This document discusses addictive behavior and the neurobiology of addiction. It defines addictive behavior as compulsive drug use despite negative consequences and craving effects beyond pain relief. It describes how drugs of abuse hijack the brain's reward system and lead to long-term changes in gene expression and neural plasticity through mechanisms like conditioning and memory formation. These changes help explain why addiction is persistent and why drug cues can trigger intense craving and relapse. The neurobiology of addiction involves dysregulation of the dopamine and other neurotransmitter systems in the brain's reward pathways.

1. Addictive Behavior
Addictive behavior is defined by compulsive drug use despite negative
physical and social consequences and the craving for effects other than
pain relief.
From: Management of Cancer in the Older Patient, 2012
Related terms:
​ Opiate
​ Drug Abuse
​ Dopamine
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Biology of Addiction
Lee Goldman MD, in Goldman-Cecil Medicine, 2020
Drug-Induced Neural Plasticity Relevant to Addiction

2. Neurobiologic research on addiction has focused intensely on
compulsive aspects of drug use, the ability of specific cues to activate
drug seeking and craving, and the long persistence of stress and
cue-dependent relapse risk. As described previously, compulsive drug
use and the power of drug-associated cues reflect the usurpation of
the brain’s reward circuitry by drugs of abuse.7 The persistence of
addiction reflects long-term changes in neurons and synapses and
their interacting circuits. Research during more than a decade has
identified long-term changes in gene expression resulting from use of
addictive drugs; recently, some long-lived alterations in gene
expression have been attributed to drug-induced epigenetic
mechanisms, such as modifications of chromatin.8
Long-term changes in gene expression may render the addicted
person susceptible to stress and may also create persistent changes
in hedonic state and mood regulation that may motivate drug taking.
By themselves, however, changes in gene expression do not explain
the ability of exquisitely specific cues to activate drug seeking or, if
seeking is impeded, intense subjective drug craving. The ability of
specific cues to activate drug seeking and wanting is based on
long-term associative memories consolidated under the influence of
dopamine and other reward signals. Long-term memory formation
represents perhaps the most persistent changes in brain function that
may occur in adult life. The neural substrates of memory are likely to

3. include alterations in synaptic weights, such as long-term potentiation
or long-term depression, and physical remodeling of dendritic spines.
Processes of drug sensitization (or reverse tolerance), demonstrated
in animal models and in humans, may contribute to these
memory-related phenomena.
The centrality of associative learning mechanisms for addiction was
first recognized from clinical observation: much drug taking and, most
notably, late relapses follow exposure to cues previously associated
with drug use. Cues that can reinitiate drug use include environmental
stimuli (e.g., persons with whom drugs have been used, drug
paraphernalia) and body feelings. Because addictive drugs reliably
increase synaptic dopamine and other reward-related
neurotransmitters as a result of their direct pharmacologic
actions—indeed, they produce excessive and grossly distorted reward
signals—the brain receives a powerful impetus to connect the
circumstances in which the drugs have been used with the motivation
to take drugs again. Even if the drug is no longer pleasurable, the
signals continue to reinforce drug wanting and seeking. Moreover, the
certainty and magnitude of these signals give drugs a marked
advantage over natural rewards and other learned goals, including
prosocial activities.

4. In the laboratory, it has been possible to study the effects of drugs and
drug cues on neural circuits, physiology, and subjective responding in
addicted human subjects. For example, drug-associated cues have
been shown to elicit drug urges and physiologic responses (such as
sympathetic activation) as well as activation of reward circuits in
addicted human subjects. By positron emission tomography,
cocaine-related cues have been shown to elicit dopamine release in
striatal regions of addicted subjects.
View chapter on ClinicalKey
Addiction
B. Capps, ... A. Carter, in Encyclopedia of Applied Ethics (Second
Edition), 2012
Abstract
Addiction is a condition that results in significant harm to the individual
and to society more generally. Societies’ response to addiction is
influenced by how it is understood. The view that addiction is a choice
that individuals make (the choice model) has led to punitive responses

5. to drug use that punish and deter use. Neuroscience research on
addiction is challenging politicolegal responses to addiction by
suggesting that it is a brain disease that drives individuals to drug use
(the medical model). It also promises to lead to more therapeutic
responses to addiction and more effective technologies to prevent,
counter, or treat it. These possible conceptual effects and therapeutic
applications raise important ethical issues.
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Substance Use Disorder in Pregnancy
Mark B. Landon MD, in Gabbe's Obstetrics: Normal and Problem
Pregnancies, 2021
Neurobiology of Addiction
Many neurotransmitters have been implicated with regard to the
effects of substances of abuse, but dopamine is consistently

6. associated with the reinforcing effects.Drugs of abuse increase
extracellular dopamine concentrations in ways that far surpass the
effects of natural reinforcers such as nurturing, water, food, or sex.
Because dopamine is a powerful reinforcer, it is easy to learn and
repeat this pathway. Some substances of abuse directly increase
dopamine (cocaine and methamphetamine), whereas others indirectly
increase it via actions on other neurotransmitters such as
γ-aminobutyric acid (GABA) that results in a loss of inhibitory control
of dopamine (opioids, marijuana, and benzodiazepines).10 Common
drugs of abuse and mechanisms of action are outlined inTable 8.1.
Addiction can be conceptualized as a reward deficit disorder
characterized by transition from controlled to impulsive and
compulsive drug intake that is mediated by both positive and negative
reinforcement. Initial use is characterized by the reinforcing effects of
pleasure. Over time, however, one no longer uses substances to seek
pleasure, rather negative reinforcement (a behavioral mechanism
recruited to alleviate a negative emotional state in the absence of a
drug) becomes the driver of continued use. Dopamine release occurs
in the nucleus accumbens of the limbic system, which modulates
neuronal activity in subcortical and cortical brain structures. When
high levels of dopamine are encountered due to exposures to
substances, abnormally high or prolonged dopamine-related neuronal
activity in subcortical/cortical structures can produce abnormal

7. messages about reward prediction and decision making. With
prolonged drug exposure, regions of the prefrontal cortex are
damaged. Drug-induced impairments of the prefrontal cortex can exert
a twofold impact on addiction: first through its perturbed regulation of
limbic reward regions, and second through its involvement in
higher-order executive function. Therefore abnormalities in these
frontal regions may underline both the compulsive nature of drug
administration and the inability to control urgency to take drugs when
exposed.10
Although many humans have the potential to develop
neuroadaptations that lead to addiction, not everyone does. There are
many factors that may contribute to a predisposition to addiction,
including genetics, age, environmental, and psychiatric comorbidities.
It is estimated that 40% to 60% of vulnerability to addiction is
attributed to genetic factors. Animal models suggest that several
genes are involved in drug responses, and modification of those
genes affects drug self-administration. Some candidate genes for drug
responses in animals have been identified that correspond to genes
and loci in human studies.13
Exposure to drugs or alcohol during adolescence may result in
different neuroadaptations than when exposures occur in adulthood,
and the process of addiction is more likely to be triggered in the

8. adolescent brain. Perhaps rendering adolescents vulnerable is the
lack of development of the frontal cortex, with executive control,
motivation, and decision making more able to be influenced by drug
exposure.14–16
View chapter on ClinicalKey
Addiction
Scott D. Philibin, John C. Crabbe, in Rosenberg's Molecular and
Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition),
2015
Disease characteristics, clinical features and diagnostic
evaluation
Addiction is a challenging and enigmatic term to define for medical
diagnosis. Diagnostic criteria may need to employ terms and
constructs from entirely different languages, descriptions of biological
factors and intrapsychic events whose basis is unknown. Most
clinicians would agree that the main feature of addiction is compulsive,
out-of-control behavior despite adverse consequences. The American

9. Psychiatric Association’s (APA) Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV) lacked the term entirely. Addiction now
appears in the DSM-V, replacing “substance abuse and dependence”
with “addictions and related disorders.” This is fortunate as abuse can
reflect cultural norms outside medical pathology and dependence
emphasizes drug withdrawal symptoms, which occurs with
prescription antidepressants and beta-blockers that do not cause a
loss of control. A new “behavioral addictions” category has been
added that contains one disorder: gambling. There are, however,
many compulsive behaviors that could be considered addictions, such
as bulimia nervosa, Internet addiction, sexual addiction, etc.1,2
This review will focus on drug addiction because most of our
understanding of addiction per se stems from the pharmacology of
drugs of abuse. Drug addiction is a complex trait, influenced by
genetic and environmental factors, which have been extensively
characterized using genetic animal models. Drugs of abuse induce
neuroadaptations via molecular and cellular mechanisms, which are
being characterized in behavioral neuroscience. In the following
sections, we will point the reader to reviews of: 1) human molecular
genetic evidence associated with addiction (primarily related to
alcoholism, as it is one of the longest-studied complex traits in human
genetics); 2) neurobiological basis of addictive drug effects; 3) genetic
animal models related to addiction; and 4) therapeutic strategies.

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Smoking Cessation
V. Courtney Broaddus MD, in Murray & Nadel's Textbook of
Respiratory Medicine, 2022
Neurobiologic Mechanisms of Addiction
(S)-Nicotine binds stereoselectively tonicotinic cholinergic receptors
(nAChRs) in the brain, as well as in the autonomic ganglia, the
adrenal medulla, and neuromuscular junctions. Most relevant to
nicotine addiction are the receptors found throughout the brain, with
the greatest number in the cortex, thalamus, and interpeduncular
nucleus. There is also substantial binding in the amygdala, septum,
brainstem motor nuclei, and locus coeruleus. The nAChR is a
ligand-gated ion channel composed of five subunits. Most brain
nAChRs are composed of α- and β-subunits. Usually, there are two α-
and three β-subunits, with the α-subunits responsible for ligand

11. binding and the β-subunits mediating other aspects of receptor
function.14 Nicotinic receptors in the brain have different chemical
conductances for sodium and calcium and sensitivity to nicotinic
agonists. Brain imaging studies in smokers have confirmed that
smoking causes the upregulation of high-affinity nAChRs, which is
maintained for up to 4 weeks after cessation of nicotine
exposure.15–17
The various nicotinic receptors are believed to mediate different
pharmacologic actions of nicotine, perhaps corresponding to the
multiple effects of nicotine experienced by human smokers.18
Adolescent nicotine exposure also appears to
altergamma-aminobutyric acid (GABA) signaling in the developing
brain but not in the adult brain. GABA receptors are now known to
alter the nicotine reward effect, which may have an impact on
enhancing alcohol self-administration.19
Nicotinic receptor activation facilitates the release of
neurotransmitters, including acetylcholine, norepinephrine, dopamine,
serotonin, β-endorphin, GABA, and others.20 Pharmacologically,
nicotine is a stimulant. It enhances fast excitatory synaptic
transmission, which may contribute to learning and memory.21,22
Nicotine also releases growth hormone, prolactin, vasopressin, and
adrenocorticotropic hormone. Behavioral rewards from nicotine and

12. nicotine addiction appear to be linked largely to dopamine release23
with an impact from GABA receptors as well.
Nicotine metabolism can vary significantly among
individuals.Cytochrome P-450 (CYP) isoenzymes impact the speed of
metabolism and are categorized as poor, extensive, or ultrarapid.24
These differences can have an impact on smoking behavior and the
metabolism of nicotine replacement therapies. In addition, exposure to
tobacco smoke has a wide-ranging impact on the metabolism of many
drugs. Polycyclic aromatic hydrocarbons, products of combustion in
cigarette smoke, upregulate certain CYP enzymes, primarily CYP1A2,
and accelerate the metabolism of drugs that go through the CYP1A2
pathway. Several drugs have important pharmacokinetic interactions
with smoking. Caffeine clearance is increased by more than 50%
when a person smokes. Therefore, upon smoking cessation, it is
advised that patients cut their caffeine intake by half. Nicotine in
tobacco smoke also has pharmacodynamic interactions with certain
drugs through antagonistic pharmacologic actions. (SeeTable 66.1 for
pharmacokinetic and pharmacodynamic interactions with smoking.)
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Addictions

13. Eduardo R. Butelman, ... Mary Jeanne Kreek, in Neurobiology of Brain
Disorders, 2015
Abstract
The addictions are chronic relapsing brain diseases, with behavioral
manifestations and considerable morbidity. Addictions are complex
disorders with genetic, epigenetic, neurobiological, and drug exposure
factors, as well as environmental factors. Addictions to specific drugs
such as alcohol, nicotine/tobacco, cocaine/psychostimulants (e.g.
methamphetamine) and μ-opioid receptor agonists (e.g. heroin and
abused prescription opioids) have some common direct or
downstream effects, including modulation of dopaminergic systems
which underlie aspects of mood and reward. Specific addictions also
have unique trajectory, morbidity, and pharmacotherapeutic
approaches, based on direct and delayed neurobiological adaptations
for each drug. Several neurobiological systems have been implicated
in addictions, notably opioid receptor and opioid neuropeptide gene
systems; stress-responsive systems including corticotropin-releasing
hormone, vasopressin, and orexin; and glutamate and γ-aminobutyric
acid systems. The public health costs of the addictions are massive;
there remains a great need for translational neurobiological
understanding of these diseases, potentially leading to better
treatments, including advances in personalized medicine.

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Therapeutic Areas I: Central Nervous System,
Pain, Metabolic Syndrome, Urology,
Gastrointestinal and Cardiovascular
A.H. Newman, R.B. Rothman, in Comprehensive Medicinal Chemistry
II, 2007
6.07.8 Summary
Addiction is a disorder that has a biological basis. Addiction to drugs
and/or alcohol result in enormous costs to society in terms of
healthcare, family destruction, loss of productivity, and direct and
indirect effects on our criminal justice system. The biochemical bases
of addiction and relapse have been investigated and numerous
hypotheses of how drug seeking for pleasure evolves into compulsive
drug taking, in the face of personal destruction, have ensued. These
studies have identified central targets to which potential medications

15. can be designed. In addition, medications that have been discovered
to successfully treat related mental disorders such as anxiety and
depression have also been identified as potential medication
candidates and some of these are clinically prescribed. Moreover,
clinical evaluation of medications that are successfully used in the
treatment of one addiction (e.g., nicotine) may also be useful for
treatment of another (e.g., cocaine). Other NCEs are in various stages
of clinical development and their success or failure will dictate future
trends in research toward discovering treatment candidates, especially
for psychostimulant abuse. It is clear that addiction is a complex
disorder that will likely not be cured with a ‘magic bullet’ but rather an
array of treatment strategies that may need to be individualized
depending on the patient, the drug or drugs to which he is addicted,
and any comorbid disorders that he may also suffer from. As such, a
multidisciplinary approach to drug abuse research will be required and
consideration of many relevant biological targets as well as
combination therapies involving medication and behavioral treatments
will likely prove to have the greatest success.
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16. Addiction
Juri D. Kropotov, in Quantitative EEG, Event-Related Potentials and
Neurotherapy, 2009
A Symptoms
Addiction is an extreme state of drug abuse1. Addiction is defined as a
compulsive, out-of-control drug use despite serious negative
consequences. The behavioral pattern of an addicted person
becomes progressively focused on obtaining, using, and recovering
from the effects of drugs. It continues despite illness, disrupted
relationships and failures in life. Compulsive actions could be
misinterpreted by frustrated family members as deliberate
self-destruction.
Important character of addiction is the high risk of relapse to drug use.
The potential for relapse maintains even in abstinent addicts long after
they stop taking drugs. The relapse is caused by two factors: cues and
stress. Drug-conditioned cues can be environmental or interoceptive.
For example, the risk of relapse is elevated when addicts encounter
people or places associated with earlier drug use. Stress also plays a

17. significant role in relapses in addicts2. Current treatments for addiction
are helpful to some patients, but far from satisfactory.
From the theory presented in Part II, addiction can be conceptualized
as impairment in monitoring operation that is resolved in uncontrolled,
compulsive patterns of drug use. In this definition addiction appears to
be similar to obsessive-compulsive disorder (OCD) (see Chapter 20).
Indeed, clinical descriptions of both OCD and addiction are associated
with inability to inhibit intrusive repetitive thoughts (obsessions or
cravings, respectively) and ritualistic behaviors (compulsions or active
drug-seeking/taking, respectively).
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Addiction
J.J. Canales, in Adult Neurogenesis in the Hippocampus, 2016
Introduction

18. Addiction is a multifaceted disorder characterized by persistent
episodes of excessive and compulsive drug taking, preoccupation
over drug availability, and recurrent relapses. It is a disorder that takes
a very significant toll on the people affected, particularly in terms of
quality of life and health status, and on the health system and the
society as a whole. Many advances have been made in recent years
in identifying some of the risk factors that may predispose to addiction
and in delineating the brain mechanisms and adaptations linked to
drug-related behaviors. The Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-V), recognizes that not all
individuals have the same degree of vulnerability to develop an
addiction if exposed to drugs (American Psychiatric Association,
2013). Thus one of the key objectives of current addiction research is
to understand the biological and psychological underpinnings of such
differential predisposition to problematic drug use. The DSM-V further
recognizes that activation of the so-called brain reward systems is a
landmark that is common across addictive substances. Research in
the last 30 years into the neurobiology of drug addiction has been
mainly focused on the basal ganglia and their affiliated cortical
networks as key components of the “addiction circuitry.” Studies
conducted in the 1980s and 1990s established that the nucleus
accumbens (NAcb) and its dopamine (DA) innervation played a critical
role in the positive reinforcing and motivational effects of addictive
drugs, including cocaine, alcohol, and opiates (Koob & Weiss, 1992;
White & Kalivas, 1998; Wise, 1987). Furthermore, strong evidence

19. indicated that chronic drug exposure was associated with lasting
neuroadaptations in the DA pathways that originate in the ventral
tegmental area (VTA) and terminate in the ventral striatum
(Feltenstein & See, 2008; Self, 2004; Wolf, Sun, Mangiavacchi, &
Chao, 2004). Recently, the research focus has shifted toward
understanding the neurobiological mechanisms that mediate the
transition from sporadic drug use to full-blown addiction. On the one
hand, addiction is thought to be associated with the emergence of a
negative emotional state that is driven by hedonic dysregulation and
appears when access to the drug is prevented (Koob & Le Moal,
2008). According to this notion, escalation of drug taking and
progression to compulsion are facilitated by negative reinforcement
and dysregulation of the reward and stress systems, which are under
the control of DA and endogenous opioids in the NAcb, and of
corticotropin-releasing factor in the extended amygdala (AMY)
network (Koob, 2009). On the other hand, such transition appears to
be paralleled by a shift from ventral to dorsal striatum (DSt) in the
control of drug-associated behaviors (Belin, Jonkman, Dickinson,
Robbins, & Everitt, 2009; Everitt & Robbins, 2013; Robbins, Cador,
Taylor, & Everitt, 1989). Drugs of abuse possess, as do natural
reinforcers such as food and sexual contact, the ability to strengthen
stimulus–response associations and form pervasive drug-related
habits, which are thought to be controlled by the DSt (Belin & Everitt,
2008). This latter notion integrates concepts of the learning theory,
most notably Pavlovian and instrumental conditioning, into the defining

20. algorithm of addiction and provides a biological framework that
pictures addiction as a staging process that evolves from occasional,
reward-driven drug use to compulsive abuse triggered by drug-related
cues. Although the process seems to depend on serial connectivity
and information transfer between the midbrain DA neurons and the
striatum (Belin & Everitt, 2008; Haber, Fudge, & McFarland, 2000), the
contribution of cortical and allocortical areas projecting to the ventral
and dorsal striatum to the progression of changes associated with
addiction has not yet been fully elucidated.
In this context, one of the principal allocortical areas projecting to the
striatum is the hippocampus. Traditionally the hippocampus has not
been considered to be part of the main network of connections
implicated in the habit-forming effects of drugs; however, it is widely
interconnected with the systems that mediate drug reward and
reinforcement, as well as with brain regions that are involved in
endocrine regulation, associative learning, and decision making,
including the hypothalamus, the AMY, and the prefrontal cortex (PFC)
(Fig. 10.1). The precommissural branch of the fornix innervates the
ventral striatum, and the orbital and the anterior cingulate cortices,
which are generally involved in drug reinforcement and decision
making, respectively. Moreover, glutamatergic afferents from the
hippocampus to the NAcb strongly regulate the firing rate of DA
neurons in the VTA (Floresco, Todd, & Grace, 2001) and a

21. transsynaptic CA3–VTA loop has been demonstrated (Luo,
Tahsili-Fahadan, Wise, Lupica, & Aston-Jones, 2011), suggesting that
hippocampal activity can influence drug-stimulated effects on DA
function. Since drug-seeking behaviors are critically linked to specific
contexts, the presence of this hippocampal–NAcb–VTA transneuronal
connection provides a scaffold for the hippocampus to engage in
drug-mediated behaviors. It is also important to consider that midbrain
DA neurons project to the hippocampus and surrounding areas in the
medial temporal lobe (Gasbarri, Sulli, & Packard, 1997), thus addictive
drugs may have direct effects on hippocampal function through
stimulation of dopaminergic afferents.

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Figure 10.1. Connections of the hippocampus with functionally relevant brain regions
mediating drug-related behaviors. The discovery of neurogenesis in the adult
hippocampus, coupled with the conclusive accumulated evidence that addictive drugs
impair the neurogenic process, has led to the expansion of the addiction neurocircuitry.
The hippocampus exerts strong influences on midbrain dopamine neurons in the ventral
tegmental area (VTA) that mediate drug reward and habit learning by way of projections
to the nucleus accumbens (NAcb) and dorsal striatum (DSt) (note that for simplicity
connections between the substantia nigra and the DSt are omitted). Hippocampal
projections to the hypothalamus (HYP) provide a context for, and regulate, stress
responsiveness, while reciprocating connections with the amygdala network (AMY) may
influence drug conditioning and emotional responses to drugs. Through direct
connections with the prefrontal cortex (PFC), the hippocampus may also provide a
context for decision making and impulse control, with impaired neurogenesis resulting in
cognitive inflexibility.
The remarkable ability of the hippocampal dentate gyrus (DG) to
sustain postembryonic neurogenesis not only has added a new piece
to the puzzle of addiction but has also created a new paradigm for
understanding the neurobiology of this intricate disorder. Undoubtedly,
adult neurogenesis represents one of the most intriguing and
interesting forms of brain plasticity. The discovery that addictive drugs
alter neurogenesis in the adult hippocampus (Canales, 2007; Eisch &
Harburg, 2006), together with mounting evidence of a significant
functional role of the adult-born hippocampal neurons, has

23. consolidated the position of the hippocampal network as part of a
wider circuitry dynamically engaged in influencing addictive behavior.
To provide a framework for understanding the relationship between
adult neurogenesis and addiction, in this chapter we will first discuss
the involvement of the hippocampus in the phenomenology of drug
addiction. We will then examine accumulated experimental evidence
demonstrating deleterious effects of abused drugs on adult
hippocampal neurogenesis, and we will finally consider the potential
involvement of adult-generated neurons in the hippocampus in the
pathogenesis of addiction.
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ADDICTION
Adina Michael-Titus, ... Peter Shortland, in The Nervous System
(Second Edition), 2010
Neurobiology of addiction

24. Addictions are diseases of the brain with complex and specific
neurobiological mechanisms and behavioural manifestations. They
can be rightly considered among the most poorly understood chronic
diseases of the brain.
The description of the various types of drug that can be misused has
highlighted some common cellular aspects underlying addiction. Thus,
there is strong evidence that the dopaminergic mesolimbic system,
with its origin in the VTA and projection to the nucleus accumbens,
plays a major role in addiction (Fig. 17.4). The dopaminergic
mesolimbic system is associated with both natural rewards and the
reward induced by addictive drugs. It has been suggested that the
powerful effect of addictive drugs may be due to the inability of the
brain to distinguish between activation of reward circuitry by natural
stimuli such as food or sex, and activation by drugs. Addictive drugs
appear to ‘hijack’ a natural body response and to stimulate the reward
circuits with an intensity that is overwhelming and superior to that of
natural stimuli. Although addictive drugs belong to a variety of
pharmacological classes, many of them can increase the levels of
dopamine in the nucleus accumbens. Some of them act directly in the
VTA, and others activate endogenous opioid pathways that ultimately
lead to activation of the VTA dopaminergic neurones (e.g. alcohol and
nicotine). Dopaminergic cells in the brain have a complex response to
rewarding stimuli. When the reward is still new and unanticipated, the

25. dopamine neurones fire intensely. After a prolonged period of
repeated exposure to the reward, dopaminergic neurones fire in
anticipation of the reward. If a predicted reward is not presented, the
firing of cells is suppressed. If, on the contrary, the reward exceeds
expectation, the firing of the cells is amplified.
However, it is likely that other brain structures are also involved in the
addiction process. In particular, the craving for a drug long after
withdrawal symptoms have vanished, and the relapse upon exposure
to certain cues, strongly suggest the involvement of structures such as
the amygdala, cortex and hippocampus. Experimental evidence
shows that drug-associated cues can elicit activation of these areas,
as well as of the nucleus accumbens.
It also seems likely that prolonged exposure to drugs triggers complex
and long-lasting changes in gene expression. Among the various
cellular factors regulated by drugs of abuse, two have received
particular attention: the cyclic AMP response-element-binding protein
(CREB) and the transcription factor ΔFosB. CREB is a transcription
factor that regulates the expression of genes containing a cyclic
AMP-responsive element in their regulatory regions. It has been
shown, for example, that chronic opiate or cocaine exposure leads to
a significant increase in the expression of CREB in several brain
regions. Interestingly, transgenic animals with a mutated CREB gene

26. show decreased dependence after chronic opiate administration.
However, changes in CREB are reversed within a week of the
cessation of drug intake. Therefore, it is likely that they are involved
only in the subacute changes induced by abused drugs, and the
withdrawal phase in particular. In contrast, ΔFosB is a much stronger
candidate for a role in long-term changes. ΔFosB is a member of the
Fos family of transcription factors. As shown in Figure 17.5, the acute
administration of a drug of abuse induces a complex pattern of
upregulation of members of the Fos-related antigen (Fras) family of
proteins in the nucleus accumbens. The upregulation is transient,
apart from certain ΔFosB isoforms, which are much more stable. Upon
chronic exposure, the modifications in these isoforms, although
discrete at the beginning, begin to take on increasing importance, and
the cumulative effect is significant. As a result, ΔFosB persists in the
brain for a long time. Finally, it has been shown experimentally that
drugs of abuse, such as cocaine and amphetamine, can induce
significant and long-lasting structural changes, such as increased
branching of dendrites and an increased number of dendritic spines
on neurones in structures such as the prefrontal cortex and nucleus
accumbens. Such structural changes can be seen for a very long time
after cessation of drug intake.
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