaine [772]. However, other studies found that
infusion of the high-afnity nonpeptide NK-1 receptor antago-
nist L-733,060 prior to a systemic injection of cocaine
signicantly attenuated the cocaine-evoked release of DA in
the striatum [773,774]; that infusion of the NK-1 receptor
antagonist WIN-51,708 prevented the massive release of
acetylcholine in the striatum that cocaine injection would
ordinarily evoke [774]; that intrastriatal NK-1 receptor blockade
by the specic NK-1 receptor antagonist LY306740 decreased
amphetamine-induced behavior [775]; and that pre-treatment
with the NK-1 receptor antagonist WIN-51,708 30 min before
injections of methamphetamine prevented both the loss of
dopamine transporters (DAT) in the striatum and metham-
phetamine-inducedcell death[774]. Anattempt toreconcilethe
conicting studies by questioning whether different NK-1R
antagonists are functionally equivalent would miss the larger
point of perplexity: that a disruption of the mesocorticolimbic
DA system that blocks incentive-reward for opiates but not for
psychostimulants seems to be inconsistent withthe consensus
that the mesocorticolimbic DA system where SP exerts its
inuence is the primary conduit of incentive-reward-reinforce-
ment for both opiates and psychostimulants. Whether SP is to
be considered as a potential contributor to anaddictive process
hingesonhowtheseapparent contradictionsareresolved. If the
SP functions that are most relevant to addiction are found to
characterize opiates but not psychostimulants, then variations
of the SP-NK1 systemcould be factors that inuence whether a
person who is predisposed to developing an addictive disorder
is more likely to addictively use opiates or psychostimulants,
but they would not be factors in an addictive process.
2.1.20. Melanocortins (MCs) and melanocortin receptors
(MCRs)
Adrenocorticotropin (ACTH) and h-, 1-, and #-melanocyte-
stimulating hormones (h-, 1-, and #-MSH) are derived by
enzymatic processing from proopiomelanocortin (POMC), a
propeptide that is produced in the arcuate nucleus of the
hypothalamus. Collectively, they are called melanocortins.
The hypothalamic arcuate nucleus (ARC) contains two
discrete cell groups. One group co-expresses the anorexigenic
peptides a-MSH and cocaine- and amphetamine-regulated
transcript peptide (CART). The second group coexpresses the
orexigenic peptides agouti-related protein (AGRP) and neuro-
peptide Y. Melanocortins act via ve receptor subtypes (MC1R
MC5R), all of which belong to the G protein-coupled receptor
superfamily andare positively coupledto adenylate cyclase. In
the brain, MC3R and melanocortin-4 receptor (MC4R) are
mainly expressed, with little expression of MC5R. They are
expressed in brain regions that modulate the reinforcing
properties of drugs of abuse and natural reinforcers (e.g., food
and sex), including the NAc, the VTA, and the hypothalamus
[776,777]. All melanocortin receptors are activated by ACTH,
whereas all melanocortin receptors except MC2R are activated
by MSH. While a-MSH and AGRP bind as high-afnity agonist
and antagonist, respectively, at the melanocortin MC3R and
MC4R receptors, their opponent effects on feeding seem to be
mediated by MC4R [778780].
Studies indicate that melanocortins operate inrelationships
of mutual inuence with the mesolimbic DA and endogenous
opioidreward-relatedsystems. Melanocortins have beenfound
to enhance dopaminergic neurotransmission, and DAhas been
found to increase melanocortin function [781]. MCR signaling
has been reported to regulate ethanol consumption by
modulating endogenous opioid activity within mesolimbic
DA pathways [782]. Repeated administration of cocaine has
been found to increase the expression of MC4R mRNA, and
administrationof a lowdoseof morphine has beenfoundtoup-
regulate the expression of MC4R mRNA in the striatum [783].
Meanwhile, chronic administration of morphine has been
found to result in down-regulation of MC4R mRNA expression
inthe striatumandperiaqueductal gray[784]. This MC4Rdown-
regulation and the associated decrease in melanocortin func-
tion have been hypothesized to promote the development of
opiate addiction [784].
At rst glance, the results of research that concerns
melanocortin and drugs of abuse may seem to be contra-
dictory. The selective MC4R agonist MTII was reported to
reduce ethanol self-administration, and MCR antagonists
were reported to increase it [785]. Similarly, melanocortins
were reported to reduce opiate self-administration [786], and
mutations in MC4R were found to be associated with binge-
eating disorder [787]. On the other hand, infusion of the
melanocortin MC4R antagonist SHU-9119 into the NAc was
reported to block the rewarding effects of cocaine: cocaine-
induced CPP, cocaine-enhanced responding for conditioned
reinforcement, and the reinforcing effectiveness of stimuli
that were conditioned by being paired with cocaine [781]. And
treatment with the MC4R agonist MTII was found to produce a
robust augmentation of amphetamine reward, as measured in
terms of its ability to lower the threshold for lateral
hypothalamic self-stimulation (LHSS) [788]. Whether the
contradiction is more apparent than real is hard to discern,
since the outcome measures are not really comparable.
Measures of self-administration of a substance are unques-
tionably related to its reward value, but not necessarily in the
same way as is CPP or the lowering of the LHSS threshold. In
fact, the correlation is not always in the same direction:
increased reward is associated sometimes with increased self-
administration and sometimes with decreased self-adminis-
tration.
2.1.21. Leptin
Leptin is a protein hormone that is generated in adipocytes
and interacts with six types of receptor (LepRaLepRf). Its
primary physiological function is the regulation of appetite.
When leptin binds to LepRb receptors in the ventral medial
hypothalamus (VMH), a satiety signal is generated that
instructs the brain to direct the body to stop eating. The cells
of the ARC, located in the VMH, receive leptin signals and then
communicate to other hypothalamic and extrahypothalamic
structures via neuropeptide transmission [reviewed in 789].
Leptinreceptors are expressedalso by some neurons inthe LH,
including orexin and MCH neurons [790], which suggests that
these neurons may respond directly to peripheral leptin
signals. In addition, the VMH has extensive connections to
the LH.
Leptin works by inhibiting the activity of neurons that
contain NPY and agouti-related peptide (AgRP), and by
increasing the activity of neurons that express a-MSH. It also
down-regulates the expression of endocannabinoids in the
hypothalamus [632].
Leptin not only suppresses food intake, but also reverses
the effects of food restriction on brain stimulation reward
thresholds [791] and on the reinstatement of drug-seeking
[792]. Food and drugs work through common molecular
substrates within the brain [793], and connections between
the hypothalamus and the NAc may underlie some of the
behavioral observations of cross-sensitization between nat-
ural rewards and drugs of abuse [243]. Most drugs are self-
administered to higher levels after food deprivation [794], and
food deprivation increases cocaine-conditioned place prefer-
ence [795]. Leptin acts to reduce heroin self-administration
[792], and has been shown to modulate LHSS [796]. Investi-
gators are beginning to consider impaired leptin activity as a
potential factor in a shared vulnerability to psychoactive
substance addiction and bulimia [228,239].
2.1.22. Glutamate
Burst ring in mesencephalic DA neurons is dependent on
excitatory afferents that activate ionotropic glutamatergic
receptors on DA cells [498,797,798] The pause after a burst
can be mediated by glutamate acting on metabotropic
glutamatergic receptors (mGluRs), which induces inhibitory
postsynaptic potentials (IPSPs) [799,800]. Psychostimulants
selectively reduce the mGluR-induced IPSPs in DA neurons
through cross-desensitization that is mediated by a-adreno-
ceptors [801]. As a result, acute exposure to a psychostimulant
increases DA neuron bursting via a-adrenoceptors [802]. This
suggests that a-adrenergic receptors play an important role in
mediating drug reinforcement [803]. Indeed, Drouin et al.
found that mice that lacked a-adrenoceptors exhibited neither
psychostimulant-induced locomotor hyperactivity [804] nor
rewarding effects [479]. Therefore, an interaction between
noradrenergic and glutamatergic systems may modulate the
ring pattern of DA neurons, which in turn may underlie the
reinforcing value of drugs and the establishment of addictive
behavior [805].
In a study by Tremblay et al. [806], a group of patients with
major depressive disorder who were administered d-amphe-
tamine demonstrated enhanced rewarding effects, compared
with the control group. The degree of enhancement that d-
amphetamine elicited correlated with the severity of the
depressed patients anhedonic symptoms. The hypersensitive
response to d-amphetamine was associated with negative
blood oxygen level-dependent (BOLD) signals in most of the
regions of interaction. The physiological counterparts of
negative BOLD signals are thought to be induced by reduced
blood ow (i.e., active neuronal inhibition and decreased
cortical excitability) [807809]. The relative decrease in brain
activity among depressed subjects could reect exaggerated
deactivation of glutamatemediated transmission by amphe-
tamine (as per the preceding paragraph).
We are considering a distinction between two groups of
people that renders one of them more susceptible to develop
an addictive disorder, and three possible constituents of this
distinction that emerge out of the preceding discussion.
First, Tremblay et al. [806] referenced a study that reported
evidence of abnormal glutamate transmission in major
depression [810], by way of suggesting that abnormal
glutamate transmission could have generated the depressed
groups enhanced sensitivity to the effects of d-ampheta-
mine. Second, the converse of Drouin et al.s ndings that a-
adrenoceptor hypoactivity reduces psychostimulant-induced
locomotor hyperactivity and reward is that a-adrenoceptor
hyperactivity could intensify these psychostimulant-induced
effects. Such adrenergic hyperactivity is not unusual in
states of chronic stress. Finally, Tremblay et al. [806] noted
that the degree of enhancement that d-amphetamine
elicited correlated with the severity of the depressed
patients anhedonic symptoms. Thus, anhedonia emerges
as a risk factor or marker for the development of an addictive
disorder.
2.1.23. Glucocorticoids
Both in rodents and in primates, positive correlations have
been observed between circulating glucocorticoid levels and
psychostimulant self-administration [811813]. Most studies
on self-administration have reported increases in drug
responding following repeated or prolonged exposure to
stress levels of glucocorticoids [812815]. Glucocorticoids,
probably via glucocorticoid receptors, facilitate DA transmis-
sion in the NAc shell [816]. During chronic stress, the repeated
increase in glucocorticoid hormones and DA could result in
sensitization of the reward system. This sensitized state,
which can persist after the end of the stress, would render the
subject more responsive to drugs of abuse and consequently
more vulnerable to the development of addiction.
Glucocorticoids, the hypothalamicpituitaryadrenal (HPA)
axis, and the stress response system are discussed more
extensively in the following section, where we consider the
impaired affect regulation component of the addictive
process.
2.2. Impaired affect regulation
Affect regulation comprises the neurobiological processes that
maintain emotional states within ranges of intensity and
stability that do not impair functioning or lead to over-
whelming distress. The addictive disorders literature employs
the term impaired affect regulation less often than it uses
terms that refer to its more clearly dened and experience-
near manifestations, such as chronic stress, stress hypersen-
sitivity, depression, and anxiety. A term as important and
apparently vague as stress also merits denition. While
diverse and elaborate denitions abound, the words etymol-
ogy might be an expeditious beginning: Middle English
stresse, short for destresse (from Old French), distress.
Stress/distress seems to be a synonym of pain or suffering,
with a connotation of tension or strain.
2.2.1. Corticotropin releasing factor (CRF)
Corticotropin releasing factor (CRF) is released from two brain
regions to participate in two separate (but connected) stress
systems [817]. In the hypothalamicpituitaryadrenal (HPA)
stress system, CRF neurons in the parvocellular region of the
paraventricular nucleus of the hypothalamus (PVNh) regulate
the release of pituitary adrenocorticotropic hormone (ACTH)
and adrenal glucocorticoids (GC). In the extrahypothalamic
(EH) stress system, CRF neurons in the central nucleus of the
amygdala (CeA) project to the locus coeruleus (LC) and
increase the ring rate of LC neurons, resulting in increased
NE release in the terminal elds of this ascending noradre-
nergic system [818821]. One of the principal noradrenergic
targets of this systemis actually the CRF neurons of the PVNh.
NE is the major known source of drive over CRF release from
PVNh neurons during stress [822,823]. The activation of the
CRF neurons of the PVNh is associated with increased activity
in the nucleus tractus solitarius (NTS) and the dorsal
medullary nucleus, as well as the LC.
Either stress system can contribute to both a pre-existing
vulnerability to use drugs addictively and a later vulnerability
to relapse. The HPA stress system seems to have the more
important role in the initiation of drug-seeking and in the
maintenance of drug-taking behavior, while the EH stress
system seems to have the more important role in the
motivational effects of both protracted abstinence and
stress-induced reinstatement [824827].
In the stress-induced reinstatement procedure, rats that
previously had been trained to self-administer cocaine or
heroinand thenextinguished will reinstate their responding if
a mild footshock is administered immediately prior to the
testing session[828832]. This reinstatement was reportedtobe
blocked by pre-treatment with CRF antagonists administered
directly into the brain, but not by removal of glucocorticoids
[833836]. Research results indicated that the key neural
pathway for this process originates in CRF neurons of the
CeA and ends at CRF
1
receptors on the ventral BNST [835838].
Stress stimuli that activate CRF circuits have been found
also to potentiate mesolimbic dopaminergic reward pathways
in laboratory animals [839]. Similarly, human laboratory
studies have shown that emotional stress and negative affect
states increase drug craving in drug-addicted individuals
[841,842]. Preclinical studies have demonstrated that early life
stress and chronic stress can result in enduring changes in
stress responses [817,839850]. Such changes can alter the
sensitivity of the DA system to stress and can increase
susceptibility to self-administration of substances of abuse
[840,851,852].
A suggestion by some investigators [853855] that anxiety
and affective disorders be considered to be chronic stress
states makes immediate sense of the data on comorbidity
between these disorders and addictive disorders. The high
levels of serum cortisol that issue from a hyper-responsive
HPA axis during chronic stress enhance the sensitivity of the
mesolimbic DA system to the reinforcing properties of
psychoactive substances and rewarding behaviors, thereby
increasing the risk that affected individuals will use such
substances and behaviors addictively [824,856]. Accordingly,
Tremblay et al. [857] found a strong positive relationship
between the severity of subjects depressive symptoms and
the degree of reward effect that they experienced from a dose
of d-amphetamine. Compared to healthy controls, individuals
with PTSD [858,859] and with depression [860862] were found
to have higher levels of CRF in their CSF.
Finally, a series of stressful episodes were reported to have
led to a marked and prolonged increase in ethanol consump-
tion in CRF
1
receptor-decient mice but not in wild-type mice,
even though CRF
1
receptor-decient mice and the wild-type
mice had not differed in ethanol consumption prior to the
stressful episodes [863]. These data suggest that the CRF
1
receptor is involved in adaptive responses to stress, the lack of
which leads the CRF
1
receptor-decient mice to resort to
ethanol to manage their stress [864].
Research results seem to concur that a hyper-responsive
HPAaxis and chronic stress conditions including anxiety and
affective disorders are likely to be signicant risk factors for
the development of addictive disorders.
2.2.2. Cortisol
Receptors for cortisol (or glucocorticoid receptors [GRs]) are
located in the hippocampus, the limbic system, and the PFC
[865,866]. During periods of psychological distress, cortisols
diurnal pattern is overridden by signals to the hypothalamus
that originate in the amygdala and the BNST, structures that
are activated by conditioned and unconditioned stimuli and
that convey information having survival value [867869]. The
BNST also provides the primary inputs to the PVN that
generate an HPA response to psychological stress. These
inuences are augmented during periods of psychological
stress by NE inputs that ascend from the LC to activate the
cerebral cortex and limbic system [870,871].
Acute cortisol administration has been found to precipitate
cocaine craving in human addicts [872], as has stress [873].
Stress also has been demonstrated to increase drug self-
administration in animal models [874]. The stress-charged
drive to self-administer drugs of abuse has been linked to
increased activation of the mesolimbic DA system, which is
mediated by glucocorticoid release [874877]. Repeated expo-
sure to stress has been shown to induce a long-lasting
enhancement of the mesolimbic DA response to drugs of
abuse [878].
Interestingly, a hypo-responsive HPAaxis withlowlevels of
cortisol also has been associated with enhanced drug self-
administration [879,880]. These ndings are consistent with
human studies that demonstrated lower cortisol response to
stress in individuals who had behavioral conduct problems,
externalizing symptoms, and antisocial personality [881885].
In adolescent boys, lower stress-related cortisol levels were
found to be associated with subsequent increased frequency
of drug use [886].
Wei et al. [887] found that transgenic mice with over-
expressed GRs manifested a signicant increase in anxiety-
like and depression-like behaviors relative to wild type, and
also to show enhanced sensitization to cocaine [887]. Mean-
while, decreasing the production of central nervous system
(CNS) GRs reduced cocaine self-administration [888], which
suggests that self-administrationdepends onfeedback signals
from cortisol receptors to the CNS [889].
The cortisol variant that seems to be the more likely to
contribute to an addictive process is enhanced secretion or
increased receptor sensitivity, which would increase activa-
tion of the mesolimbic DA system in the short run and
chronically would induce a long-lasting enhancement of the
mesolimbic DA response to drugs of abuse.
2.2.3. Norepinephrine (NE)
When the LC is ring at normal rates, NE increases the signal
to noise ratio of responses evoked by other afferents, both
excitatory and inhibitory, and enhances synaptic transmis-
sion in target circuits [890892]. In an acute stress situation,
the LC ring rate increases, enhancement of signal to noise
ratio decreases, and the LC becomes the brains alarmsystem.
Another important role of the LC-NE system during stress is
inhibition of the PFC, thereby favoring rapid instinctual
responses over more complex ones in the service of surviving
acute life-threatening situations [890].
Early studies suggested that LC neuronal activity was
driven primarily by aversive stimuli and that NE was
essentially a stress neurotransmitter. These observations
led to a number of hypotheses that the function of the LC-
NE system was alarm- or anxiety-related. However, electro-
physiological studies demonstrated that phasic responses are
elicited by appetitive as well as aversive stimuli, provided that
a stimulus is perceived as salient [893,894]. And microdialysis
studies demonstrated elevated extracellular NE levels in
response to appetitively conditioned stimuli [895897]. Com-
bined, these observations suggest that both phasic and tonic
LC discharge activity is related to the overall salience and/or
arousing nature of a given stimulus more closely than it is to
the affective valence of the stimulus [898]. In this regard, our
understanding of NE seems to be following the same
developmental path as has our understanding of DA and
CREB, from affective-hedonic valence to salience.
Noradrenergic antagonists were found to block stress-
induced reinstatement [487,489,899], much as did CRF antago-
nists. The brain sites for these effects appear to have been the
ventral noradrenergic bundle projections to the BNST. Neuro-
toxin-specic lesions of the ventral noradrenergic bundle were
found to attenuate stress-induced reinstatement of heroin
responding [489], and local injection of a b-adrenergic receptor
antagonist intothe BNSTalsoblockedstress-inducedreinstate-
ment in cocaine-trained rats [488]. The conditioned release of
NE in the BNST in response to stressors may elevate anxiety,
which then augments the reward value of drugs through
negative reinforcement processes [827,900].
2.2.4. Norepinephrine (NE) and serotonin (5-HT)
The College de France group [496] rst demonstrated that
psychostimulant- or opiate-induced locomotor activation and
behavioral sensitizationare entirely dependent onthe stimula-
tion of two non-dopaminergic monoaminergic receptors, a
1b
-
adrenergic and 5-HT
2A
. They then followed up with another
study [901], in which they found that repeated treatments with
d-amphetamine increased the reactivity of both noradrenergic
and serotonergic neurons, and that this hyperreactivity could
be blocked by pre-treatment withana
1b
-adrenergic or a 5-HT
2A
receptor antagonist. Theypostulatedthat innaveanimals both
types of neuron regulate one another through these two
receptors. For example, the activation of noradrenergic cells
by external stimuli would be immediately attenuated by
serotonergic cells, the activation of which is itself triggered
by noradrenergic neurons. They hypothesized that this closely
coupled control vanishes after repeated administration of d-
amphetamine. And they proposed that this long-term uncou-
pling between noradrenergic and serotonergic neurons may
explain the extreme sensitivity to emotions described by
human addicts during withdrawal. After noting that stressful
situations cross-sensitize with the effects of psychostimulants
or opiates on behavioral sensitization, they concluded with the
statement that chronic stress could therefore also induce an
uncoupling between noradrenergic and serotonergic systems
and thus be one source of mental illnesses such as bipolar
disorder. They might just as easily have concluded that this
noradrenergic-serotonergic uncoupling due to chronic stress
could be a source of addictive disorders.
Serotonin (5-HT), 5-HT receptors, and the 5-HT transporter (5-
HTT) have been the subjects of considerable interest in recent
years. Genetic research has focused on the 5-HTT-linked
polymorphic region (5-HTTLPR), the promoter region of the
gene that encodes 5-HTT, which contains a common func-
tional polymorphism with a variable number of tandem
repeats (the short allele has 14 repeat elements, the long allele
has 16) [226,680,902910]. Research that investigates the
effects of the postnatal environment on neurobiological
development has focused on the 5-HT receptors, primarily
the 5-HT
1A
and to a lesser extent the 5-HT
1B
and the 5-HT
2A
[911914]. And research that explores the interaction between
genetic and environmental factors has thus far focused
primarily on the 5-HTTLPR [915918], and to a lesser extent
on the 5-HT
2A
receptor [919]. While discussion of develop-
mental research has been deferred to another publication, its
mention here may serve to indicate that the 5-HT system is
receiving a lot more scientic attention than might be inferred
from the following review.
The 5-HTT is an integral membrane glycoprotein that
occurs in pre-synaptic neuronal membranes. Its job is to take
up 5-HT into the pre-synaptic neurons after its release in
synaptic spaces, with the function of terminating the synaptic
action of 5-HT and recycling it [689].
A study reported that alcoholic subjects had a lower 5-HTT
density in perigenual anterior cingulate cortex than did
control subjects [920]. The difference was not explained by a
nonspecic ethanol-induced down-regulation of 5-HTT, nor
by a general neuronal loss inthe frontal cortex [921,922]. These
results also indicated that lower 5-HTT density in the
perigenual anterior cingulate cortex was not correlated with
age at time of death (which was presumed roughly to reect
the duration of ethanol abuse). Another study found lower
midbrain and amygdala 5-HTT radioligand [11C]McN 5652 BP2
(binding potential) in subjects with major depressive disorder
than in controls [850]. BP2 did not correlate with depression
severity. The authors interpreted the lower [11C]McN5652 BP2
in the subjects with major depressive disorder to reect lower
Bmax, or lower total number of available 5-HTT binding sites.
Less 5-HTinput to the amygdala, as suggestedby the nding of
lower 5-HTT BP2, may result in increased amygdala activity
[923], as 5-HT enhances inhibition in the amygdala, presum-
ably through activation of GABA interneurons [924].
The chronic mild stress model has been suggested to have the
best face validity of any animal model of depression, in that
repeated mild stresses over time gradually induce a state of
decreased responsiveness to rewards and reduced sexual and
aggressive behaviors [925]. Rodents exposed to this model
demonstrate decreased D
2
/D
3
receptor binding in the NAc,
which is reversed by chronic antidepressant treatment (TCAs,
SSRIs, or mianserin) [926].
A recent study used functional magnetic resonance
imaging to assess the activity of brain reward systems after
d-amphetamine challenge in 12 drug-free depressed patients
and 12 matched controls [806]. The depressed subjects had a
markedly greater behavioral response to the rewarding effects
of the psychostimulant and altered brain activation of the
ventrolateral PFC, orbitofrontal cortex, caudate, and putamen.
These ndings suggest that major depressive disorder
involves dysfunction of the dopaminergic system. Two earlier
sets of research results round out the picture: (1) the nding
that glucocorticoids selectively facilitated DA transmission in
the NAc [816]; and (2) the nding that when subjects who
reported poor early life maternal care were exposed to a
psychosocial stressor, their ventral striatal DA concentrations
increased more than did those of subjects who did not so
report, and the DAincrease was correlated with an increase in
salivary cortisol concentrations [927].
The high incidence of hypercortisolemia in depression,
particularly in severe depression, raises speculation that
elevated cortisol concentrations alter dopaminergic reward
systems, thereby altering hedonic responsiveness [928]. One
proposed model posits that over time, frequent bouts of stress
associated with intermittent increased exposure to glucocor-
ticoids sensitizes the mesolimbic DA system [929]. Such
sensitization of the mesolimbic DA system would predispose
a person to develop an addictive disorder.
2.2.7. Endocannabinoids
The endocannabinoid (eCB) system appears to be involved in
modulation of depression [930], stress [931,932] and anxiety
[933935], while its absence results in a greater vulnerability to
stress [936]. Chronic stress was reported to down-regulate CB
1
receptor expression and signicantly reduce the content of
the endocannabinoid 2-arachidonoyl glycerol within the
hippocampus [937]. CB
1
knockout mice were found to
show increased aggressiveness, anxiety-like responses,
depressive-like responses in the chronic unpredictable mild
stress procedure [938], and HPA axis changes that included
reduced basal corticosterone secretion and hypersensitivity to
restraint stress [939]. Evidence for an endogenous anxiolytic
cannabinoid tone also comes from the anxiogenic effects of
the CB
1
receptor antagonist rimonabant [940]. The eCB system
might be activated in response to anxiogenic situations and
might regulate emotional states by modulating amygdala
outputs, as part of a negative feedback system that limits
anxiety [932,941].
The primary function of the eCB system seems to be
regulation or containment of chronic stress. Disruption of the
eCB system would be likely to increase the level of chronic
stress, which in turn would increase the likelihood of an
addictive disorder developing.
2.2.8. Cyclic AMP response element binding protein (CREB)
A review article [942] proposed that cAMP response element-
binding protein (CREB) has a role in anxiety and ethanol-
drinking behaviors. Wistar rats with high levels of anxiety
were reported to consume more ethanol than did those with
lowlevels of anxiety [943], and strains of rats that were bred to
consume large quantities of ethanol were reported to exhibit
more anxiety-like behaviors than did their ethanol-nonpre-
ferring counterparts [944946]. The transcription factor CREB
regulates the expression of the gene that encodes neuropep-
tide Y(NPY), which is involved in the regulation of anxiety and
the modulation of ethanol consumption. Intracerebroventri-
cular (icv) infusionof NPYwas found to signicantly attenuate
the ethanol intake of P rats but not of NP rats [686] and to
produce electrophysiological effects similar to those that
ethanol produced in P rats [947]. Transgenic mice that
overexpress NPY also were found to have a lower preference
for ethanol [695]. Conversely, NPY-null mutant mice were
observed to consume greater quantities of ethanol, and mice
that lacked the RII1 regulatory subunit of the PKA gene and
thus were unable to phosphorylate CREB were reported to
consume greater amounts of ethanol than did wild-type mice
[948]. CREB has been proposed to regulate anxiety and ethanol
abuse behaviors via NPY [949]. Noting that CREB is associated
also with the molecular effects of other addictive drugs, the
author suggested that changes in synaptic plasticity that are
mediated by CREB might be a common factor in ethanol and
drug addiction.
Another review [950] reported that CREB is stimulated in
the NAc by exposure to several types of drugs of abuse or
stress, and that CREB function in the NAc normally is
regulated by glutamatergic and dopaminergic inputs [951].
Numerous studies have established that CREB activity in this
region has a profound effect on an animals responsiveness to
emotional stimuli [952,953]. The authors understood these
ndings to suggest that by determining the set point of NAc
neurons [954] CREB represents an emotional gate for
behavioral responsivity. Viral vector-mediated elevations of
CREB within the rat NAc were found to produce anhedonia-
like signs and a generalized numbing of behavioral responses
to both aversive and pleasurable emotional stimuli
[646,647,649]. Similarly, overexpression of CREB in the NAc
of inducible transgenic mice was found to produce a
depression-like phenotype [955] and to reduce the rewarding
effects of cocaine [659]. The authors observed that short-term
increases in CREB activity in the NAc, induced by normal
rewarding or aversive stimuli, can serve to dampen responses
to subsequent stimuli and facilitate the ability to actively deal
with the situation at hand. However, they noted, under more
pathological conditions, larger and more sustained increases
in CREB activity, induced by drugs of abuse or excessive stress,
can lead to an excessive dampening of emotional reactivity
and to the depression-like phenotype outlined above.
These two reviews the rst by Pandey in 2003, the second
by Nestler andCarlezonin2006 present perspectives onCREB
that are thought-provokingly divergent, yet mutually compa-
tible. For immediate purposes, we can note that affect
regulation is a non-linear dynamic balance, and that anhe-
donia is probably just as conducive to addictive behavior as is
anxiety.
2.2.9. Brain-derived neurotrophic factor (BDNF)
Brain-derived neurotrophic factor (BDNF) is a member of the
neurotrophin family. It is highly expressed in various brain
regions and is involved in neuronal survival, functional
differentiation, and synaptic strength [956961]. Its action is
mediated by binding to tyrosine kinase B (TrkB), a high-afnity
receptor that is localized on cell bodies and dendrites as well
as postsynaptically [962,963]. BDNF is involved in synaptic
plasticity and cellular processes of learning, such as long-term
potentiation (LTP) or memory consolidation [956]. BDNF
application facilitates LTP, while reduction of BDNF levels
attenuates LTP [467]. BDNF is synthesized in mesolimbic
dopaminergic neurons [964]. It is responsible for the devel-
opmental appearance of the D
3
receptor, which is selective for
the NAc, andfor maintaining expressionof the receptor during
adulthood [965,966]. BDNF has been strongly connected to the
effects of serotonergic agents in animal studies [967,968], and
augmentation of serotonergic activity within various brain
areas after infusion of BDNF into the midbrain has been
reported [969].
Infusion of BDNF into the VTA promotes the behavioral
actions of drugs of abuse [540]. When administered directly
into the VTAor NAc, it causes a signicant increase incocaine-
induced locomotor activity and in cocaine reward [970972].
Meanwhile, a deciency inBDNF has beenreportedto promote
ethanol intake in mice [973,974]. Application of any of several
abusable drugs including amphetamine [975], morphine
[976], cocaine [977], D9-tetrahydrocannabinol [978], and
nicotine [979] was found to up-regulate the expression of
BDNF. Intermittent, exogenous application of BDNF either
centrally or into the VTA was reported to decrease food intake
and body weight and to increase behavioral activity [980983],
a set of effects that is reminiscent of the psychostimulants.
Patients with eating disorders were reported to have low
serum levels of BDNF, which rose to the normal range when
the patients were treated with antidepressant medications
[984].
Pandey et al. [985] reported nding that CREB-decient
mice that had been displaying anxiety-like behaviors and
increased ethanol consumption turned out also to have
decient expression of BDNF in several brain regions,
including the amygdala [986]. These results suggested that
the effects of decreased CREB levels on anxiety-like behaviors
and ethanol consumption may have been mediated by the
reduction of BDNF levels in amygdaloid structures. Pandey
et al. proposed that a deciency of BDNF in the CeA and MeA
(medial amygdala) results in decreased CREB phosphorylation
inthe CeAand MeAand inlowlevels of NPYinthe CeA, bothof
which promote anxiety-like behaviors and ethanol consump-
tion. A similar association between low BDNF level and the
combination of anxiety-like behaviors and increased ethanol
consumption was reported by Yan et al. [987] to occur in P rats,
though the low BDNF levels (as compared to NP rats) were
observed in the NAc, not the amygdala.
Most of the clinically relevant researchabout BDNF that has
been published concerns the relationship between BDNF and
depression. Serum levels of BDNF in patients with major
depressive disorder prior to initiation of antidepressant
treatment were found to be lower than were those of healthy
subjects [988992], and moreover were found to be negatively
correlated with the severity of depression [988,990,992]. After
several weeks of treatment with antidepressant medication
(presumably effective), patients BDNF levels increased to
levels similar to those of the control subjects [991,993995]. In
studies that used animal models of depression, depressive
states were shown to be associated with reduced BDNF levels
in the brain, and central administration of BDNF was shownto
reverse such depressive states [9961000].
What about the relationship between BDNF and depres-
sion? One hypothesis would be that reduced BDNF might
reect a genetic vulnerability to develop depression. Another
possible explanation would be that stress-induced BDNF
reductions might cause neuronal damage, which would in
turn lead to acquired biological vulnerability. Stress decreases
levels of BDNF expression in the dentate gyrus and pyramidal
cell layer of hippocampus [999,1001]. This reductionappears to
be mediated partly via stress-induced glucocorticoids and
partly via other processes, such as stress-induced increases in
serotonergic activity [9991003]. Stress, which can precipitate
and exacerbate depression, causes neuronal atrophy and
death, especially in the hippocampus [10041008].
From the viewpoint of stress-induced BDNF reduction, low
BDNF levels in our antidepressant-na ve patients with
depression may reect the collapse of the stress-adaptation
systemand its failure to protect the brain fromstress-induced
neuronal degeneration [990]. Addictive behavior can be
understood as the last resort of a stress-adaptation system
that is failing to maintain allostasis.
2.2.10. Neuropeptide Y (NPY)
Inrecent years, NPYhas emergedas asignicant factor inaffect
regulation. In rodent models, central NPY is released following
stress and attenuates the behavioral consequences of stress
[10091012]. WhileNPYknockout micewere foundtodisplayan
anxiety-like phenotype [684,1013], transgenic rats with selec-
tive NPY overexpression were shown to be resistant to stress-
induced increases in anxiety-like behavior [1014,1015]. The Y1
subtype of NPY receptor has been most strongly implicated in
mediating anxiolytic behaviors [10161021]. Meanwhile, Y2
receptors seem to be anxiogenic [10221026], with the possible
exception of Y2 receptors in the locus coeruleus, which were
reported to be involved in mediating decreases in anxiety-like
behavior [1008].
The anxiolytic effects of NPY appear to be mediated by Y1
receptors in the amygdala, particularly in its central nucleus
[670,1025]. The CeA receives NPYergic innervation from the
nucleus of the solitary tract, arcuate nucleus, and lateral
septum [1009,1027]. NPY neurons in the amygdala project to
the BNST [1028], which also contains NPY Y1 receptors and
NPY Y1 and Y2 receptor mRNA[10291031]. The BNST projects
to the dorsal vagal complex and consequently may have
effects on the autonomic nervous system [1028,1032].
The Y2 receptor is believedto be a presynaptic autoreceptor
that limits the transmission of NPY [1033,1034]. Therefore, Y2
agonists could produce an anxiogenic-like effect by inhibiting
NPY release. NPY is found within GABA interneurons in the
basolateral nucleus of the amygdala (BLA) [1035], and also is
colocalized with GABA in the suprachiasmatic nucleus. In the
latter region, NPY can decrease the inhibitory effects of tonic
GABA release via presynaptic Y2 receptors [10361038]. When
the inhibitory actions of GABA are reduced, both inhibition of
and opposition to stimulatory glutamatergic function dimin-
ish, and neuronal activity increases signicantly. Activation of
Y2 receptors in the BLAcould suppress the release of both NPY
and GABA, thereby producing an excitatory state in the
nucleus that results inthe expression of anxiety-like behavior.
A number of studies have reported that ethanol-preferring
P rats have lower levels of NPY in the CeA than do
nonpreferring NP rats [10391041], and that P rats also have
been found to display more anxiety-like behavior and to be
more sensitive to the anxiolytic effects of ethanol [944]. Some
investigators have taken the next step and hypothesized that
the higher consumption of ethanol by P rats could be
motivated by higher anxiety levels [10411043]. Pandey et al.
[1041] reported that both anxiety and ethanol drinking were
reduced in P rats when NPY activity in the central or medial
amygdala was increased, either directly by infusion of NPY, or
indirectly by increasing CREBfunction. They reportedalso that
anxiety and ethanol drinking were increased in NP rats when
NPY activity was reduced by decreasing CREB function in the
same brain area [1041]. Primeaux et al. [1044] found that rats
that had been identied as anxious on the basis of their
performance in an elevated plus maze consumed more
ethanol solution than did the nonanxious rats. They then
found that treatment of anxious rats with a viral vector that
mediated an increase in CeA NPY decreased their ethanol
preference more than did treatment of other anxious rats with
an antisense NPY vector. Combined with previous research
ndings that virally mediated increases in CeA NPY decreased
anxiety-related behaviors [1045], these data canbe understood
to suggest that treatment that increased CeA NPY activity in
anxious rats led to a reduction in their anxiety, and thus to a
reduction in their preference for ethanol. The results of these
studies support Valdez and Koobs [1046] revisionist tension
reduction hypothesis that consumption of ethanol (espe-
cially to the point that it becomes self-damaging) subserves a
motivation to alleviate negative affect and stress.
2.2.11. Galanin
In rodent models, expression of galanin in the brain is altered
by various stressors, while administration of galanin can
modulate anxiety-like responses to stress. A recent study of
the central amygdala showed that, while mild stress did not
alter galanin levels, a model of high stress did increase galanin
release [1047]. Other studies of centrally administered galanin
in rats [1048] and of galanin overexpressing transgenic mice
[1049,1050] appear to support the view that galanin may
modulate behavioral responses to signicant stress (i.e., high
levels of noradrenergic activationinthe central amygdala), but
may remain dormant under conditions of mild stress [1051].
Emerging evidence further supports a role for galanin in the
mediation of depression-related behaviors in rodents [1052].
Stress can evoke a variety of potential modulatory interac-
tions involving NE andgalanininthe CeAand BNST, depending
on the nature of the stressor and the response elicited, the
subset of noradrenergic neurons activated, and the degree to
whichthesesystems are activated. Dysregulationof the normal
interaction between NE and galanin may contribute to the
development of stress-related behavioral disorders, including,
for example, stress-induced reinstatement of drug-seeking
behavior, aprocessthat hasbeenassociatedwithnoradrenergic
mechanisms in the CeA and BNST [488] More generally,
dysregulation of the interaction between NE and galanin may
be involved in stress-related neuropsychiatric illnesses such as
depression, PTSD, or other anxiety disorders.
Ethanol intake increases galanin mRNA expression in the
rat hypothalamus [1053], whereas galanin injected into the
third ventricle or the hypothalamus increases ethanol con-
sumption in rats that have learned to consume ethanol at
moderate levels [1054,781]. This suggests the possibility of a
positive feedback loop between galanin and ethanol intake
[1055].
A signicant association between galanin haplotypes and
alcoholism has been demonstrated in both Finnish Caucasian
and Plains American Indian men [1056]. In both populations,
the two haplotypes A and B, differing by only one allele and
therefore originating from a common ancestral haplotype,
were risk factors for alcoholism. The other two haplotypes, C
and D, also differing by only one allele and also derived from
a shared ancestral haplotype, were protective against alco-
holism. These ndings from two independent populations
suggest that galanin may contribute to vulnerability to
alcoholism, perhaps mediated by dimensional anxiety.
2.2.12. Substance P (SP)
Anatomical and functional studies suggest that SP is a central
stress neurotransmitter. SP and its preferred tachykinin NK-1
receptor are expressed throughout the fear-processing path-
ways of the brain, including the amygdala, hippocampus,
hypothalamus and periaqueductal grey [10571059]. Central
injection of SP agonists produces a range of defensive
behavioral and cardiovascular reactions in animals, including
conditioned place aversion [1060].
Observations from basic research had suggested that SP
might be involved in the etiology of affective and anxiety
disorders [10611064]. Inanimal models of depression(chronic
mild stress) and anxiety (social interaction test), the NK-1
receptor antagonist NKP608 was shown to exert antidepres-
sant and anxiolytic activity [1061,1064]. A randomized double-
blind placebo-controlled study was conducted to evaluate the
safety and efcacy of the NK-1 receptor antagonist MK-869,
and the results were encouraging [1065]. Rupniak and Kramer
[1061] suggested that SP might be the neurobiological correlate
of the subjective experience that has been called emotional
pain a state in which the type of affect caused by trauma is
expressed, but devoid of the sensation of pain. They
speculated that autonomous hyperactivity in SP neurotrans-
mission might contribute to the anxiety, fear, and emotional
pain that accompany affective and anxiety disorders.
2.2.13. Dynorphin
Shirayama et al. [1066] reported that levels of dynorphin A and
dynorphin B immunoreactivity in rats hippocampus and NAc
increased when the rats were exposed to learned helplessness
(LH) and immobilization stress, and that exposure to forced
swim stress increased dynorphin A levels in the hippocampus.
Additionally, they found that infusions of the k-opioid
antagonist nor-binaltorphimine dihydrochloride into the den-
tate gyrus or CA3 regions of the hippocampus and into the shell
or core regions of the NAc produced antidepressant-like effects
intheLHparadigm. Earlier studies hadreportedthat infusionof
an antagonist of the k-opioid receptor, the primary receptor for
dynorphin, producedanantidepressant effect intwobehavioral
models of depression, the forced swim test [649,1067] and the
learned helplessness paradigm [955].
Dynorphin is co-localized with glutamate, the primary
neurotransmitter in granule cells, and synaptic release of
dynorphin has been reported to cause pre-synaptic inhibition
of glutamate release from the mossy ber and perforant
pathway terminals [1068].
Shirayama et al. [997] found that microinfusions of BDNF
into the hippocampus produced an effect similar to blockade
of k-opioid receptors. Previous studies had provided evidence
of a link between BDNF and dynorphin. Infusions of BDNF
were reported to decrease levels of dynorphin [1069], raising
the possibility that the actions of BDNF could be accounted for
by down-regulation of dynorphin. This also is consistent with
reports that stress decreases BDNF, which could result in
increased dynorphin, and that antidepressant treatment up-
regulates the expression of this neurotrophic factor in the
hippocampus [996,999; reviewed in 1070].
GABAergic projection neurons in the NAc receive inputs
from VTA DA neurons that express dynorphin. Dynorphin
serves a negative feedback process by acting on presynaptic k-
opioid receptors to inhibit DA neuronal function.
2.2.14. DFosB
The expression of DFosB can be induced by either chronic drug
exposure or chronic stress. Chronic drug exposure has been
reported to induce DFosB expression primarily in the NAc and
dorsal striatum, with lower levels of induction observed in the
frontal cortex and amygdala [654,10711075]. Chronic stress
has been reported to induce DFosB expression predominantly
in the frontal cortex, NAc, and amygdala. Perrotti et al. [1075]
suggested that stress induction of DFosB within dynorphin + -
NAc and dorsal striatal neurons would increase the drive for
drugs, and could thereby mediate in part the tendency of
stress to increase vulnerability for drug addiction and relapse.
2.2.15. GABA
Ethanol has been found to produce anti-conict (anti-anxiety)
actions in the social interaction test, elevated plus maze, and
in operant procedures [1076]. These anti-anxiety effects were
shown to be blocked by administration of the GABA
A
receptor
antagonist picrotoxin [1077] and by isopropylcyclophosphate,
a compound that binds near or at the GABA
A
chloride
ionophore [1078]. Low doses of benzodiazepine inverse
agonists also were found to block the anti-anxiety effects of
ethanol, but to have anxiogenic-like effects on their own at
these doses [1079,1080]. Administration of picrotoxin was
reported to decrease ethanol intake [1081], as was pre-
treatment with the picrotoxin ligand isopropylbicyclopho-
sphate or with the benzodiazepine inverse agonist RO 15-4513
[552]. GABA
A
receptors seem to mediate a critical component
of ethanols anti-anxiety effect, and to affect ethanol intake in
ways that suggest the signicant contribution that negative
reinforcement (alleviation of anxiety) makes to the motivation
to consume ethanol.
A study that was reported by Castelli et al. [1082] demon-
strated that GABA
B
receptors in limbic areas and to a lesser
extent in the cortex functioned about half as well in ethanol-
na ve ethanol-preferring sP rats as they did in ethanol-na ve
ethanol-nonpreferring sNP rats. The sP rats required more
than twice the concentration of the GABA
B
agonist baclofen as
did the sNP rats to achieve the same result. The diminished
responsivity of the GABA
B
receptors was attributed to
genetically determined differences in G-protein activation.
Previous studies were reported to have found that ethanol-
na ve sP rats displayed a higher degree of anxiety-related
behaviors than did ethanol-na ve sNP rats [945,1083,1084], and
that GABA
B
receptors are involved in the neural substrate
mediating anxiety-related behaviors [1085]. The authors
proposed that the lower GABA
B
receptor function in sP than
in sNP rats that they observed could have contributed to the
development of the higher degree of anxiety-related behaviors
that sP rats had been found to display. They suggested that
baclofen-induced suppression of ethanol-drinking behavior in
sP rats might have been secondary to the substitution of its
anxiolytic effect for that of voluntarily consumed ethanol.
Their hypothesis seems to be that genetically determined
alterations of their GABA
B
receptors left sP rats susceptible to
higher degrees of anxiety (chronic stress), the alleviation of
whichprovided themwith substantial negative reinforcement
for consuming ethanol. The rats predilection for imbibing
thus resulted not from their preference for ethanol, as their sP
designation implies, but from their preference for freedom
from anxiety. This hypothetical vignette exemplies the
impaired affect regulation aspect of the addictive process.
2.3. Impaired behavioral inhibition
Impulsivity has increasingly come to be understood as a
heterogeneous phenomenon that includes impaired inhibi-
tory control of behavior, intolerance to delay of reward, and
premature decision-making [1086,1087]. However, these three
forms of impulsivity are not on the same level, neither
theoretically nor practically. Theoretically, impaired inhibi-
tory control of behavior is the nal common pathway of all
forms of impulsivity. If an organism can refrain from acting in
response to an instance of delay intolerance or a premature
decision, impulsive behavior does not occur. Practically,
unless we are dealing with organisms that can communicate
their subjective experiences of delay-intolerance, decision-
making, and intent to inhibit behavior, we must infer these
processes from behavior that we observe. Compared to
intolerance to delay of reward and premature decision-
making, impaired inhibitory control of behavior remains
closer to the observational data and depends on a simpler,
more direct form of inference. These considerations informed
the identicationof this component of the addictive process as
impaired behavioral inhibition.
Serotonin (5-HT) has come to be recognized as being the main
player in behavioral inhibition [1088]. Studies have deter-
mined that low levels of cerebrospinal uid (CSF) 5-hydro-
xylindolacetic acid (5-HIAA), a major metabolite of 5-HT and
an indicator of 5-HT activity, are associated primarily with
impulsivity and to a lesser but still signicant extent
with aggression, depression, and early-onset alcoholism
[1089,1090; reviewed in 1091, 1092]. An association between
low 5-HT activity and impulsive behavior has been demon-
strated also by prolactin release after fenuramine challenge
[1093]. Low levels of 5-HIAA were found in the CSF of bulimic
subjects [1094], and a preclinical study found decreased levels
of 5-HT and 5-HIAAin the brains of rats that tended to acquire
self-administration of amphetamine [1095].
The 5-HT receptors that have been most often associated
withaddictive disorders are 5-HT
1A
, 5-HT
1B
, and5-HT
2A
. The 5-
HT
2C
receptor is the only receptor that when stimulated
inhibits many addiction-related behaviors [468]. Interestingly,
most of the recent research on 5-HT receptors and impaired
behavioral inhibition has focused on bulimia (other than
genetic and developmental studies, which are reviewed in a
separate publication).
PET studies have demonstrated increased 5-HT
1A
receptor
binding inseveral cortical areas of patients withactive bulimia
[1096], and in subjects who had recovered from bulimia or
from bulimic-type anorexia [1097,1098]. A wide cortical
distribution of increased 5-HT
1A
receptor binding might reect
a diffuse dysregulation of 5-HT activity that could be
associated with impaired impulse control [1096,1099].
Increased receptor binding (i.e., binding of labeled ligand to
receptor) can indicate either increased receptor density or
decreased intrasynaptic neurotransmitter/neuromodulator
concentration. In the absence of evidence that a functional
5-HT
1A
receptor gene polymorphism is associated with
bulimia [1096], increased 5-HT
1A
receptor binding most likely
reects low levels of intrasynaptic 5-HT.
A study with mice revealed a specic association between
the 5-HT
1B
receptor and impulsivity [1100]. 5-HT
1B
receptors
are expressed on the terminals of GABAergic striatal neurons
that project to the substantia nigra and VTA [1101,1102].
Activation of these receptors may inhibit the release of GABA
onto dopaminergic neurons, thereby disinhibiting the dopa-
minergic neurons [1103].
5-HT
2A
receptor binding was found to be reduced in the
orbitofrontal cortex of subjects who had recovered from
bulimia [1104], and in the cingulate, parietal, and mesial
temporal cortices of subjects who hadrecoveredfrombulimic-
type anorexia [1105]. Decreased 5-HT activity at orbitofrontal,
cingulate, parietal, or mesial temporal 5-HT
2A
receptors could
reect impulsiveness and altered emotional processing [1106].
5-HTtransporter (5-HTT) binding was found to be decreased
in the midbrain of obese binge-eating women [1107]. A follow-
up of treated patients whose binge-eating disorder was in
remission showed signicantly increased 5-HTT binding, as
compared to unchanged results in controls [1108].
While decreased 5-HTT binding in association with active
binge-eating disorder that increases when the disorder remits
indicates a transitory state condition, reduced 5-HT activity
(or increased 5-HT receptor binding) in bulimic syndromes
that persists long after the disorder has gone into remission
implies a chronic trait condition. The latter is likely to
represent a primary vulnerability that arose independently of
the eating disorder and contributed to its pathogenesis
[1104,1105,1109]. Collateral information about the 5-HT sys-
tem suggests that this vulnerability relates not to food
ingestion or gustatory-gastric sensations, but to impaired
behavioral inhibition or impulsivity. Thus it is not specic to
bulimia, but could contribute to the development of any
addictive disorder.
Jentsch and Taylor [1110] hypothesized that the inhibitory
modulation of reward-seeking behavior may depend critically
upon the corticostriatal projections from the medial frontal
cortex to the caudate nucleus and NAc. Studies had demon-
strated that lesions to the frontal cortex [1111] or DA depletion
within the PFC [1112,1113] can augment the locomotive
and reinforcing effects of psychostimulants. A hypothesis
emerged, according to which the cortical DA system tonically
inhibits subcortical DA systems [1114]. Under such circum-
stances, dopaminergic hypofunction in the frontal cortex
can result in the disinhibition of mesolimbic DA systems
[1115,1116; review1117]. Thus, a loss of DAfunction in the PFC
can result in an increased vulnerability to self-administer
psychostimulant drugs [1118,1119] or to engage addictively in
another behavior that activates the mesolimbic DA system.
This hypothesis is supported by the preclinical nding that
animals that were more vulnerable to acquiring intravenous
drug self-administration showed reduced dopaminergic activ-
ity in the PFC [1117].
Amphetamine has been shown to increase premature
responding in the 5-choice serial reaction time task (5-CSRTT),
which is generally considered to represent behavioral disin-
hibition[11201122]. This premature responding was shownto
be attenuated by DA depletion of the NAc [1121] and by
systemic administration of the non-selective DA receptor
antagonist a-upentixol [1120]. Van Gaalen et al. [1087]
investigated the effects of a number of substances on rats
that had been well-trained in the 5-CSRTT. Premature
responding was found to be increased by amphetamine,
cocaine, nicotine, and the DA reuptake inhibitor GBR 12909. It
was found to be decreased by the NE reuptake inhibitor
desipramine and by the DA D
1
receptor antagonist SCH 23390,
but not by the DA D
2
receptor antagonist eticlopride. Mean-
while, the increments in premature responding that had been
evoked by amphetamine, cocaine, and nicotine were found to
be attenuated by eticlopride, whereas SCH 23390 reduced the
drug-induced behavioral disinhibition only at a dose that by
itself decreased premature responding. The authors con-
cluded that premature responding in general is regulated by
DA D
1
, while behavioral disinhibition that is induced by drugs
of abuse depends on activation of DA D
2
receptors. Super-
sensitivity of either D
1
or D
2
receptors could conceivably
result, directly or indirectly (respectively), in impaired beha-
vioral inhibitionand thus could contribute to the development
of an addictive process.
An elegant study by Dalley et al. [1123] demonstrated
relationships between trait impulsivity, reduced D
2
/D
3
recep-
tor availability, and tendency to escalate self-administration
of cocaine. Rats performance on the 5-CSRTT was used to
identify a group of high-impulsive rats and a group of non-
impulsive rats. Positron emission tomography then demon-
strated that D
2
/D
3
4
receptor availability was signicantly
4
Dalley et al (2007) used the high-afnity DA D
2
/D
3
receptor
radiotracer [
18
F] fallypride, which does not distinguish between
D
2
and D
3
receptors.
reduced in the ventral striatum but not in the dorsolateral
striatumof high-impulsive rats as compared to non-impulsive
rats, and that D
2
/D
3
receptor availability in the ventral
striatum was inversely correlated with impulsivity. When
the heretofore cocaine-nave rats were trained to self-
administer cocaine, rats that exhibited trait impulsivity on
the 5-CSRTT showed a greater tendency for escalation of
intravenous cocaine self-administration than did their non-
impulsive counterparts. The authors concluded that their
ndings demonstrated that trait impulsivity predicts cocaine
reinforcement and that decreased D
2
receptor availability in
the striatum may be a predisposing neurobiological trait and
not only a consequence of chronic cocaine exposure. This
study echoes and afrms the ndings related to D
2
receptors
that we reviewed in the Motivation-Reward section. Further
investigation of the relationships between D
2
receptors,
motivation-reward, behavioral inhibition, and addictive beha-
vior patterns is likely to be both fascinating and productive.
Research on the relationship between addiction and DA D
4
and D
5
receptors has been concerned primarily with genetic
factors. A variable number tandem repeat (VNTR) polymorph-
ism located in the third exon of the DA D
4
receptor gene has
been found to be associated with impulsive personality traits
[1124] and to be a risk factor for adolescent ethanol abuse
[1125], adolescent hard drug use [1126], heroin abuse [1127],
cue-elicited heroin craving [1128], severity of ethanol and
opiate addiction [1129], pathological gambling [1124], binge-
eating [1130], and cue-elicited craving for food [1131]. On the
other hand, a few studies found no or negligible association
between D
4
receptor gene exon III polymorphism and
alcoholism [1132,1133] or heroin addiction [1134]. The com-
mon 148 bp allele of a microsatellite polymorphism at the D
5
receptor gene was foundto be correlatedwithsubstance abuse
and novelty seeking in females [220]. It also was found to be
associated with attention-decit/hyperactivity disorder
[1135,1136], which is only weakly suggestive of a relationship
to addiction but indicates a potentially fruitful direction for
further research.
3. Conclusion
The present article represents the owering of an idea that
was planted in 1990:
A hypothesis may be submitted, the gist of which is that
similar patterns in behavioral manifestations of the
various addictive disorders. . .reect similarities in some
set of personality and/or biological variables, which may or
may not be measurable by instruments currently available.
In other words, addictive disorders would be most
accurately described, not as a variety of addictions, but
as a basic underlying addictive process, which may be
expressed in one or more of various behavioral manifesta-
tions. [1]
At the time that the preceding sentences were published,
addiction neuroscience was young, and much of the research
that could evaluate the hypothesis of an underlying addictive
process had not yet been conducted. In the intervening years,
addiction neuroscience has advanced so considerably that the
hypothesis is no longer radical. Perhaps the continuing
trajectory of scientic progress soon will render it no longer
necessary.
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