Addiction is a brain disorder characterized by compulsive engagement
in rewarding stimuli despite adverse consequences. Despite the
involvement of a number of psychosocial factors, a biological
process – one which is induced by repeated exposure to an
addictive stimulus – is the core pathology that drives the
development and maintenance of an addiction. The two properties
that characterize all addictive stimuli are that they are reinforcing
(i.e., they increase the likelihood that a person will seek repeated
exposure to them) and intrinsically rewarding (i.e., they are
perceived as being inherently positive, desirable, and
Addiction is a disorder of the brain's reward system which arises
through transcriptional and epigenetic mechanisms and occurs over time
from chronically high levels of exposure to an addictive stimulus
(e.g., eating food, the use of cocaine, engagement in sexual
intercourse, participation in high-thrill cultural activities such as
gambling, etc.). ΔFosB, a gene transcription factor, is a
critical component and common factor in the development of virtually
all forms of behavioral and drug addictions. Two
decades of research into ΔFosB's role in addiction have demonstrated
that addiction arises, and the associated compulsive behavior
intensifies or attenuates, along with the overexpression of
D1-type medium spiny neurons of the nucleus
accumbens. Due to the causal relationship between
ΔFosB expression and addictions, it is used preclinically as an
ΔFosB expression in these neurons
directly and positively regulates drug self-administration and reward
sensitization through positive reinforcement, while decreasing
sensitivity to aversion.[note 1]
As described by two groups of researchers, addiction exacts an
"astoundingly high financial and human toll" on individuals and
society as a whole through the direct adverse effects of drugs,
associated healthcare costs, long-term complications (e.g., lung
cancer with smoking tobacco, liver cirrhosis with drinking alcohol, or
meth mouth from intravenous methamphetamine), the functional
consequences of altered neural plasticity in the brain, and the
consequent loss of productivity. Classic hallmarks of
addiction include impaired control over substances or behavior,
preoccupation with substance or behavior, and continued use despite
consequences. Habits and patterns associated with addiction are
typically characterized by immediate gratification (short-term
reward), coupled with delayed deleterious effects (long-term
Examples of drug and behavioral addictions include: alcoholism,
amphetamine addiction, cocaine addiction, nicotine addiction, opiate
addiction, food addiction, gambling addiction, and sexual addiction.
The only behavioral addiction recognized by the
DSM-5 and the ICD-10
is gambling addiction. The term addiction is misused frequently to
refer to other compulsive behaviors or disorders, particularly
dependence, in news media. An important distinction between drug
addiction and dependence is that drug dependence is a disorder in
which cessation of drug use results in an unpleasant state of
withdrawal, which can lead to further drug use.
Addiction is the
compulsive use of a substance or performance of a behavior that is
independent of withdrawal.
Stimulus control of behavior
Cognitive control of behavior
2 Behavioral addiction
3 Risk factors
3.1 Genetic factors
3.2 Environmental factors
3.3 Transgenerational epigenetic factors
4.1 Summary of addiction-related plasticity
4.2 Reward system
4.2.1 Mesocorticolimbic pathway
4.2.2 Role of dopamine and glutamate
4.3 Reward sensitization
6.1 Behavioral therapy
6.2.1 Alcohol addiction
6.2.2 Behavioral addictions
6.2.6 Psychostimulant addiction
7.4 United States
7.5 South America
8 Personality theories of addiction
10 See also
12 External links
This section needs expansion. You can help by adding to it. (February
Cognitive control and stimulus control, which is associated with
operant and classical conditioning, represent opposite processes
(i.e., internal vs external or environmental, respectively) that
compete over the control of an individual's elicited behaviors.
Cognitive control, and particularly inhibitory control over behavior,
is impaired in both addiction and attention deficit hyperactivity
disorder. Stimulus-driven behavioral responses (i.e., stimulus
control) that are associated with a particular rewarding stimulus tend
to dominate one's behavior in an addiction.
Stimulus control of behavior
See also: Stimulus control
Cognitive control of behavior
See also: Cognitive control
Main article: Behavioral addiction
The term behavioral addiction correctly refers to a compulsion to
engage in a natural reward – which is a behavior that is inherently
rewarding (i.e., desirable or appealing) – despite adverse
consequences. Preclinical evidence has demonstrated that
marked increases in the expression of
ΔFosB through repetitive and
excessive exposure to a natural reward induces the same behavioral
effects and neuroplasticity as occurs in a drug
Reviews of both clinical research in humans and preclinical studies
ΔFosB have identified compulsive sexual activity –
specifically, any form of sexual intercourse – as an addiction
(i.e., sexual addiction). Moreover, reward cross-sensitization
between amphetamine and sexual activity, meaning that exposure to one
increases the desire for both, has been shown to occur preclinically
and clinically as a dopamine dysregulation syndrome;
ΔFosB expression is required for this cross-sensitization effect,
which intensifies with the level of
Reviews of preclinical studies indicate that long-term frequent and
excessive consumption of high fat or sugar foods can produce an
addiction (food addiction).
Gambling is a natural reward which is associated with compulsive
behavior and for which clinical diagnostic manuals, namely the DSM-5,
have identified diagnostic criteria for an "addiction". There is
evidence from functional neuroimaging that gambling activates the
reward system and the mesolimbic pathway in particular.
Similarly, shopping and playing videogames are associated with
compulsive behaviors in humans and have also been shown to activate
the mesolimbic pathway and other parts of the reward system. Based
upon this evidence, gambling addiction, video game addiction and
shopping addiction are classified accordingly.
There are a range of genetic and environmental risk factors for
developing an addiction that vary across the population.
Roughly half of an individual's risk for developing an addiction is
derived from genetics, while the other half is derived from the
environment. However, even in individuals with a relatively low
genetic loading, exposure to sufficiently high doses of an addictive
drug for a long period of time (e.g., weeks–months) can result in an
addiction. In other words, anyone can become an addict under the
It has long been established that genetic factors along with
environmental (e.g., psychosocial) factors are significant
contributors to addiction vulnerability. Epidemiological studies
estimate that genetic factors account for 40–60% of the risk factors
for alcoholism. Similar rates of heritability for other types of drug
addiction have been indicated by other studies. Knestler
hypothesized in 1964 that a gene or group of genes might contribute to
predisposition to addiction in several ways. For example, altered
levels of a normal protein due to environmental factors could then
change the structure or functioning of specific brain neurons during
development. These altered brain neurons could change the
susceptibility of an individual to an initial drug use experience. In
support of this hypothesis, animal studies have shown that
environmental factors such as stress can affect an animal's
Overall, the data implicating specific genes in the development of
drug addiction is mixed for most genes. One reason for this may be
that the case is due to a focus of current research on common
variants. Many addiction studies focus on common variants with an
allele frequency of greater than 5% in the general population, however
when associated with disease, these only confer a small amount of
additional risk with an odds ratio of 1.1–1.3 percent. On the other
hand, the rare variant hypothesis states that genes with low
frequencies in the population (<1%) confer much greater additional
risk in the development of disease.
Genome-wide association studies (GWAS) are a recently developed
research method which are used to examine genetic associations with
dependence, addiction, and drug use. These studies employ an unbiased
approach to finding genetic associations with specific phenotypes and
give equal weight to all regions of DNA, including those with no
ostensible relationship to drug metabolism or response. These studies
rarely identify genes from proteins previously described via animal
knockout models and candidate gene analysis. Instead, large
percentages of genes involved in processes such as cell adhesion are
commonly identified. This is not to say that previous findings, or the
GWAS findings, are erroneous. The important effects of endophenotypes
are typically not capable of being captured by these methods.
Furthermore, genes identified in GWAS for drug addiction may be
involved either in adjusting brain behavior prior to drug experiences,
subsequent to them, or both. 
A study that highlights the significant role genetics play in
addiction is the twin studies. Twins have similar and sometimes
identical genetics. Analyzing these genes in relation to genetics has
helped geneticists understand how much of a role genes play in
addiction. Studies performed on twins found that rarely did only one
twin have an addiction. In most cases where at least one twin suffered
from an addiction, both did, and often to the same substance.
Environmental risk factors for addiction are the experiences of an
individual during their lifetime that interact with the individual's
genetic composition to increase or decrease the his or her
vulnerability to addiction. A number of different environmental
factors have been implicated as risk factors for addiction, including
various psychosocial stressors; however, an individual's exposure
to an addictive drug is by far the most significant environmental risk
factor for addiction. The
National Institute on Drug Abuse
National Institute on Drug Abuse cites
lack of parental supervision, the prevalence of peer substance use,
drug availability, and poverty as risk factors for substance use among
children and adolescents.
Adverse childhood experiences (ACEs) are various forms of maltreatment
and household dysfunction experienced in childhood. The Adverse
Childhood Experiences Study by the Centers for Disease Control and
Prevention has shown a strong dose–response relationship between
ACEs and numerous health, social, and behavioral problems throughout a
person's lifespan, including those associated with substance
abuse. Children's neurological development can be permanently
disrupted when they are chronically exposed to stressful events such
as physical, emotional, or sexual abuse, physical or emotional
neglect, witnessing violence in the household, or a parent being
incarcerated or suffering from a mental illness. As a result, the
child's cognitive functioning or ability to cope with negative or
disruptive emotions may be impaired. Over time, the child may adopt
substance use as a coping mechanism, particularly during
adolescence. A study of 900 court cases involving children who
experienced abuse found that a vast amount of them went on to suffer
from some form of addiction in their adolescence or adult life.
This pathway towards addiction that is opened through stressful
experiences during childhood can be avoided by a change in
environmental factors throughout an individuals life and opportunities
of professional help.
Adolescence represents a period of unique vulnerability for developing
addiction. In adolescence, the incentive–rewards systems in the
brain mature well before the cognitive control center. This
consequentially grants the incentive–rewards systems a
disproportionate amount of power in the behavioral decision making
process. Therefore, adolescents are increasingly likely to act on
their impulses and engage in risky, potentially addicting behavior
before considering the consequences. Not only are adolescents more
likely to initiate and maintain drug use, but once addicted they are
more resistant to treatment and more liable to relapse.
Statistics have shown that those who start to drink alcohol at a
younger age are more likely to become dependent later on. About 33% of
the population tasted their first alcohol between the ages of 15 and
17, while 18% experienced it prior to this. As for alcohol abuse or
dependence, the numbers start off high with those who first drank
before they were 12 and then drop off after that. For example, 16% of
alcoholics began drinking prior to turning 12 years old, while only 9%
first touched alcohol between 15 and 17. This percentage is even
lower, at 2.6%, for those who first started the habit after they were
Most individuals are exposed to and use addictive drugs for the first
time during their teenage years. In the United States, there were
just over 2.8 million new users of illicit drugs in 2013, or about
7,800 new users per day. Over half (54.1 percent) were under
18 years of age.
Individuals with comorbid (i.e., co-occurring) mental health disorders
such as depression, anxiety, attention-deficit/hyperactivity disorder
(ADHD) or post-traumatic stress disorder are more likely to develop
substance use disorders. The National Institute on Drug
Abuse cites early aggressive behavior as a risk factor for substance
Transgenerational epigenetic factors
See also: Transgenerational epigenetic inheritance
Epigenetic genes and their products (e.g., proteins) are the key
components through which environmental influences can affect the genes
of an individual; they also serve as the mechanism responsible for
the transgenerational epigenetic inheritance of behavioral phenotypes,
a phenomenon in which environmental influences on the genes of a
parent can affect the associated traits and behavioral phenotypes of
their offspring (e.g., behavioral responses to certain environmental
stimuli). In addiction, epigenetic mechanisms play a central role
in the pathophysiology of the disease; it has been noted that some
of the alterations to the epigenome which arise through chronic
exposure to addictive stimuli during an addiction can be transmitted
across generations, in turn affecting the behavior of one's children
(e.g., the child's behavioral responses to addictive drugs and natural
rewards). More research is needed to determine the specific
epigenetic mechanisms and the nature of heritable behavioral
phenotypes that arise from addictions in humans. Based upon
preclinical evidence with lab animals, the addiction-related
behavioral phenotypes that are transmitted across generations may
serve to increase or decrease the child's risk of developing an
Transcription factor glossary
gene expression – the process by which information from a gene is
used in the synthesis of a functional gene product such as a protein
transcription – the process of making messenger RNA (mRNA) from a
DNA template by RNA polymerase
transcription factor – a protein that binds to
DNA and regulates
gene expression by promoting or suppressing transcription
transcriptional regulation – controlling the rate of gene
transcription for example by helping or hindering RNA polymerase
binding to DNA
upregulation, activation, or promotion – increase the rate of gene
downregulation, repression, or suppression – decrease the rate of
coactivator – a protein that works with transcription factors to
increase the rate of gene transcription
corepressor – a protein that works with transcription factors to
decrease the rate of gene transcription
response element – a specific sequence of
DNA that a transcription
factor binds to
Signaling cascade in the nucleus accumbens that results in
Note: colored text contains article links.
[Color legend 1]
This diagram depicts the signaling events in the brain's reward center
that are induced by chronic high-dose exposure to psychostimulants
that increase the concentration of synaptic dopamine, like
amphetamine, methamphetamine, and phenethylamine. Following
presynaptic dopamine and glutamate co-release by such
psychostimulants, postsynaptic receptors for these
neurotransmitters trigger internal signaling events through a
cAMP-dependent pathway and a calcium-dependent pathway that ultimately
result in increased
CREB phosphorylation. Phosphorylated
CREB increases levels of ΔFosB, which in turn represses the c-Fos
gene with the help of corepressors; c-Fos repression acts
as a molecular switch that enables the accumulation of
ΔFosB in the
neuron. A highly stable (phosphorylated) form of ΔFosB, one that
persists in neurons for 1–2 months, slowly accumulates
following repeated high-dose exposure to stimulants through this
ΔFosB functions as "one of the master control
proteins" that produces addiction-related structural changes in the
brain, and upon sufficient accumulation, with the help of its
downstream targets (e.g., nuclear factor kappa B), it induces an
Chronic addictive drug use causes alterations in gene expression in
the mesocorticolimbic projection. The most important
transcription factors that produce these alterations are ΔFosB, cAMP
response element binding protein (CREB), and nuclear factor kappa B
ΔFosB is the most significant biomolecular mechanism in
addiction because the overexpression of
ΔFosB in the
spiny neurons in the nucleus accumbens is necessary and sufficient for
many of the neural adaptations and behavioral effects (e.g.,
expression-dependent increases in drug self-administration and reward
sensitization) seen in drug addiction.
ΔFosB expression in
D1-type medium spiny neurons directly and positively
regulates drug self-administration and reward sensitization through
positive reinforcement while decreasing sensitivity to aversion.[note
1] Specific drug addictions in which
ΔFosB has been implicated
in addictions to alcohol, amphetamine, cannabinoids, cocaine,
methylphenidate, nicotine, phenylcyclidine, propofol, opiates, and
substituted amphetamines, among others. ΔJunD, a
transcription factor, and G9a, a histone methyltransferase, both
oppose the function of
ΔFosB and inhibit increases in its
expression. Increases in nucleus accumbens ΔJunD
expression (via viral vector-mediated gene transfer) or
(via pharmacological means) reduces, or with a large increase can even
block, many of the neural and behavioral alterations seen in chronic
drug abuse (i.e., the alterations mediated by ΔFosB).
ΔFosB also plays an important role in regulating behavioral responses
to natural rewards, such as palatable food, sex, and exercise.
Natural rewards, like drugs of abuse, induce gene expression of ΔFosB
in the nucleus accumbens, and chronic acquisition of these rewards can
result in a similar pathological addictive state through ΔFosB
ΔFosB is the key
transcription factor involved in addictions to natural rewards (i.e.,
behavioral addictions) as well; in particular,
the nucleus accumbens is critical for the reinforcing effects of
sexual reward. Research on the interaction between natural and
drug rewards suggests that dopaminergic psychostimulants (e.g.,
amphetamine) and sexual behavior act on similar biomolecular
mechanisms to induce
ΔFosB in the nucleus accumbens and possess
bidirectional cross-sensitization effects that are mediated through
ΔFosB. This phenomenon is notable since, in humans, a
dopamine dysregulation syndrome, characterized by drug-induced
compulsive engagement in natural rewards (specifically, sexual
activity, shopping, and gambling), has also been observed in some
individuals taking dopaminergic medications.
ΔFosB inhibitors (drugs or treatments that oppose its action) may be
an effective treatment for addiction and addictive disorders.
The release of dopamine in the nucleus accumbens plays a role in the
reinforcing qualities of many forms of stimuli, including naturally
reinforcing stimuli like palatable food and sex. Altered
dopamine neurotransmission is frequently observed following the
development of an addictive state. In humans and lab animals that
have developed an addiction, alterations in dopamine or opioid
neurotransmission in the nucleus accumbens and other parts of the
striatum are evident. Studies have found that use of certain drugs
(e.g., cocaine) affect cholinergic neurons that innervate the reward
system, in turn affecting dopamine signaling in this region.
Summary of addiction-related plasticity
Form of neuroplasticity
or behavioral plasticity
Type of reinforcer
High fat or sugar food
ΔFosB expression in
Escalation of intake
conditioned place preference
Reinstatement of drug-seeking behavior
in the nucleus accumbens
Sensitized dopamine response
in the nucleus accumbens
Altered striatal dopamine signaling
↑DRD1, ↓DRD2, ↑DRD3
↑DRD1, ↓DRD2, ↑DRD3
Altered striatal opioid signaling
No change or
Changes in striatal opioid peptides
No change: enkephalin
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens
Dendritic spine density in
the nucleus accumbens
Main article: Reward system
This section needs expansion. You can help by adding to it. (August
ΔFosB accumulation from excessive drug use
Top: this depicts the initial effects of high dose exposure to an
addictive drug on gene expression in the nucleus accumbens for various
Fos family proteins (i.e., c-Fos, FosB, ΔFosB, Fra1, and Fra2).
Bottom: this illustrates the progressive increase in
in the nucleus accumbens following repeated twice daily drug binges,
where these phosphorylated (35–37 kilodalton)
persist in the
D1-type medium spiny neurons of the nucleus accumbens
for up to 2 months.
Understanding the pathways in which drugs act and how drugs can alter
those pathways is key when examining the biological basis of drug
addiction. The reward pathway, known as the mesolimbic pathway, or its
extension, the mesocorticolimbic pathway, is characterized by the
interaction of several areas of the brain.
The projections from the ventral tegmental area (VTA) are a network of
dopaminergic neurons with co-localized postsynaptic glutamate
AMPAR and NMDAR). These cells respond when stimuli
indicative of a reward are present. The VTA supports learning and
sensitization development and releases DA into the forebrain.
These neurons also project and release DA into the nucleus
accumbens, through the mesolimbic pathway. Virtually all drugs
causing drug addiction increase the dopamine release in the mesolimbic
pathway, in addition to their specific effects.
The nucleus accumbens (NAcc) is one output of the VTA projections. The
nucleus accumbens itself consists mainly of
GABAergic medium spiny
neurons (MSNs). The NAcc is associated with acquiring and
eliciting conditioned behaviors, and is involved in the increased
sensitivity to drugs as addiction progresses.
ΔFosB in the nucleus accumbens is a necessary common factor in
essentially all known forms of addiction;
ΔFosB is a strong
positive modulator of positively reinforced behaviors.
The prefrontal cortex, including the anterior cingulate and
orbitofrontal cortices, is another VTA output in the
mesocorticolimbic pathway; it is important for the integration of
information which helps determine whether a behavior will be
elicited. It is also critical for forming associations between the
rewarding experience of drug use and cues in the environment.
Importantly, these cues are strong mediators of drug-seeking behavior
and can trigger relapse even after months or years of abstinence.
Other brain structures that are involved in addiction include:
The basolateral amygdala projects into the NAcc and is thought to also
be important for motivation.
The hippocampus is involved in drug addiction, because of its role in
learning and memory. Much of this evidence stems from investigations
showing that manipulating cells in the hippocampus alters dopamine
levels in NAcc and firing rates of VTA dopaminergic cells.
Role of dopamine and glutamate
Dopamine is the primary neurotransmitter of the reward system in the
brain. It plays a role in regulating movement, emotion, cognition,
motivation, and feelings of pleasure. Natural rewards, like
eating, as well as recreational drug use cause a release of dopamine,
and are associated with the reinforcing nature of these
stimuli. Nearly all addictive drugs, directly or indirectly,
act upon the brain's reward system by heightening dopaminergic
Excessive intake of many types of addictive drugs results in repeated
release of high amounts of dopamine, which in turn affects the reward
pathway directly through heightened dopamine receptor activation.
Prolonged and abnormally high levels of dopamine in the synaptic cleft
can induce receptor downregulation in the neural pathway.
Downregulation of mesolimbic dopamine receptors can result in a
decrease in the sensitivity to natural reinforcers.
Drug seeking behavior is induced by glutamatergic projections from the
prefrontal cortex to the nucleus accumbens. This idea is supported
with data from experiments showing that drug seeking behavior can be
prevented following the inhibition of
AMPA glutamate receptors and
glutamate release in the nucleus accumbens.
Neural and behavioral effects of validated
Molecular switch enabling the chronic
induction of ΔFosB[note 2]
Downregulation of κ-opioid feedback loop
• Increased drug reward
• Expansion of NAcc dendritic processes
NF-κB inflammatory response in the NAcc
NF-κB inflammatory response in the CP
• Increased drug reward
• Increased drug reward
• Locomotor sensitization
• Decreased sensitivity to glutamate
• Increased drug reward
GluR1 synaptic protein phosphorylation
• Expansion of NAcc dendritic processes
Decreased drug reward
Reward sensitization is a process that causes an increase in the
amount of reward (specifically, incentive salience[note 4]) that is
assigned by the brain to a rewarding stimulus (e.g., a drug). In
simple terms, when reward sensitization to a specific stimulus (e.g.,
a drug) occurs, an individual's "wanting" or desire for the stimulus
itself and its associated cues increases. Reward
sensitization normally occurs following chronically high levels of
exposure to the stimulus.
ΔFosB (DeltaFosB) expression in D1-type
medium spiny neurons in the nucleus accumbens has been shown to
directly and positively regulate reward sensitization involving drugs
and natural rewards.
"Cue-induced wanting" or "cue-triggered wanting", a form of craving
that occurs in addiction, is responsible for the majority of
compulsive behavior that addicts exhibit. These cues create
overwhelming short-term urges to engage an addictive stimulus by
acting as conditioned reinforcers for the addictive stimulus (a
primary reinforcer) that are assigned pathologically high levels of
incentive salience ("want").
Research on the interaction between natural and drug rewards suggests
that dopaminergic psychostimulants (e.g., amphetamine) and sexual
behavior act on similar biomolecular mechanisms to induce
the nucleus accumbens and possess a bidirectional reward
cross-sensitization effect[note 5] that is mediated through
In contrast to ΔFosB's reward-sensitizing effect, CREB
transcriptional activity decreases user's sensitivity to the rewarding
effects of the substance.
CREB transcription in the nucleus accumbens
is implicated in psychological dependence and symptoms involving a
lack of pleasure or motivation during drug withdrawal.
The set of proteins known as "regulators of G protein signaling"
RGS4 and RGS9-2, have been implicated in
modulating some forms of opioid sensitization, including reward
The 5th edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5) uses the term "Substance Use Disorder" to refer to a
spectrum of use-related conditions. The
DSM-5 eliminates the terms
"abuse" and "dependence" from diagnostic categories, instead using the
specifiers of "mild", "moderate" and "severe" to indicate the extent
of disordered use. Specifiers are determined by the number of
diagnostic criteria present in a given case. The manual has never
actually used the term "addiction" clinically. Currently, only
drug addictions and gambling addiction are listed in the DSM-5. Past
editions have used physical dependence and the associated withdrawal
syndrome to identify an addictive state.
Physical dependence occurs
when the body has adjusted by incorporating the substance into its
"normal" functioning – i.e., attains homeostasis – and therefore
physical withdrawal symptoms occur upon cessation of use.
Tolerance is the process by which the body continually adapts to the
substance and requires increasingly larger amounts to achieve the
original effects. Withdrawal refers to physical and psychological
symptoms experienced when reducing or discontinuing a substance that
the body has become dependent on. Symptoms of withdrawal generally
include but are not limited to anxiety, irritability, intense cravings
for the substance, nausea, hallucinations, headaches, cold sweats, and
Medical researchers who actively study addiction have criticized the
DSM classification of addiction for being flawed and involving
arbitrary diagnostic criteria. Writing in 2013, the director of
the United States
National Institute of Mental Health
National Institute of Mental Health discussed the
invalidity of the DSM-5's classification of mental disorders:
While DSM has been described as a "Bible" for the field, it is, at
best, a dictionary, creating a set of labels and defining each. The
strength of each of the editions of DSM has been "reliability" –
each edition has ensured that clinicians use the same terms in the
same ways. The weakness is its lack of validity. Unlike our
definitions of ischemic heart disease, lymphoma, or AIDS, the DSM
diagnoses are based on a consensus about clusters of clinical
symptoms, not any objective laboratory measure. In the rest of
medicine, this would be equivalent to creating diagnostic systems
based on the nature of chest pain or the quality of fever.
Most recently, though, the NIH acknowledged advances in identifying
biomarkers, noting they outperform traditional phenomenological
categories in identifying types of psychosis. As a diagnostic
ΔFosB expression could be used to diagnose an addiction in
humans, but this would require a brain biopsy and therefore isn't used
in clinical practice.
Addiction recovery groups, Cognitive behavioral therapy, and
According to a review, "in order to be effective, all pharmacological
or biologically based treatments for addiction need to be integrated
into other established forms of addiction rehabilitation, such as
cognitive behavioral therapy, individual and group psychotherapy,
behavior-modification strategies, twelve-step programs, and
residential treatment facilities."
A meta-analytic review on the efficacy of various behavioral therapies
for treating drug and behavioral addictions found that cognitive
behavioral therapy (e.g., relapse prevention and contingency
management), motivational interviewing, and a community reinforcement
approach were effective interventions with moderate effect sizes.
Preclinical research using a rodent model of cue exposure therapy
(CET) show that this type of treatment is more effective in adults
compared to adolescents, however that adolescent outcomes can be
improved by acute treatment at the time of (CET) with a dopamine 2
Clinical and preclinical evidence indicate that consistent aerobic
exercise, especially endurance exercise (e.g., marathon running),
actually prevents the development of certain drug addictions and is an
effective adjunct treatment for drug addiction, and for
psychostimulant addiction in particular.
Consistent aerobic exercise magnitude-dependently (i.e., by duration
and intensity) reduces drug addiction risk, which appears to occur
through the reversal of drug induced addiction-related
neuroplasticity. One review noted that exercise may prevent
the development of drug addiction by altering
ΔFosB or c-Fos
immunoreactivity in the striatum or other parts of the reward
system. Aerobic exercise decreases drug self-administration,
reduces the likelihood of relapse, and induces opposite effects on
striatal dopamine receptor D2 (DRD2) signaling (increased DRD2
density) to those induced by addictions to several drug classes
DRD2 density). Consequently, consistent aerobic
exercise may lead to better treatment outcomes when used as an adjunct
treatment for drug addiction.
Further information: Alcoholism
Alcohol, like opioids, can induce a severe state of physical
dependence and produce withdrawal symptoms such as delirium tremens.
Because of this, treatment for alcohol addiction usually involves a
combined approach dealing with dependence and addiction
Pharmacological treatments for alcohol addiction include drugs like
naltrexone (opioid antagonist), disulfiram, acamprosate, and
topiramate. Rather than substituting for alcohol, these drugs
are intended to affect the desire to drink, either by directly
reducing cravings as with acamprosate and topiramate, or by producing
unpleasant effects when alcohol is consumed, as with disulfiram. These
drugs can be effective if treatment is maintained, but compliance can
be an issue as alcoholic patients often forget to take their
medication, or discontinue use because of excessive side
effects. According to a
Cochrane Collaboration review, the
opioid antagonist naltrexone has been shown to be an effective
treatment for alcoholism, with the effects lasting three to twelve
months after the end of treatment.
This section is transcluded from Behavioral addiction. (edit
Behavioral addiction is a treatable condition. Treatment options
include psychotherapy and psychopharmacotherapy (i.e., medications) or
a combination of both.
Cognitive behavioral therapy
Cognitive behavioral therapy (CBT) is the most
common form of psychotherapy used in treating behavioral addictions;
it focuses on identifying patterns that trigger compulsive behavior
and making lifestyle changes to promote healthier behaviors.
Currently, there are no medications approved for treatment of
behavioral addictions in general, but some medications used for
treatment of drug addiction may also be beneficial with specific
behavioral addictions. Any unrelated psychiatric disorders should
be kept under control, and differentiated from the contributing
factors that cause the addiction.
As of 2010[update], there are no effective pharmacological
interventions for cannabinoid addiction. A 2013 review on
cannabinoid addiction noted that the development of CB1 receptor
agonists that have reduced interaction with β-arrestin 2 signaling
might be therapeutically useful.
Further information: Smoking cessation
Another area in which drug treatment has been widely used is in the
treatment of nicotine addiction, which usually involves the use of
nicotine replacement therapy, nicotinic receptor antagonists, or
nicotinic receptor partial agonists. Examples of drugs that
act on nicotinic receptors and have been used for treating nicotine
addiction include antagonists like bupropion and the partial agonist
Opioid use disorder
Opioids cause physical dependence, and treatment typically addresses
both dependence and addiction.
Physical dependence is treated using replacement drugs such as
suboxone or subutex (both containing the active ingredients
buprenorphine) and methadone. Although these drugs perpetuate
physical dependence, the goal of opiate maintenance is to provide a
measure of control over both pain and cravings. Use of replacement
drugs increases the patient's ability to function normally and
eliminates the negative consequences of obtaining controlled
substances illicitly. Once a prescribed dosage is stabilized,
treatment enters maintenance or tapering phases. In the United States,
opiate replacement therapy is tightly regulated in methadone clinics
and under the
DATA 2000 legislation. In some countries, other opioid
derivatives such as levomethadyl acetate, dihydrocodeine,
dihydroetorphine and even heroin are used as substitute
drugs for illegal street opiates, with different prescriptions being
given depending on the needs of the individual patient.
led to successful reductions of cravings for stimulants, alcohol, and
opioids, and also alleviates alcohol withdrawal syndrome. Many
patients have stated they "became indifferent to alcohol" or
"indifferent to cocaine" overnight after starting baclofen
As of May 2014[update], there is no effective pharmacotherapy for any
form of psychostimulant addiction. Reviews from 2015
and 2016 indicated that TAAR1-selective agonists have significant
therapeutic potential as a treatment for psychostimulant
addictions; however, as of February 2016[update], the only
compounds which are known to function as TAAR1-selective agonists are
This section needs expansion. You can help by adding to it. (April
Research indicates that vaccines which utilize anti-drug monoclonal
antibodies can mitigate drug-induced positive reinforcement by
preventing the drug from moving across the blood–brain barrier;
however, current vaccine-based therapies are only effective in a
relatively small subset of individuals. As of November
2015[update], vaccine-based therapies are being tested in human
clinical trials as a treatment for addiction and preventative measure
against drug overdoses involving nicotine, cocaine, and
Since addiction involves abnormalities in glutamate and GABAergic
neurotransmission, receptors associated with these
AMPA receptors, NMDA receptors, and GABAB
receptors) are potential therapeutic targets for
addictions. N-acetylcysteine, which affects
metabotropic glutamate receptors and NMDA receptors, has shown some
benefit in preclinical and clinical studies involving addictions to
cocaine, heroin, and cannabinoids. It may also be useful as an
adjunct therapy for addictions to amphetamine-type stimulants, but
more clinical research is required.
Current medical reviews of research involving lab animals have
identified a drug class – class I histone deacetylase
inhibitors[note 6] – that indirectly inhibits the function and
further increases in the expression of accumbal
ΔFosB by inducing G9a
expression in the nucleus accumbens after prolonged
use. These reviews and subsequent preliminary
evidence which used oral administration or intraperitoneal
administration of the sodium salt of butyric acid or other class I
HDAC inhibitors for an extended period indicate that these drugs have
efficacy in reducing addictive behavior in lab animals[note 7] that
have developed addictions to ethanol, psychostimulants (i.e.,
amphetamine and cocaine), nicotine, and opiates;
however, as of August 2015[update] no clinical trials involving human
addicts and any HDAC class I inhibitors have been conducted to test
for treatment efficacy in humans or identify an optimal dosing
Gene therapy for addiction is an active area of research. One line of
gene therapy research involves the use of viral vectors to increase
the expression of dopamine D2 receptor proteins in the
Due to cultural variations, the proportion of individuals who develop
a drug or behavioral addiction within a specified time period (i.e.,
the prevalence) varies over time, by country, and across national
population demographics (e.g., by age group, socioeconomic status,
This section is empty. You can help by adding to it. (December 2015)
The prevalence of substance abuse disorder among Australians was
reported at 5.1% in 2009.
This section is empty. You can help by adding to it. (December 2015)
This section is missing information about prescription drug addiction
prevalence rate(s). Please expand the section to include this
information. Further details may exist on the talk page. (June 2015)
Based upon representative samples of the US youth population in 2011,
the lifetime prevalence[note 8] of addictions to alcohol and illicit
drugs has been estimated to be approximately 8% and 2–3%
respectively. Based upon representative samples of US adult
population in 2011, the 12 month prevalence of alcohol and illicit
drug addictions were estimated at roughly 12% and 2–3%
respectively. The 12 month and lifetime prevalence of prescription
drug addictions is currently unknown.
As of 2016,[update] about 22 million Americans need treatment for
an addiction to alcohol, nicotine, or other drugs. Only about
10%, or a little over 2 million, receive any form of treatments,
and those that do generally do not receive evidence-based
care. One-third of inpatient hospital costs and 20% of all
deaths in the US every year are the result of untreated addictions and
risky substance use. In spite of the massive overall economic
cost to society, which is greater than the cost of diabetes and all
forms of cancer combined, most doctors in the US lack the training to
effectively address a drug addiction.
Another review listed estimates of lifetime prevalence rates for
several behavioral addictions in the United States, including 1–2%
for compulsive gambling, 5% for sexual addiction, 2.8% for food
addiction, and 5–6% for compulsive shopping. A systematic review
indicated that the time-invariant prevalence rate for sexual addiction
and related compulsive sexual behavior (e.g., compulsive masturbation
with or without pornography, compulsive cybersex, etc.) within the
United States ranges from 3–6% of the population.
According to a 2017 poll conducted by the Pew Research Center, almost
half of US adults know a family member or close friend who has
struggled with a drug addiction at some point in their life.
This section is empty. You can help by adding to it. (November 2017)
Personality theories of addiction
Main article: Personality theories of addiction
Personality theories of addiction are psychological models that
associate personality traits or modes of thinking (i.e., affective
states) with an individual's proclivity for developing an addiction.
Models of addiction risk that have been proposed in psychology
literature include an affect dysregulation model of positive and
negative psychological affects, the reinforcement sensitivity theory
model of impulsiveness and behavioral inhibition, and an impulsivity
model of reward sensitization and
^ a b A decrease in aversion sensitivity, in simpler terms, means that
an individual's behavior is less likely to be influenced by
^ In other words, c-Fos repression allows
ΔFosB to more rapidly
accumulate within the
D1-type medium spiny neurons of the nucleus
accumbens because it is selectively induced in this state. Prior to
c-Fos repression, all Fos family proteins (e.g., c-Fos, Fra1, Fra2,
FosB, and ΔFosB) are induced together, with
increasing to a lesser extent.
^ According to two medical reviews,
ΔFosB has been implicated in
causing both increases and decreases in dynorphin expression in
different studies; this table entry reflects only a decrease.
^ Incentive salience, the "motivational salience" for a reward, is a
"desire" or "want" attribute, which includes a motivational component,
that the brain assigns to a rewarding stimulus. As a
consequence, incentive salience acts as a motivational "magnet" for a
rewarding stimulus that commands attention, induces approach, and
causes the rewarding stimulus to be sought out.
^ In simplest terms, this means that when either amphetamine or sex is
perceived as more alluring or desirable through reward sensitization,
this effect occurs with the other as well.
^ Inhibitors of class I histone deacetylase (HDAC) enzymes are drugs
that inhibit four specific histone-modifying enzymes: HDAC1, HDAC2,
HDAC3, and HDAC8. Most of the animal research with HDAC inhibitors has
been conducted with four drugs: butyrate salts (mainly sodium
butyrate), trichostatin A, valproic acid, and SAHA; butyric
acid is a naturally occurring short-chain fatty acid in humans, while
the latter two compounds are FDA-approved drugs with medical
indications unrelated to addiction.
^ Specifically, prolonged administration of a class I HDAC inhibitor
appears to reduce an animal's motivation to acquire and use an
addictive drug without affecting an animals motivation to attain other
rewards (i.e., it does not appear to cause motivational anhedonia) and
reduce the amount of the drug that is self-administered when it is
^ The lifetime prevalence of an addiction is the percentage of
individuals in a population that developed an addiction at some point
in their life.
G proteins & linked receptors
(Text color) Transcription factors
Binge eating disorder
Discrimination against drug addicts
^ a b c d e f g h i j k l m n o p q r s t u v w Nestler EJ (December
2013). "Cellular basis of memory for addiction". Dialogues Clin.
Neurosci. 15 (4): 431–443. PMC 3898681 . PMID 24459410.
Despite the importance of numerous psychosocial factors, at its core,
drug addiction involves a biological process: the ability of repeated
exposure to a drug of abuse to induce changes in a vulnerable brain
that drive the compulsive seeking and taking of drugs, and loss of
control over drug use, that define a state of addiction. ... A
large body of literature has demonstrated that such
D1-type [nucleus accumbens] neurons increases an animal's
sensitivity to drug as well as natural rewards and promotes drug
self-administration, presumably through a process of positive
reinforcement ... Another
ΔFosB target is cFos: as ΔFosB
accumulates with repeated drug exposure it represses c-Fos and
contributes to the molecular switch whereby
ΔFosB is selectively
induced in the chronic drug-treated state.41. ... Moreover, there
is increasing evidence that, despite a range of genetic risks for
addiction across the population, exposure to sufficiently high doses
of a drug for long periods of time can transform someone who has
relatively lower genetic loading into an addict.
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement
and Addictive Disorders". In Sydor A, Brown RY. Molecular
Neuropharmacology: A Foundation for Clinical
Neuroscience (2nd ed.).
New York: McGraw-Hill Medical. pp. 364–375.
^ a b c "Glossary of Terms". Mount Sinai School of Medicine.
Department of Neuroscience. Retrieved 9 February 2015.
^ a b Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic
Advances from the Brain Disease Model of Addiction". N. Engl. J. Med.
374 (4): 363–371. doi:10.1056/NEJMra1511480. PMID 26816013.
Substance-use disorder: A diagnostic term in the fifth edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-5)
referring to recurrent use of alcohol or other drugs that causes
clinically and functionally significant impairment, such as health
problems, disability, and failure to meet major responsibilities at
work, school, or home. Depending on the level of severity, this
disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of
substance-use disorder, in which there is a substantial loss of
self-control, as indicated by compulsive drug taking despite the
desire to stop taking the drug. In the DSM-5, the term addiction is
synonymous with the classification of severe substance-use
^ Angres DH, Bettinardi-Angres K (October 2008). "The disease of
addiction: origins, treatment, and recovery". Dis Mon. 54 (10):
^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15:
Reinforcement and Addictive Disorders". In Sydor A, Brown RY.
Molecular Neuropharmacology: A Foundation for Clinical Neuroscience
(2nd ed.). New York: McGraw-Hill Medical. pp. 364–365, 375.
ISBN 9780071481274. The defining feature of addiction is
compulsive, out-of-control drug use, despite negative
compulsive eating, shopping, gambling, and sex–so-called "natural
addictions"– Indeed, addiction to both drugs and behavioral
rewards may arise from similar dysregulation of the mesolimbic
^ a b c d Taylor SB, Lewis CR, Olive MF (February 2013). "The
neurocircuitry of illicit psychostimulant addiction: acute and chronic
effects in humans". Subst. Abuse Rehabil. 4: 29–43.
doi:10.2147/SAR.S39684. PMC 3931688 . PMID 24648786.
Initial drug use can be attributed to the ability of the drug to act
as a reward (ie, a pleasurable emotional state or positive
reinforcer), which can lead to repeated drug use and dependence.8,9 A
great deal of research has focused on the molecular and
neuroanatomical mechanisms of the initial rewarding or reinforcing
effect of drugs of abuse. ... At present, no pharmacological
therapy has been approved by the FDA to treat psychostimulant
addiction. Many drugs have been tested, but none have shown conclusive
efficacy with tolerable side effects in humans.172 ... A new
emphasis on larger-scale biomarker, genetic, and epigenetic research
focused on the molecular targets of mental disorders has been recently
advocated.212 In addition, the integration of cognitive and behavioral
modification of circuit-wide neuroplasticity (ie, computer-based
training to enhance executive function) may prove to be an effective
adjunct-treatment approach for addiction, particularly when combined
with cognitive enhancers.198,213–216 Furthermore, in order to be
effective, all pharmacological or biologically based treatments for
addiction need to be integrated into other established forms of
addiction rehabilitation, such as cognitive behavioral therapy,
individual and group psychotherapy, behavior-modification strategies,
twelve-step programs, and residential treatment facilities. CS1
maint: Uses authors parameter (link)
^ American Society for
Addiction Medicine (2012). "Definition of
^ a b c d e f g h i j Ruffle JK (November 2014). "Molecular
neurobiology of addiction: what's all the (Δ)
FosB about?". Am. J.
Drug Alcohol Abuse. 40 (6): 428–437.
doi:10.3109/00952990.2014.933840. PMID 25083822.
The strong correlation between chronic drug exposure and ΔFosB
provides novel opportunities for targeted therapies in addiction
(118), and suggests methods to analyze their efficacy (119). Over the
past two decades, research has progressed from identifying ΔFosB
induction to investigating its subsequent action (38). It is likely
ΔFosB research will now progress into a new era – the use of
ΔFosB as a biomarker. ...
ΔFosB is an essential transcription factor implicated in the
molecular and behavioral pathways of addiction following repeated drug
exposure. The formation of
ΔFosB in multiple brain regions, and the
molecular pathway leading to the formation of AP-1 complexes is well
understood. The establishment of a functional purpose for
allowed further determination as to some of the key aspects of its
molecular cascades, involving effectors such as
GluR2 (87,88), Cdk5
(93) and NFkB (100). Moreover, many of these molecular changes
identified are now directly linked to the structural, physiological
and behavioral changes observed following chronic drug exposure
(60,95,97,102). New frontiers of research investigating the molecular
ΔFosB have been opened by epigenetic studies, and recent
advances have illustrated the role of
ΔFosB acting on
histones, truly as a molecular switch (34). As a consequence of our
improved understanding of
ΔFosB in addiction, it is possible to
evaluate the addictive potential of current medications (119), as well
as use it as a biomarker for assessing the efficacy of therapeutic
interventions (121,122,124). Some of these proposed interventions have
limitations (125) or are in their infancy (75). However, it is hoped
that some of these preliminary findings may lead to innovative
treatments, which are much needed in addiction.
^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae
af ag ah ai aj ak al Olsen CM (December 2011). "Natural rewards,
neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7):
PMC 3139704 . PMID 21459101. Functional neuroimaging
studies in humans have shown that gambling (Breiter et al, 2001),
shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004),
playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the
sight of appetizing food (Wang et al, 2004a) activate many of the same
brain regions (i.e., the mesocorticolimbic system and extended
amygdala) as drugs of abuse (Volkow et al, 2004). ...
Cross-sensitization is also bidirectional, as a history of amphetamine
administration facilitates sexual behavior and enhances the associated
increase in NAc DA ... As described for food reward, sexual
experience can also lead to activation of plasticity-related signaling
cascades. The transcription factor delta
FosB is increased in the NAc,
PFC, dorsal striatum, and VTA following repeated sexual behavior
(Wallace et al., 2008; Pitchers et al., 2010b). This natural increase
FosB or viral overexpression of delta
FosB within the NAc
modulates sexual performance, and NAc blockade of delta FosB
attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b).
Further, viral overexpression of delta
FosB enhances the conditioned
place preference for an environment paired with sexual experience
(Hedges et al., 2009). ... In some people, there is a transition
from "normal" to compulsive engagement in natural rewards (such as
food or sex), a condition that some have termed behavioral or non-drug
addictions (Holden, 2001; Grant et al., 2006a). ... In humans,
the role of dopamine signaling in incentive-sensitization processes
has recently been highlighted by the observation of a dopamine
dysregulation syndrome in some patients taking dopaminergic drugs.
This syndrome is characterized by a medication-induced increase in (or
compulsive) engagement in non-drug rewards such as gambling, shopping,
or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."
Table 1: Summary of plasticity observed following exposure to drug or
^ a b c d e f Biliński P, Wojtyła A, Kapka-Skrzypczak L,
Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic
regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3):
491–496. PMID 23020045. For these reasons,
ΔFosB is considered
a primary and causative transcription factor in creating new neural
connections in the reward centre, prefrontal cortex, and other regions
of the limbic system. This is reflected in the increased, stable and
long-lasting level of sensitivity to cocaine and other drugs, and
tendency to relapse even after long periods of abstinence. These newly
constructed networks function very efficiently via new pathways as
soon as drugs of abuse are further taken ... In this way, the
induction of CDK5 gene expression occurs together with suppression of
the G9A gene coding for dimethyltransferase acting on the histone H3.
A feedback mechanism can be observed in the regulation of these 2
crucial factors that determine the adaptive epigenetic response to
cocaine. This depends on
G9a gene expression, i.e.
H3K9me2 synthesis which in turn inhibits transcription factors for
ΔFosB. For this reason, the observed hyper-expression of G9a, which
ensures high levels of the dimethylated form of histone H3, eliminates
the neuronal structural and plasticity effects caused by cocaine by
means of this feedback which blocks
^ a b c d e f g h i j k l Robison AJ, Nestler EJ (November 2011).
Transcriptional and epigenetic mechanisms of addiction". Nat. Rev.
Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111.
PMC 3272277 . PMID 21989194.
ΔFosB has been linked
directly to several addiction-related behaviors ... Importantly,
genetic or viral overexpression of ΔJunD, a dominant negative mutant
JunD which antagonizes ΔFosB- and other AP-1-mediated
transcriptional activity, in the NAc or OFC blocks these key effects
of drug exposure14,22–24. This indicates that
ΔFosB is both
necessary and sufficient for many of the changes wrought in the brain
by chronic drug exposure.
ΔFosB is also induced in
D1-type NAc MSNs
by chronic consumption of several natural rewards, including sucrose,
high fat food, sex, wheel running, where it promotes that
consumption14,26–30. This implicates
ΔFosB in the regulation of
natural rewards under normal conditions and perhaps during
pathological addictive-like states.
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 1: Basic
Principles of Neuropharmacology". In Sydor A, Brown RY. Molecular
Neuropharmacology: A Foundation for Clinical
Neuroscience (2nd ed.).
New York: McGraw-Hill Medical. p. 4. ISBN 9780071481274.
Drug abuse and addiction exact an astoundingly high financial and
human toll on society through direct adverse effects, such as lung
cancer and hepatic cirrhosis, and indirect adverse effects—for
example, accidents and AIDS—on health and productivity.
^ a b c KR Merikangas KR, McClair VL (June 2012). "Epidemiology of
Substance Use Disorders". Hum. Genet. 131 (6): 779–789.
doi:10.1007/s00439-012-1168-0. PMC 4408274 .
PMID 22543841. CS1 maint: Uses authors parameter (link)
^ a b c d e "AMERICAN BOARD OF MEDICAL SPECIALTIES RECOGNIZES THE NEW
SUBSPECIALTY OF ADDICTION MEDICINE" (PDF). American Board of Addiction
Medicine. 14 March 2016. Retrieved 3 April 2016. Sixteen percent of
the non-institutionalized U.S. population age 12 and over – more
than 40 million Americans – meets medical criteria for addiction
involving nicotine, alcohol or other drugs. This is more than the
number of Americans with cancer, diabetes or heart conditions. In
2014, 22.5 million people in the United States needed treatment for
addiction involving alcohol or drugs other than nicotine, but only
11.6 percent received any form of inpatient, residential, or
outpatient treatment. Of those who do receive treatment, few receive
evidence-based care. (There is no information available on how many
individuals receive treatment for addiction involving nicotine.)
Risky substance use and untreated addiction account for one-third of
inpatient hospital costs and 20 percent of all deaths in the United
States each year, and cause or contribute to more than 100 other
conditions requiring medical care, as well as vehicular crashes, other
fatal and non-fatal injuries, overdose deaths, suicides, homicides,
domestic discord, the highest incarceration rate in the world and many
other costly social consequences. The economic cost to society is
greater than the cost of diabetes and all cancers combined. Despite
these startling statistics on the prevalence and costs of addiction,
few physicians have been trained to prevent or treat it.
^ Morse RM, Flavin DK (August 1992). "The definition of alcoholism.
The Joint Committee of the National Council on
Alcoholism and Drug
Dependence and the American Society of
Addiction Medicine to Study the
Definition and Criteria for the Diagnosis of Alcoholism". JAMA. 268
(8): 1012–4. doi:10.1001/jama.1992.03490080086030.
^ Marlatt GA, Baer JS, Donovan DM, Kivlahan DR (1988). "Addictive
behaviors: etiology and treatment". Annu Rev Psychol. 39: 223–52.
doi:10.1146/annurev.ps.39.020188.001255. PMID 3278676.
^ a b American Psychiatric Association (2013). "Substance-Related and
Addictive Disorders" (PDF). American Psychiatric Publishing.
pp. 1–2. Archived from the original (PDF) on 15 August 2015.
Retrieved 10 July 2015. Additionally, the diagnosis of dependence
caused much confusion. Most people link dependence with "addiction"
when in fact dependence can be a normal body response to a
^ a b Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter
Reinforcement and Addictive Disorders". Molecular
Neuropharmacology: A Foundation for Clinical
Neuroscience (3rd ed.).
New York: McGraw-Hill Medical. ISBN 9780071827706. The official
diagnosis of drug addiction by the Diagnostic and Statistic Manual of
Mental Disorders (2013), which uses the term substance use disorder,
is flawed. Criteria used to make the diagnosis of substance use
disorders include tolerance and somatic dependence/withdrawal, even
though these processes are not integral to addiction as noted. It is
ironic and unfortunate that the manual still avoids use of the term
addiction as an official diagnosis, even though addiction provides the
best description of the clinical syndrome.
^ Washburn DA (2016). "The Stroop effect at 80: The competition
between stimulus control and cognitive control". J Exp Anal Behav. 105
(1): 3–13. doi:10.1002/jeab.194. PMID 26781048. Today, arguably
more than at any time in history, the constructs of attention,
executive functioning, and cognitive control seem to be pervasive and
preeminent in research and theory. Even within the cognitive
framework, however, there has long been an understanding that behavior
is multiply determined, and that many responses are relatively
automatic, unattended, contention-scheduled, and habitual. Indeed, the
cognitive flexibility, response inhibition, and self-regulation that
appear to be hallmarks of cognitive control are noteworthy only in
contrast to responses that are relatively rigid, associative, and
^ Diamond A (2013). "Executive functions". Annu Rev Psychol. 64:
PMC 4084861 . PMID 23020641. Core EFs are inhibition
[response inhibition (self-control—resisting temptations and
resisting acting impulsively) and interference control (selective
attention and cognitive inhibition)], working memory, and cognitive
flexibility (including creatively thinking "outside the box," seeing
anything from different perspectives, and quickly and flexibly
adapting to changed circumstances). ... EFs and prefrontal cortex
are the first to suffer, and suffer disproportionately, if something
is not right in your life. They suffer first, and most, if you are
stressed (Arnsten 1998, Liston et al. 2009, Oaten & Cheng 2005),
sad (Hirt et al. 2008, von Hecker & Meiser 2005), lonely
(Baumeister et al. 2002, Cacioppo & Patrick 2008, Campbell et al.
2006, Tun et al. 2012), sleep deprived (Barnes et al. 2012, Huang et
al. 2007), or not physically fit (Best 2010, Chaddock et al. 2011,
Hillman et al. 2008). Any of these can cause you to appear to have a
disorder of EFs, such as ADHD, when you do not. You can see the
deleterious effects of stress, sadness, loneliness, and lack of
physical health or fitness at the physiological and neuroanatomical
level in prefrontal cortex and at the behavioral level in worse EFs
(poorer reasoning and problem solving, forgetting things, and impaired
ability to exercise discipline and self-control). ...
EFs can be improved (Diamond & Lee 2011, Klingberg 2010). ...
At any age across the life cycle EFs can be improved, including in the
elderly and in infants. There has been much work with excellent
results on improving EFs in the elderly by improving physical fitness
(Erickson & Kramer 2009, Voss et al. 2011) ... Inhibitory
control (one of the core EFs) involves being able to control one's
attention, behavior, thoughts, and/or emotions to override a strong
internal predisposition or external lure, and instead do what's more
appropriate or needed. Without inhibitory control we would be at the
mercy of impulses, old habits of thought or action (conditioned
responses), and/or stimuli in the environment that pull us this way or
that. Thus, inhibitory control makes it possible for us to change and
for us to choose how we react and how we behave rather than being
unthinking creatures of habit. It doesn’t make it easy. Indeed, we
usually are creatures of habit and our behavior is under the control
of environmental stimuli far more than we usually realize, but having
the ability to exercise inhibitory control creates the possibility of
change and choice. ... The subthalamic nucleus appears to play a
critical role in preventing such impulsive or premature responding
^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher
Cognitive Function and Behavioral Control". In Sydor A, Brown RY.
Molecular Neuropharmacology: A Foundation for Clinical Neuroscience
(2nd ed.). New York: McGraw-Hill Medical. pp. 313–321.
ISBN 9780071481274. • Executive function, the cognitive
control of behavior, depends on the prefrontal cortex, which is highly
developed in higher primates and especially humans.
• Working memory is a short-term, capacity-limited cognitive
buffer that stores information and permits its manipulation to guide
decision-making and behavior. ...
These diverse inputs and back projections to both cortical and
subcortical structures put the prefrontal cortex in a position to
exert what is often called "top-down" control or cognitive control of
behavior. ... The prefrontal cortex receives inputs not only from
other cortical regions, including association cortex, but also, via
the thalamus, inputs from subcortical structures subserving emotion
and motivation, such as the amygdala (Chapter 14) and ventral striatum
(or nucleus accumbens; Chapter 15). ...
In conditions in which prepotent responses tend to dominate behavior,
such as in drug addiction, where drug cues can elicit drug seeking
(Chapter 15), or in attention deficit hyperactivity disorder (ADHD;
described below), significant negative consequences can
result. ... ADHD can be conceptualized as a disorder of executive
function; specifically, ADHD is characterized by reduced ability to
exert and maintain cognitive control of behavior. Compared with
healthy individuals, those with ADHD have diminished ability to
suppress inappropriate prepotent responses to stimuli (impaired
response inhibition) and diminished ability to inhibit responses to
irrelevant stimuli (impaired interference suppression). ...
Functional neuroimaging in humans demonstrates activation of the
prefrontal cortex and caudate nucleus (part of the striatum) in tasks
that demand inhibitory control of behavior. Subjects with ADHD exhibit
less activation of the medial prefrontal cortex than healthy controls
even when they succeed in such tasks and utilize different
circuits. ... Early results with structural MRI show thinning of
the cerebral cortex in ADHD subjects compared with age-matched
controls in prefrontal cortex and posterior parietal cortex, areas
involved in working memory and attention.
^ a b c d Karila L, Wéry A, Weinstein A, Cottencin O, Petit A,
Reynaud M, Billieux J (2014). "
Sexual addiction or hypersexual
disorder: different terms for the same problem? A review of the
literature". Curr. Pharm. Des. 20 (25): 4012–4020.
doi:10.2174/13816128113199990619. PMID 24001295. Sexual
addiction, which is also known as hypersexual disorder, has largely
been ignored by psychiatrists, even though the condition causes
serious psychosocial problems for many people. A lack of empirical
evidence on sexual addiction is the result of the disease's complete
absence from versions of the Diagnostic and Statistical Manual of
Mental Disorders. ... Existing prevalence rates of sexual
addiction-related disorders range from 3% to 6%. Sexual
addiction/hypersexual disorder is used as an umbrella construct to
encompass various types of problematic behaviors, including excessive
masturbation, cybersex, pornography use, sexual behavior with
consenting adults, telephone sex, strip club visitation, and other
behaviors. The adverse consequences of sexual addiction are similar to
the consequences of other addictive disorders. Addictive, somatic and
psychiatric disorders coexist with sexual addiction. In recent years,
research on sexual addiction has proliferated, and screening
instruments have increasingly been developed to diagnose or quantify
sexual addiction disorders. In our systematic review of the existing
measures, 22 questionnaires were identified. As with other behavioral
addictions, the appropriate treatment of sexual addiction should
combine pharmacological and psychological approaches.
^ a b c d e Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman
MN, Coolen LM (February 2013). "Natural and drug rewards act on common
neural plasticity mechanisms with
ΔFosB as a key mediator". The
Journal of Neuroscience. 33 (8): 3434–3442.
doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508 .
PMID 23426671. Drugs of abuse induce neuroplasticity in the
natural reward pathway, specifically the nucleus accumbens (NAc),
thereby causing development and expression of addictive
behavior. ... Together, these findings demonstrate that drugs of
abuse and natural reward behaviors act on common molecular and
cellular mechanisms of plasticity that control vulnerability to drug
addiction, and that this increased vulnerability is mediated by ΔFosB
and its downstream transcriptional targets. ... Sexual behavior
is highly rewarding (Tenk et al., 2009), and sexual experience causes
sensitized drug-related behaviors, including cross-sensitization to
amphetamine (Amph)-induced locomotor activity (Bradley and Meisel,
2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et
al., 2010a). Moreover, sexual experience induces neural plasticity in
the NAc similar to that induced by psychostimulant exposure, including
increased dendritic spine density (Meisel and Mullins, 2006; Pitchers
et al., 2010a), altered glutamate receptor trafficking, and decreased
synaptic strength in prefrontal cortex-responding NAc shell neurons
(Pitchers et al., 2012). Finally, periods of abstinence from sexual
experience were found to be critical for enhanced Amph reward, NAc
spinogenesis (Pitchers et al., 2010a), and glutamate receptor
trafficking (Pitchers et al., 2012). These findings suggest that
natural and drug reward experiences share common mechanisms of neural
^ a b c d e Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM
(February 2016). "
NMDA receptor activation regulates
amphetamine cross-sensitization and delta
FosB expression following
sexual experience in male rats". Neuropharmacology. 101: 154–164.
doi:10.1016/j.neuropharm.2015.09.023. PMID 26391065.
^ a b c Grant JE, Potenza MN, Weinstein A, Gorelick DA (September
2010). "Introduction to behavioral addictions". Am. J. Drug Alcohol
Abuse. 36 (5): 233–241. doi:10.3109/00952990.2010.491884.
PMC 3164585 . PMID 20560821. Naltrexone, a mu-opioid
receptor antagonist approved by the US Food and Drug Administration
for the treatment of alcoholism and opioid dependence, has shown
efficacy in controlled clinical trials for the treatment of
pathological gambling and kleptomania (76–79), and promise in
uncontrolled studies of compulsive buying (80), compulsive sexual
behavior (81), internet addiction (82), and pathologic skin picking
(83). ... Topiramate, an anti-convulsant which blocks the AMPA
subtype of glutamate receptor (among other actions), has shown promise
in open-label studies of pathological gambling, compulsive buying, and
compulsive skin picking (85), as well as efficacy in reducing alcohol
(86), cigarette (87), and cocaine (88) use. N-acetyl cysteine, an
amino acid that restores extracellular glutamate concentration in the
nucleus accumbens, reduced gambling urges and behavior in one study of
pathological gamblers (89), and reduces cocaine craving (90) and
cocaine use (91) in cocaine addicts. These studies suggest that
glutamatergic modulation of dopaminergic tone in the nucleus accumbens
may be a mechanism common to behavioral addiction and substance use
^ a b c d e f g Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of
transgenerational inheritance of addictive-like behaviors".
Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064.
PMC 3872494 . PMID 23920159. However, the components that
are responsible for the heritability of characteristics that make an
individual more susceptible to drug addiction in humans remain largely
unknown given that patterns of inheritance cannot be explained by
simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al.,
1972). The environment also plays a large role in the development of
addiction as evidenced by great societal variability in drug use
patterns between countries and across time (UNODC, 2012). Therefore,
both genetics and the environment contribute to an individual's
vulnerability to become addicted following an initial exposure to
drugs of abuse. ...
The evidence presented here demonstrates that rapid environmental
adaptation occurs following exposure to a number of stimuli.
Epigenetic mechanisms represent the key components by which the
environment can influence genetics, and they provide the missing link
between genetic heritability and environmental influences on the
behavioral and physiological phenotypes of the offspring.
^ a b Kendler KS, Neale MC, Heath AC, Kessler RC, Eaves LJ (May 1994).
"A twin-family study of alcoholism in women". Am J Psychiatry. 151
(5): 707–15. PMID 8166312.
^ Clarke TK, Crist RC, Kampman KM, Dackis CA, Pettinati HM, O'Brien
CP, Oslin DW, Ferraro TN, Lohoff FW, Berrettini WH (2013). "Low
frequency genetic variants in the μ-opioid receptor (OPRM1) affect
risk for addiction to heroin and cocaine".
Neuroscience Letters. 542:
71–5. doi:10.1016/j.neulet.2013.02.018. PMC 3640707 .
^ Hall, F. Scott; Drgonova, Jana; Jain, Siddharth; Uhl, George R.
(December 2013). "Implications of genome wide association studies for
addiction: Are our a priori assumptions all wrong?". Pharmacology
& Therapeutics. 140 (3): 267–279.
doi:10.1016/j.pharmthera.2013.07.006. PMC 3797854 .
^ Crowe, J.R. "Genetics of alcoholism". Alcohol health and research
world: 1–11. Retrieved 13 December 2017.
^ a b Abuse, National Institute on Drug. "What are risk factors and
protective factors?". Retrieved 13 December 2017.
^ a b "Adverse Childhood Experiences". samhsa.gov. Rockville,
Maryland, United States: Substance Abuse and Mental Health Services
Administration. Retrieved 26 September 2016.
^ a b Enoch, Mary (2011). "The role of early life stress as a
predictor for alcohol and drug dependence". Psychopharmacology. 214:
17–31. doi:10.1007/s00213-010-1916-6. PMC 3005022 .
^ Spear LP (June 2000). "The adolescent brain and age-related
Neuroscience and Biobehavioral Reviews. 24
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^ Hammond, Christopher J.; Mayes, Linda C.; Potenza, Marc N. (April
2014). "Neurobiology of Adolescent Substance Use and Addictive
Behaviors: Prevention and Treatment Implications". Adolescent
medicine: state of the art reviews. 25 (1): 15–32.
ISSN 1934-4287. PMC 4446977 . PMID 25022184.
^ Catalano RF, Hawkins JD, Wells EA, Miller J, Brewer D (1990).
"Evaluation of the effectiveness of adolescent drug abuse treatment,
assessment of risks for relapse, and promising approaches for relapse
prevention". The International Journal of the Addictions. 25 (9A-10A):
1085–140. PMID 2131328.
^ Perepletchikova F, Krystal JH, Kaufman J (November 2008).
"Practitioner review: adolescent alcohol use disorders: assessment and
treatment issues". Journal of Child
Psychology and Psychiatry, and
Allied Disciplines. 49 (11): 1131–1154.
doi:10.1111/j.1469-7610.2008.01934.x. PMC 4113213 .
^ a b c "Nationwide Trends". National Institute on Drug Abuse. June
2015. Retrieved 15 December 2017.
^ SAMHSA. "Risk and Protective Factors". Substance Abuse and Mental
Health Administration. Retrieved 19 December 2016.
^ "Infographic – Risk Factors of
Addiction Recovery Research
Institute". www.recoveryanswers.org. Retrieved 19 December 2016.
Drug addiction Risk factors – Mayo Clinic". www.mayoclinic.org.
Retrieved 19 December 2016.
^ a b c Yuan TF, Li A, Sun X, Ouyang H, Campos C, Rocha NB,
Arias-Carrión O, Machado S, Hou G, So KF (2015). "Transgenerational
Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction,
Ageing and Metabolism". Mol. Neurobiol. doi:10.1007/s12035-015-9526-2.
^ a b c Renthal W, Nestler EJ (September 2009). "Chromatin regulation
in drug addiction and depression". Dialogues Clin. Neurosci. 11 (3):
257–268. PMC 2834246 . PMID 19877494. [Psychostimulants]
increase cAMP levels in striatum, which activates protein kinase A
(PKA) and leads to phosphorylation of its targets. This includes the
cAMP response element binding protein (CREB), the phosphorylation of
which induces its association with the histone acetyltransferase, CREB
binding protein (CBP) to acetylate histones and facilitate gene
activation. This is known to occur on many genes including fosB and
c-fos in response to psychostimulant exposure.
ΔFosB is also
upregulated by chronic psychostimulant treatments, and is known to
activate certain genes (eg, cdk5) and repress others (eg, c-fos) where
HDAC1 as a corepressor. ... Chronic exposure to
psychostimulants increases glutamatergic [signaling] from the
prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+
levels in NAc postsynaptic elements where it activates CaMK
(calcium/calmodulin protein kinases) signaling, which, in addition to
phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events
^ Broussard JI (January 2012). "Co-transmission of dopamine and
glutamate". J. Gen. Physiol. 139 (1): 93–96.
doi:10.1085/jgp.201110659. PMC 3250102 . PMID 22200950.
Coincident and convergent input often induces plasticity on a
postsynaptic neuron. The NAc integrates processed information about
the environment from basolateral amygdala, hippocampus, and prefrontal
cortex (PFC), as well as projections from midbrain dopamine neurons.
Previous studies have demonstrated how dopamine modulates this
integrative process. For example, high frequency stimulation
potentiates hippocampal inputs to the NAc while simultaneously
depressing PFC synapses (Goto and Grace, 2005). The converse was also
shown to be true; stimulation at PFC potentiates PFC–NAc synapses
but depresses hippocampal–NAc synapses. In light of the new
functional evidence of midbrain dopamine/glutamate co-transmission
(references above), new experiments of NAc function will have to test
whether midbrain glutamatergic inputs bias or filter either limbic or
cortical inputs to guide goal-directed behavior.
^ Kanehisa Laboratories (10 October 2014). "
Amphetamine – Homo
sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most
addictive drugs increase extracellular concentrations of dopamine (DA)
in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC),
projection areas of mesocorticolimbic DA neurons and key components of
the "brain reward circuit".
Amphetamine achieves this elevation in
extracellular levels of DA by promoting efflux from synaptic
terminals. ... Chronic exposure to amphetamine induces a unique
transcription factor delta FosB, which plays an essential role in
long-term adaptive changes in the brain.
^ Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015).
Transcriptional and epigenetic substrates of methamphetamine
addiction and withdrawal: evidence from a long-access
self-administration model in the rat". Mol. Neurobiol. 51 (2):
696–717. doi:10.1007/s12035-014-8776-8. PMC 4359351 .
PMID 24939695. Figure 1
^ a b c Robison AJ, Nestler EJ (November 2011). "
epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11):
623–637. doi:10.1038/nrn3111. PMC 3272277 .
ΔFosB serves as one of the master control
proteins governing this structural plasticity. ...
G9a expression, leading to reduced repressive histone
methylation at the cdk5 gene. The net result is gene activation and
increased CDK5 expression. ... In contrast,
ΔFosB binds to the
c-fos gene and recruits several co-repressors, including HDAC1
(histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net
result is c-fos gene repression.
Epigenetic basis of drug regulation of gene expression
^ a b c d Nestler EJ (December 2012). "
Transcriptional mechanisms of
drug addiction". Clin. Psychopharmacol. Neurosci. 10 (3): 136–143.
doi:10.9758/cpn.2012.10.3.136. PMC 3569166 .
PMID 23430970. The 35-37 kD
ΔFosB isoforms accumulate with
chronic drug exposure due to their extraordinarily long
half-lives. ... As a result of its stability, the
persists in neurons for at least several weeks after cessation of drug
ΔFosB overexpression in nucleus accumbens induces
NFκB ... In contrast, the ability of
ΔFosB to repress the c-Fos
gene occurs in concert with the recruitment of a histone deacetylase
and presumably several other repressive proteins such as a repressive
^ Nestler EJ (October 2008). "Review.
Transcriptional mechanisms of
addiction: role of DeltaFosB". Philos. Trans. R. Soc. Lond., B, Biol.
Sci. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067.
PMC 2607320 . PMID 18640924. Recent evidence has shown
ΔFosB also represses the c-fos gene that helps create the
molecular switch—from the induction of several short-lived Fos
family proteins after acute drug exposure to the predominant
ΔFosB after chronic drug exposure
^ a b Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of
addiction: the role of reward-related learning and memory". Annu. Rev.
Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009.
^ Steiner H, Van Waes V (January 2013). "Addiction-related gene
regulation: risks of exposure to cognitive enhancers vs. other
psychostimulants". Prog. Neurobiol. 100: 60–80.
doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776 .
^ Kanehisa Laboratories (2 August 2013). "
Alcoholism – Homo sapiens
(human)". KEGG Pathway. Retrieved 10 April 2014.
^ Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February
2009). "Methylphenidate-induced dendritic spine formation and
FosB expression in nucleus accumbens". Proc. Natl. Acad. Sci.
U.S.A. 106 (8): 2915–2920. doi:10.1073/pnas.0813179106.
PMC 2650365 . PMID 19202072.
^ a b c d Nestler EJ (January 2014). "
Epigenetic mechanisms of drug
addiction". Neuropharmacology. 76 Pt B: 259–268.
doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384 .
PMID 23643695. Short-term increases in histone acetylation
generally promote behavioral responses to the drugs, while sustained
increases oppose cocaine's effects, based on the actions of systemic
or intra-NAc administration of HDAC inhibitors. ... Genetic or
pharmacological blockade of
G9a in the NAc potentiates behavioral
responses to cocaine and opiates, whereas increasing
exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a).
Such drug-induced downregulation of
G9a and H3K9me2 also sensitizes
animals to the deleterious effects of subsequent chronic stress
(Covington et al., 2011).
G9a increases the
dendritic arborization of NAc neurons, and is associated with
increased expression of numerous proteins implicated in synaptic
function, which directly connects altered G9a/H3K9me2 in the synaptic
plasticity associated with addiction (Maze et al., 2010).
G9a appears to be a critical control point for epigenetic regulation
in NAc, as we know it functions in two negative feedback loops. It
opposes the induction of ΔFosB, a long-lasting transcription factor
important for drug addiction (Robison and Nestler, 2011), while ΔFosB
in turn suppresses
G9a expression (Maze et al., 2010; Sun et al.,
2012a). ... Also,
G9a is induced in NAc upon prolonged HDAC
inhibition, which explains the paradoxical attenuation of cocaine's
behavioral effects seen under these conditions, as noted above
(Kennedy et al., 2013). GABAA receptor subunit genes are among those
that are controlled by this feedback loop. Thus, chronic cocaine, or
prolonged HDAC inhibition, induces several GABAA receptor subunits in
NAc, which is associated with increased frequency of inhibitory
postsynaptic currents (IPSCs). In striking contrast, combined exposure
to cocaine and HDAC inhibition, which triggers the induction of G9a
and increased global levels of H3K9me2, leads to blockade of GABAA
receptor and IPSC regulation.
^ a b c d Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano
J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll:
hypothesizing common mesolimbic activation as a function of reward
gene polymorphisms". J. Psychoactive Drugs. 44 (1): 38–55.
doi:10.1080/02791072.2012.662112. PMC 4040958 .
PMID 22641964. It has been found that delta
FosB gene in the NAc
is critical for reinforcing effects of sexual reward. Pitchers and
colleagues (2010) reported that sexual experience was shown to cause
FosB accumulation in several limbic brain regions including the
NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the
medial preoptic nucleus. Next, the induction of c-Fos, a downstream
(repressed) target of DeltaFosB, was measured in sexually experienced
and naive animals. The number of mating-induced c-Fos-IR cells was
significantly decreased in sexually experienced animals compared to
sexually naive controls. Finally, Delta
FosB levels and its activity in
the NAc were manipulated using viral-mediated gene transfer to study
its potential role in mediating sexual experience and
experience-induced facilitation of sexual performance. Animals with
FosB overexpression displayed enhanced facilitation of sexual
performance with sexual experience relative to controls. In contrast,
the expression of DeltaJunD, a dominant-negative binding partner of
DeltaFosB, attenuated sexual experience-induced facilitation of sexual
performance, and stunted long-term maintenance of facilitation
compared to Delta
FosB overexpressing group. Together, these findings
support a critical role for Delta
FosB expression in the NAc in the
reinforcing effects of sexual behavior and sexual experience-induced
facilitation of sexual performance. ... both drug addiction and
sexual addiction represent pathological forms of neuroplasticity along
with the emergence of aberrant behaviors involving a cascade of
neurochemical changes mainly in the brain's rewarding circuitry.
^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement
and addictive disorders". In Sydor A, Brown RY. Molecular
Neuropharmacology: A Foundation for Clinical
Neuroscience (2nd ed.).
New York: McGraw-Hill Medical. pp. 384–385.
^ Salamone, J.D. (1992). "Complex motor and sensorimotor function of
striatal and accumbens dopamine: Involvement in instrumental behavior
processes". Psychopharmacology. 107: 160–174.
^ Kauer, J.A.; R.C. Malenka (2007). "
Synaptic plasticity and
addiction". Nature Reviews Neuroscience. 8 (11): 844–858.
doi:10.1038/nrn2234. PMID 17948030.
^ Witten, I; S.-C. Lin; M Brodsky (2010). "Cholinergic interneurons
control local circuit activity and cocaine conditioning". Science.
330: 1677–1681. doi:10.1126/science.1193771. PMC 3142356 .
^ a b Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a
sustained molecular switch for addiction". Proc. Natl. Acad. Sci.
U.S.A. 98 (20): 11042–11046. doi:10.1073/pnas.191352698.
PMC 58680 . PMID 11572966. Although the
ΔFosB signal is
relatively long-lived, it is not permanent.
ΔFosB degrades gradually
and can no longer be detected in brain after 1–2 months of drug
withdrawal ... Indeed,
ΔFosB is the longest-lived adaptation
known to occur in adult brain, not only in response to drugs of abuse,
but to any other perturbation (that doesn't involve lesions) as
^ a b Jones S, Bonci A (2005). "
Synaptic plasticity and drug
addiction". Current Opinion in Pharmacology. 5 (1): 20–5.
doi:10.1016/j.coph.2004.08.011. PMID 15661621.
^ a b Eisch AJ, Harburg GC (2006). "Opiates, psychostimulants, and
adult hippocampal neurogenesis: Insights for addiction and stem cell
biology". Hippocampus. 16 (3): 271–86. doi:10.1002/hipo.20161.
^ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone.
p. 596. ISBN 0-443-07145-4.
^ Kourrich S, Rothwell PE, Klug JR, Thomas MJ (2007). "Cocaine
experience controls bidirectional synaptic plasticity in the nucleus
accumbens". J. Neurosci. 27 (30): 7921–8.
doi:10.1523/JNEUROSCI.1859-07.2007. PMID 17652583.
^ a b Kalivas PW, Volkow ND (August 2005). "The neural basis of
addiction: a pathology of motivation and choice". The American Journal
of Psychiatry. 162 (8): 1403–13. doi:10.1176/appi.ajp.162.8.1403.
^ a b Floresco SB, Ghods-Sharifi S (February 2007).
"Amygdala-prefrontal cortical circuitry regulates effort-based
decision making". Cerebral Cortex. 17 (2): 251–60.
doi:10.1093/cercor/bhj143. PMID 16495432.
^ Perry CJ, Zbukvic I, Kim JH, Lawrence AJ (October 2014). "Role of
cues and contexts on drug-seeking behaviour". British Journal of
Pharmacology. 171 (20): 4636–72. doi:10.1111/bph.12735.
PMC 4209936 . PMID 24749941.
^ a b c Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F (2007).
Dopamine in drug abuse and addiction: results of imaging studies and
treatment implications". Arch. Neurol. 64 (11): 1575–9.
doi:10.1001/archneur.64.11.1575. PMID 17998440.
^ "Drugs, Brains, and Behavior: The Science of Addiction". National
Institute on Drug Abuse.
^ "Understanding Drug Abuse and Addiction". National Institute on Drug
Abuse. November 2012.
^ a b c Nestler EJ (October 2008). "Review.
of addiction: role of DeltaFosB". Philosophical Transactions of the
Royal Society of London. Series B, Biological Sciences. 363 (1507):
3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320 .
PMID 18640924. Recent evidence has shown that
represses the c-fos gene that helps create the molecular switch—from
the induction of several short-lived Fos family proteins after acute
drug exposure to the predominant accumulation of
ΔFosB after chronic
drug exposure—cited earlier (Renthal et al. in press). The mechanism
ΔFosB repression of c-fos expression is complex and
is covered below. ...
Examples of validated targets for
ΔFosB in nucleus accumbens ...
GluR2 ... dynorphin ... Cdk5 ... NFκB ...
^ a b c d e Berridge KC (April 2012). "From prediction error to
incentive salience: mesolimbic computation of reward motivation". Eur.
J. Neurosci. 35 (7): 1124–1143.
doi:10.1111/j.1460-9568.2012.07990.x. PMC 3325516 .
PMID 22487042. Here I discuss how mesocorticolimbic mechanisms
generate the motivation component of incentive salience. Incentive
salience takes Pavlovian learning and memory as one input and as an
equally important input takes neurobiological state factors (e.g. drug
states, appetite states, satiety states) that can vary independently
of learning. Neurobiological state changes can produce unlearned
fluctuations or even reversals in the ability of a previously learned
reward cue to trigger motivation. Such fluctuations in cue-triggered
motivation can dramatically depart from all previously learned values
about the associated reward outcome. ... Associative learning and
prediction are important contributors to motivation for rewards.
Learning gives incentive value to arbitrary cues such as a Pavlovian
conditioned stimulus (CS) that is associated with a reward
(unconditioned stimulus or UCS). Learned cues for reward are often
potent triggers of desires. For example, learned cues can trigger
normal appetites in everyone, and can sometimes trigger compulsive
urges and relapse in addicts.
Cue-triggered ‘wanting’ for the UCS
A brief CS encounter (or brief UCS encounter) often primes a pulse of
elevated motivation to obtain and consume more reward UCS. This is a
signature feature of incentive salience.
Cue as attractive motivational magnets
When a Pavlovian CS+ is attributed with incentive salience it not only
triggers ‘wanting’ for its UCS, but often the cue itself becomes
highly attractive – even to an irrational degree. This cue
attraction is another signature feature of incentive salience ...
Two recognizable features of incentive salience are often visible that
can be used in neuroscience experiments: (i) UCS-directed
‘wanting’ – CS-triggered pulses of intensified ‘wanting’ for
the UCS reward; and (ii) CS-directed ‘wanting’ – motivated
attraction to the Pavlovian cue, which makes the arbitrary CS stimulus
into a motivational magnet.
^ a b Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, eds.
Molecular Neuropharmacology: A Foundation for Clinical Neuroscience
(2nd ed.). New York: McGraw-Hill Medical. pp. 147–148,
366–367, 375–376. ISBN 978-0-07-148127-4. VTA DA neurons play
a critical role in motivation, reward-related behavior (Chapter 15),
attention, and multiple forms of memory. This organization of the DA
system, wide projection from a limited number of cell bodies, permits
coordinated responses to potent new rewards. Thus, acting in diverse
terminal fields, dopamine confers motivational salience ("wanting") on
the reward itself or associated cues (nucleus accumbens shell region),
updates the value placed on different goals in light of this new
experience (orbital prefrontal cortex), helps consolidate multiple
forms of memory (amygdala and hippocampus), and encodes new motor
programs that will facilitate obtaining this reward in the future
(nucleus accumbens core region and dorsal striatum). In this example,
dopamine modulates the processing of sensorimotor information in
diverse neural circuits to maximize the ability of the organism to
obtain future rewards. ...
The brain reward circuitry that is targeted by addictive drugs
normally mediates the pleasure and strengthening of behaviors
associated with natural reinforcers, such as food, water, and sexual
Dopamine neurons in the VTA are activated by food and water,
and dopamine release in the NAc is stimulated by the presence of
natural reinforcers, such as food, water, or a sexual
The NAc and VTA are central components of the circuitry underlying
reward and memory of reward. As previously mentioned, the activity of
dopaminergic neurons in the VTA appears to be linked to reward
prediction. The NAc is involved in learning associated with
reinforcement and the modulation of motoric responses to stimuli that
satisfy internal homeostatic needs. The shell of the NAc appears to be
particularly important to initial drug actions within reward
circuitry; addictive drugs appear to have a greater effect on dopamine
release in the shell than in the core of the NAc. ... If
motivational drive is described in terms of wanting, and hedonic
evaluation in terms of liking, it appears that wanting can be
dissociated from liking and that dopamine may influence these
phenomena differently. Differences between wanting and liking are
confirmed in reports by human addicts, who state that their desire for
drugs (wanting) increases with continued use even when pleasure
(liking) decreases because of tolerance.
^ a b c Edwards S (2016). "
Reinforcement principles for addiction
medicine; from recreational drug use to psychiatric disorder". Prog.
Brain Res. 223: 63–76. doi:10.1016/bs.pbr.2015.07.005.
PMID 26806771. An important dimension of reinforcement highly
relevant to the addiction process (and particularly relapse) is
secondary reinforcement (Stewart, 1992). Secondary reinforcers (in
many cases also considered conditioned reinforcers) likely drive the
majority of reinforcement processes in humans. In the specific case of
drug addition, cues and contexts that are intimately and repeatedly
associated with drug use will often themselves become
reinforcing ... A fundamental piece of Robinson and Berridge's
incentive-sensitization theory of addiction posits that the incentive
value or attractive nature of such secondary reinforcement processes,
in addition to the primary reinforcers themselves, may persist and
even become sensitized over time in league with the development of
drug addiction (Robinson and Berridge, 1993).
^ Traynor J (March 2012). "μ-
Opioid receptors and regulators of G
protein signaling (RGS) proteins: from a symposium on new concepts in
mu-opioid pharmacology". Drug Alcohol Depend. 121 (3): 173–80.
doi:10.1016/j.drugalcdep.2011.10.027. PMC 3288798 .
^ Torres G, Horowitz JM (1999). "Drugs of abuse and brain gene
expression". Psychosom Med. 61 (5): 630–50.
doi:10.1097/00006842-199909000-00007. PMID 10511013.
^ Thomas Insel. "Transforming Diagnosis". National Institute of Mental
Health. Retrieved 17 June 2015.
^ "Biomarkers outperform symptoms in parsing psychosis subgroups".
National Institutes of Health. 8 December 2015. Retrieved 20 May
^ Clementz BA, Sweeney JA, Hamm JP, Ivleva EI, Ethridge LE, Pearlson
GD, Keshavan MS, Tamminga CA (2016). "Identification of Distinct
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^ Walter M, Dürsteler KM, Petitjean SA, Wiesbeck GA, Euler S,
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Addictive Disorders—An Overview of Psychotherapeutic Options and
their Efficacy]". Fortschr Neurol Psychiatr (in German). 83 (4):
201–210. doi:10.1055/s-0034-1399338. PMID 25893493. Addictive
disorders are chronic relapsing conditions marked by compulsive and
often uncontrolled use of psychotropic substances or stimuli. In this
review, we present and discuss the current specific psychosocial
interventions for addictive disorders and their effectiveness. In
particular cognitive behavioral therapy, motivational interviewing,
relapse prevention, the community reinforcement approach, and
contingency management were found to be effective. For these
psychotherapeutic treatments, mostly moderate effect sizes have been
found. Their effectiveness seems to be highest in cannabis dependence.
Empirical evidence for dependence on "hard" drugs is largest for
contingency management, while for alcohol dependence motivational
interviewing and the community reinforcement approach show the largest
effect sizes. Presumably, combinations of different approaches as well
as online interventions will bring further progress in the
psychosocial treatment of addictive disorders in the future.
^ Zbukvic, Isabel C.; Ganella, Despina E.; Perry, Christina J.;
Madsen, Heather B.; Bye, Christopher R.; Lawrence, Andrew J.; Kim, Jee
Hyun (5 March 2016). "Role of
Dopamine 2 Receptor in Impaired Drug-Cue
Extinction in Adolescent Rats". Cerebral Cortex. 26: bhw051.
doi:10.1093/cercor/bhw051. ISSN 1047-3211. PMC 4869820 .
^ Carroll ME, Smethells JR (February 2016). "Sex Differences in
Behavioral Dyscontrol: Role in Drug
Addiction and Novel Treatments".
Front. Psychiatry. 6: 175. doi:10.3389/fpsyt.2015.00175.
PMC 4745113 . PMID 26903885. Environmental
In humans, non-drug rewards delivered in a contingency management (CM)
format successfully reduced drug dependence ... In general, CM
programs promote drug abstinence through a combination of positive
reinforcement for drug-free urine samples. For instance, voucher-based
reinforcement therapy in which medication compliance, therapy session
attendance, and negative drug screenings reinforced with vouchers to
local business (e.g., movie theater, restaurants, etc.) directly
reinforces drug abstinence, provides competing reinforcers, enriches
the environment, and it is a robust treatment across a broad range of
abused drugs (189). ...
There is accelerating evidence that physical exercise is a useful
treatment for preventing and reducing drug addiction ... In some
individuals, exercise has its own rewarding effects, and a behavioral
economic interaction may occur, such that physical and social rewards
of exercise can substitute for the rewarding effects of drug
abuse. ... The value of this form of treatment for drug addiction
in laboratory animals and humans is that exercise, if it can
substitute for the rewarding effects of drugs, could be
self-maintained over an extended period of time. Work to date in
[laboratory animals and humans] regarding exercise as a treatment for
drug addiction supports this hypothesis. ... However, a RTC study
was recently reported by Rawson et al. (226), whereby they used
8 weeks of exercise as a post-residential treatment for METH
addiction, showed a significant reduction in use (confirmed by urine
screens) in participants who had been using meth 18 days or less a
month. ... Animal and human research on physical exercise as a
treatment for stimulant addiction indicates that this is one of the
most promising treatments on the horizon. [emphasis added]
^ a b c d Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA
(September 2013). "Exercise as a novel treatment for drug addiction: a
neurobiological and stage-dependent hypothesis". Neurosci Biobehav
Rev. 37 (8): 1622–44. doi:10.1016/j.neubiorev.2013.06.011.
PMC 3788047 . PMID 23806439. [exercise] efficacy may be
related to its ability to normalize glutamatergic and dopaminergic
signaling and reverse drug-induced changes in chromatin via epigenetic
interactions with brain-derived neurotrophic factor (BDNF) in the
reward pathway. ... these data show that exercise can affect
dopaminergic signaling at many different levels, which may underlie
its ability to modify vulnerability during drug use initiation.
Exercise also produces neuroadaptations that may influence an
individual's vulnerability to initiate drug use. Consistent with this
idea, chronic moderate levels of forced treadmill running blocks not
only subsequent methamphetamine-induced conditioned place preference,
but also stimulant-induced increases in dopamine release in the NAc
(Chen et al., 2008) and striatum (Marques et al., 2008). ...
[These] findings indicate the efficacy of exercise at reducing drug
intake in drug-dependent individuals ... wheel running [reduces]
methamphetamine self-administration under extended access conditions
(Engelmann et al., 2013) ... These findings suggest that exercise
may "magnitude"-dependently prevent the development of an addicted
phenotype possibly by blocking/reversing behavioral and neuro-adaptive
changes that develop during and following extended access to the
drug. ... Exercise has been proposed as a treatment for drug
addiction that may reduce drug craving and risk of relapse. Although
few clinical studies have investigated the efficacy of exercise for
preventing relapse, the few studies that have been conducted generally
report a reduction in drug craving and better treatment outcomes (see
Table 4). ... Taken together, these data suggest that the
potential benefits of exercise during relapse, particularly for
relapse to psychostimulants, may be mediated via chromatin remodeling
and possibly lead to greater treatment outcomes.
^ a b Linke SE, Ussher M (2015). "Exercise-based treatments for
substance use disorders: evidence, theory, and practicality". Am J
Drug Alcohol Abuse. 41 (1): 7–15. doi:10.3109/00952990.2014.976708.
PMC 4831948 . PMID 25397661. The limited research
conducted suggests that exercise may be an effective adjunctive
treatment for SUDs. In contrast to the scarce intervention trials to
date, a relative abundance of literature on the theoretical and
practical reasons supporting the investigation of this topic has been
published. ... numerous theoretical and practical reasons support
exercise-based treatments for SUDs, including psychological,
behavioral, neurobiological, nearly universal safety profile, and
overall positive health effects.
^ a b Zhou Y, Zhao M, Zhou C, Li R (July 2015). "Sex differences in
drug addiction and response to exercise intervention: From human to
animal studies". Front. Neuroendocrinol. 40: 24–41.
doi:10.1016/j.yfrne.2015.07.001. PMC 4712120 .
PMID 26182835. Collectively, these findings demonstrate that
exercise may serve as a substitute or competition for drug abuse by
ΔFosB or cFos immunoreactivity in the reward system to
protect against later or previous drug use. ... As briefly
reviewed above, a large number of human and rodent studies clearly
show that there are sex differences in drug addiction and exercise.
The sex differences are also found in the effectiveness of exercise on
drug addiction prevention and treatment, as well as underlying
neurobiological mechanisms. The postulate that exercise serves as an
ideal intervention for drug addiction has been widely recognized and
used in human and animal rehabilitation. ... In particular, more
studies on the neurobiological mechanism of exercise and its roles in
preventing and treating drug addiction are needed.
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PMC 2909584 . PMID 20384422. Cannabis is the most widely
used illicit substance in the world, and demand for effective
treatment is increasing. However, abstinence rates following
behavioral therapies have been modest, and there are no effective
pharmacotherapies for the treatment of cannabis addiction.
^ Fratta W, Fattore L (August 2013). "Molecular mechanisms of
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A pioneering study revealing both positive and negative modulatory
effects of beta-arrestin2 on THC tolerance. By demonstrating that
tolerance to antinociception is reduced whereas tolerance to catalepsy
is enhanced in beta-arrestin2 knockout mice, authors suggest that
development of cannabinoid agonists that minimize interactions between
CB1Rs and beta-arrestin2 might produce improved cannabinoid analgesics
with reduced motor suppression, and be therapeutically
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^ Kenna GA, Nielsen DM, Mello P, Schiesl A, Swift RM (2007).
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^ Stoops WW, Rush CR (May 2014). "Combination pharmacotherapies for
stimulant use disorder: a review of clinical findings and
recommendations for future research". Expert Rev Clin Pharmacol. 7
(3): 363–374. doi:10.1586/17512433.2014.909283. PMC 4017926 .
PMID 24716825. Despite concerted efforts to identify a
pharmacotherapy for managing stimulant use disorders, no widely
effective medications have been approved.
^ Perez-Mana C, Castells X, Torrens M, Capella D, Farre M (September
2013). "Efficacy of psychostimulant drugs for amphetamine abuse or
dependence". Cochrane Database Syst. Rev. 9: CD009695.
doi:10.1002/14651858.CD009695.pub2. PMID 23996457. To date, no
pharmacological treatment has been approved for [addiction], and
psychotherapy remains the mainstay of treatment. ... Results of
this review do not support the use of psychostimulant medications at
the tested doses as a replacement therapy
^ Forray A, Sofuoglu M (February 2014). "Future pharmacological
treatments for substance use disorders". Br. J. Clin. Pharmacol. 77
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^ a b Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting
Addiction"-The Alamo Bears Witness to Another Revolution: An Overview
of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry
Conference". Drug Alcohol Depend. 159: 9–16.
doi:10.1016/j.drugalcdep.2015.11.014. PMC 4724540 .
PMID 26644139. When considered together with the rapidly growing
literature in the field a compelling case emerges in support of
developing TAAR1-selective agonists as medications for preventing
relapse to psychostimulant abuse.
^ a b Jing L, Li JX (August 2015). "Trace amine-associated receptor 1:
A promising target for the treatment of psychostimulant addiction".
Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019.
PMC 4532615 . PMID 26092759. Taken together, the data
reviewed here strongly support that
TAAR1 is implicated in the
functional regulation of monoaminergic systems, especially
dopaminergic system, and that
TAAR1 serves as a homeostatic "brake"
system that is involved in the modulation of dopaminergic activity.
Existing data provided robust preclinical evidence supporting the
TAAR1 agonists as potential treatment for
psychostimulant abuse and addiction. ... Given that
primarily located in the intracellular compartments and existing TAAR1
agonists are proposed to get access to the receptors by translocation
to the cell interior (Miller, 2011), future drug design and
development efforts may need to take strategies of drug delivery into
consideration (Rajendran et al., 2010).
^ a b c Zalewska-Kaszubska J (November 2015). "Is immunotherapy an
opportunity for effective treatment of drug addiction?". Vaccine. 33
(48): 6545–6551. doi:10.1016/j.vaccine.2015.09.079.
^ Laudenbach M, Baruffaldi F, Vervacke JS, Distefano MD, Titcombe PJ,
Mueller DL, Tubo NJ, Griffith TS, Pravetoni M (June 2015). "The
frequency of naive and early-activated hapten-specific B cell subsets
dictates the efficacy of a therapeutic vaccine against prescription
opioid abuse". J. Immunol. 194 (12): 5926–5936.
doi:10.4049/jimmunol.1500385. PMID 25972483. Translation of
therapeutic vaccines for addiction, cancer, or other chronic
noncommunicable diseases has been slow because only a small subset of
immunized subjects achieved effective Ab levels.
^ a b c d Cao DN, Shi JJ, Hao W, Wu N, Li J (March 2016). "Advances
and challenges in pharmacotherapeutics for amphetamine-type stimulants
addiction". Eur. J. Pharmacol. 780: 129–35.
doi:10.1016/j.ejphar.2016.03.040. PMID 27018393.
^ a b Moeller SJ, London ED, Northoff G (February 2016). "Neuroimaging
markers of glutamatergic and
GABAergic systems in drug addiction:
Relationships to resting-state functional connectivity". Neurosci
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^ Agabio R, Colombo G (April 2015). "[
GABAB receptor as therapeutic
target for drug addiction: from baclofen to positive allosteric
modulators]". Psychiatr. Pol. (in Polish). 49 (2): 215–223.
doi:10.12740/PP/33911. PMID 26093587.
^ Filip M, Frankowska M, Sadakierska-Chudy A, Suder A, Szumiec L,
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2015). "GABAB receptors as a therapeutic strategy in substance use
disorders: focus on positive allosteric modulators".
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^ a b McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The
Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl
1). PMC 4955852 . PMID 27453897.
caused by addictive drugs play an important role in neuronal
plasticity and in drug-induced behavioral responses. Although few
studies have investigated the effects of AMPH on gene regulation
(Table 1), current data suggest that AMPH acts at multiple levels to
DNA interaction and to recruit transcription factors
which ultimately cause repression of some genes and activation of
other genes. Importantly, some studies have also correlated the
epigenetic regulation induced by AMPH with the behavioral outcomes
caused by this drug, suggesting therefore that epigenetics remodeling
underlies the behavioral changes induced by AMPH. If this proves to be
true, the use of specific drugs that inhibit histone acetylation,
DNA methylation might be an important therapeutic
alternative to prevent and/or reverse AMPH addiction and mitigate the
side effects generate by AMPH when used to treat ADHD.
^ a b c d Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015).
"Regulation of chromatin states by drugs of abuse". Curr. Opin.
Neurobiol. 30: 112–121. doi:10.1016/j.conb.2014.11.002.
PMC 4293340 . PMID 25486626. Studies investigating general
HDAC inhibition on behavioral outcomes have produced varying results
but it seems that the effects are specific to the timing of exposure
(either before, during or after exposure to drugs of abuse) as well as
the length of exposure
^ a b Primary references involving sodium butyrate:
• Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E,
et al. (April 2013). "Class I HDAC inhibition blocks cocaine-induced
plasticity by targeted changes in histone methylation". Nat. Neurosci.
16 (4): 434–440. doi:10.1038/nn.3354. PMC 3609040 .
PMID 23475113. While acute HDAC inhibition enhances the
behavioral effects of cocaine or amphetamine1,3,4,13,14, studies
suggest that more chronic regimens block psychostimulant-induced
plasticity3,5,11,12. ... The effects of pharmacological
inhibition of HDACs on psychostimulant-induced plasticity appear to
depend on the timecourse of HDAC inhibition. Studies employing
co-administration procedures in which inhibitors are given acutely,
just prior to psychostimulant administration, report heightened
behavioral responses to the drug1,3,4,13,14. In contrast, experimental
paradigms like the one employed here, in which HDAC inhibitors are
administered more chronically, for several days prior to
psychostimulant exposure, show inhibited expression3 or decreased
acquisition of behavioral adaptations to drug5,11,12. The clustering
of seemingly discrepant results based on experimental methodologies is
interesting in light of our present findings. Both HDAC inhibitors and
psychostimulants increase global levels of histone acetylation in NAc.
Thus, when co-administered acutely, these drugs may have synergistic
effects, leading to heightened transcriptional activation of
psychostimulant-regulated target genes. In contrast, when a
psychostimulant is given in the context of prolonged, HDAC
inhibitor-induced hyperacetylation, homeostatic processes may direct
AcH3 binding to the promoters of genes (e.g., G9a) responsible for
inducing chromatin condensation and gene repression (e.g., via
H3K9me2) in order to dampen already heightened transcriptional
activation. Our present findings thus demonstrate clear cross talk
among histone PTMs and suggest that decreased behavioral sensitivity
to psychostimulants following prolonged HDAC inhibition might be
mediated through decreased activity of
HDAC1 at H3K9 KMT promoters and
subsequent increases in H3K9me2 and gene repression.
• Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R,
Naassila M, Vilpoux C (July 2015). "The histone deacetylase inhibitor
sodium butyrate decreases excessive ethanol intake in dependent
animals". Addict Biol. 20 (4): 676–689. doi:10.1111/adb.12161.
PMID 25041570. Altogether, our results clearly demonstrated the
efficacy of NaB in preventing excessive ethanol intake and relapse and
support the hypothesis that HDACi may have a potential use in alcohol
• Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition
of histone deacetylases facilitates extinction and attenuates
reinstatement of nicotine self-administration in rats". PLoS ONE. 10
(4): e0124796. doi:10.1371/journal.pone.0124796. PMC 4399837 .
PMID 25880762. treatment with NaB significantly attenuated
nicotine and nicotine + cue reinstatement when administered
immediately ... These results provide the first demonstration
that HDAC inhibition facilitates the extinction of responding for an
intravenously self-administered drug of abuse and further highlight
the potential of HDAC inhibitors in the treatment of drug
^ Kyzar EJ, Pandey SC (August 2015). "Molecular mechanisms of synaptic
remodeling in alcoholism". Neurosci. Lett. 601: 11–9.
doi:10.1016/j.neulet.2015.01.051. PMID 25623036. Increased HDAC2
expression decreases the expression of genes important for the
maintenance of dendritic spine density such as BDNF, Arc, and NPY,
leading to increased anxiety and alcohol-seeking behavior. Decreasing
HDAC2 reverses both the molecular and behavioral consequences of
alcohol addiction, thus implicating this enzyme as a potential
treatment target (Fig. 3).
HDAC2 is also crucial for the induction and
maintenance of structural synaptic plasticity in other neurological
domains such as memory formation . Taken together, these findings
underscore the potential usefulness of HDAC inhibition in treating
alcohol use disorders ... Given the ability of HDAC inhibitors to
potently modulate the synaptic plasticity of learning and memory
, these drugs hold potential as treatment for substance
abuse-related disorders. ... Our lab and others have published
extensively on the ability of HDAC inhibitors to reverse the gene
expression deficits caused by multiple models of alcoholism and
alcohol abuse, the results of which were discussed above [25,112,113].
This data supports further examination of histone modifying agents as
potential therapeutic drugs in the treatment of alcohol
addiction ... Future studies should continue to elucidate the
specific epigenetic mechanisms underlying compulsive alcohol use and
alcoholism, as this is likely to provide new molecular targets for
Gene Therapy For Addiction: Flooding Brain With 'Pleasure Chemical'
Receptors Works On Cocaine, As On Alcohol
Gene Transfer Therapy for
Addiction Passes Tests in Animals
^ Murthy V, Gao Y, Geng L, LeBrasseur NK, White TA, Parks RJ,
Brimijoin S (2014). "Physiologic and metabolic safety of
butyrylcholinesterase gene therapy in mice". Vaccine. 32: 4155–62.
doi:10.1016/j.vaccine.2014.05.067. PMC 4077905 .
PMID 24892251. CS1 maint: Multiple names: authors list
^ Using Adeno-Associated Virus (AAV) Mediated Sustained Expression of
an Anti-methamphetamine Antibody Fragment to Alter Methamphetamine
Disposition in Mice
Gene Therapy can Reduce Long-Term Drinking among Rodents
^ Slade, T.; Johnston, A.; Teesson, M.; Whiteford, H.; Burgess, P.;
Pirkis, J.; Saw, S (May 2009). "The Mental Health of Australians 2:
Substance Use Disorders in Australia" (PDF). Department of Health and
^ a b c d
Nora Volkow (31 March 2016). "A Major Step Forward for
Addiction Medicine". National Institute on Drug Abuse. National
Institutes of Health. Retrieved 3 April 2016. Only about 10 percent of
the 21 million Americans who meet the need for care for an alcohol or
drug use disorder receive any form of treatment, and much of the
treatment available does not meet standards for evidence-based care.
There are many attitudinal and systemic reasons for this treatment
gap, including stigma against treating people with addictions and
institutional barriers to providing or funding addiction
treatment. ... A major milestone was reached on March 14, 2016,
when the American Board of Medical Specialties (ABMS) formally
announced recognition of the field of
Addiction Medicine as a medical
subspecialty. ... In a statement issued to mark this milestone,
ABAM President Robert J. Sokol summed up its significance: 'This
landmark event, more than any other, recognizes addiction as a
preventable and treatable disease, helping to shed the stigma that has
long plagued it. It sends a strong message to the public that American
medicine is committed to providing expert care for this disease and
services designed to prevent the risky substance use that precedes
^ Gramlich J (26 October 2017). "Nearly half of Americans have a
family member or close friend who's been addicted to drugs". Pew
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