Addiction

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Brain positron emission tomography images that compare brain metabolism in a healthy individual and an individual with a cocaine addiction


Addiction and dependence glossary
* addiction – a biopsychosocial disorder characterized by compulsively seeking to achieve a desired effect, such as intoxication, despite harm and adverse consequences to self and others
  • addictive behavior – a behavior that is both rewarding and reinforcing
  • addictive drug – a drug that is both rewarding and reinforcing
  • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
  • drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
  • drug withdrawal – symptoms that occur upon cessation of repeated drug use
  • physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
  • psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
  • reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
  • rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
  • sensitization – an amplified response to a stimulus resulting from repeated exposure to it
  • substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
  • tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose

Addiction is a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences.[7] Despite the involvement of a number of psychosocial factors, a biological process—one that is induced by repeated exposure to an addictive stimulus—is the core pathology that drives the development and maintenance of an addiction.[1][8] 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 pleasurable).[1][2][6]

Classic hallmarks of addiction include impaired control over substances or behavior, preoccupation with substance or behavior, and continued use despite consequences.[9] Habits and patterns associated with addiction are typically characterized by immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs).[10]

Addiction exacts an "astoundingly high financial and human toll" on individuals and society as a whole.[11][12][13] In the United States, the total economic cost to society is greater than that of all types of diabetes and all cancers combined.[13] These costs arise from the direct adverse effects of drugs and associated healthcare costs (e.g., emergency medical services and outpatient and inpatient care), long-term complications (e.g., lung cancer from smoking tobacco products, liver cirrhosis and dementia from chronic alcohol consumption, and meth mouth from methamphetamine use), the loss of productivity and associated welfare costs, fatal and non-fatal accidents (e.g., traffic collisions), suicides, homicides, and incarceration, among others.[11][12][13][14]

Examples of drug and behavioral addictions include alcoholism, marijuana addiction, amphetamine addiction, cocaine addiction, nicotine addiction, opioid addiction, food addiction, video game addiction, gambling addiction, and sexual addiction. The only behavioral addiction recognized by the DSM-5 and the ICD-10 is gambling addiction. With the introduction of the ICD-11 gaming addiction was appended.[15] The term addiction is misused frequently to refer to other compulsive behaviors or disorders, particularly dependence, in news media.[16] 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.[17] Addiction is the compulsive use of a substance or performance of a behavior that is independent of withdrawal. Addiction can occur in the absence of dependence, and dependence can occur in the absence of addiction, although the two often occur together.


Behavioral addiction

An addictive behavior is a behavior, or a stimulus related to a behavior (e.g., sex or food), that is both rewarding and reinforcing, and is associated with the development of an addiction. Addictions involving addictive behaviors are normally referred to as behavioral addictions.

The term behavioral addiction 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.[5][18][19] 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 addiction.[18][20][21][22]

Reviews of both clinical research in humans and preclinical studies involving ΔFosB have identified compulsive sexual activity – specifically, any form of sexual intercourse – as an addiction (i.e., sexual addiction).[18][20] 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;[18][20][21][22] ΔFosB expression is required for this cross-sensitization effect, which intensifies with the level of ΔFosB expression.[18][21][22]

Reviews of preclinical studies indicate that long-term frequent and excessive consumption of high fat or sugar foods can produce an addiction (food addiction).[18][19]

Gambling provides 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".[18] In order for a person's gambling behavior to meet criteria of an addiction, it shows certain characteristics, such as mood modification, compulsivity, and withdrawal. There is evidence from functional neuroimaging that gambling activates the reward system and the mesolimbic pathway in particular.[18][23] Similarly, shopping and playing video games are associated with compulsive behaviors in humans and have also been shown to activate the mesolimbic pathway and other parts of the reward system.[18] Based upon this evidence, gambling addiction, video game addiction, and shopping addiction are classified accordingly.[18][23]

Risk factors

There are a number of genetic and environmental risk factors for developing an addiction, that vary across the population.[1][24] Genetic and environmental risk factors each account for roughly half of an individual's risk for developing an addiction;[1] the contribution from epigenetic risk factors to the total risk is unknown.[24] Even in individuals with a relatively low genetic risk, exposure to sufficiently high doses of an addictive drug for a long period of time (e.g., weeks–months) can result in an addiction.[1]

Genetic factors

See also: Alcoholism#Genetic variation

It has long been established that genetic factors along with environmental (e.g., psychosocial) factors are significant contributors to addiction vulnerability.[1][24] Epidemiological studies estimate that genetic factors account for 40–60% of the risk factors for alcoholism.[25] Similar rates of heritability for other types of drug addiction have been indicated by other studies.[26] 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 genotype.[26]

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 the disease.[27]

Genome-wide association studies (GWAS) 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.[28]

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.[29] Cross addiction is when already has a predisposed addiction and then starts to become addicted to something different. If one family member has a history of addiction, the chances of a relative or close family developing those same habits are much higher than one who has not been introduced to addiction at a young age.[30] In a recent study done by the National Institute on Drug Abuse, from 2002 to 2017, overdose deaths have almost tripled amongst male and females. In 2017, 72,306 overdose deaths happened in the U.S. that were reported.[31]

Environmental factors

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 his or her vulnerability to addiction.[1] A number of different environmental factors have been implicated as risk factors for addiction, including various psychosocial stressors;[1] however, an individual's exposure to an addictive drug is by far the most significant environmental risk factor for addiction.[1] The National Institute on Drug Abuse (NIDA) 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.[32]

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.[33] 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.[33] 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.[34] This pathway towards addiction that is opened through stressful experiences during childhood can be avoided by a change in environmental factors throughout an individual's life and opportunities of professional help.[34] If one has friends or peers who engage in drug use favorably, the chances of them developing an addiction increases. Family conflict and home management is also a cause for one to become engaged in alcohol or other drug use.[35]

Age

Adolescence represents a period of unique vulnerability for developing an addiction.[36] 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.[37] 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.[38][39]

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 21.[40]

Most individuals are exposed to and use addictive drugs for the first time during their teenage years.[41] In the United States, there were just over 2.8 million new users of illicit drugs in 2013 (~7,800 new users per day);[41] among them, 54.1% were under 18 years of age.[41] In 2011, there were approximately 20.6 million people in the United States over the age of 12 with an addiction.[42] Over 90% of those with an addiction began drinking, smoking or using illicit drugs before the age of 18.[42]

Comorbid disorders

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.[43][44][45] The NIDA cites early aggressive behavior as a risk factor for substance use.[32] A study by the National Bureau of Economic Research found that there is a "definite connection between mental illness and the use of addictive substances" and a majority of mental health patients participate in the use of these substances: 38% alcohol, 44% cocaine, and 40% cigarettes.[46]

Epigenetic factors

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;[24] they also serve as the mechanism responsible for transgenerational epigenetic inheritance, 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 environmental stimuli).[24] In addiction, epigenetic mechanisms play a central role in the pathophysiology of the disease;[1] 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).[24][47]

The general classes of epigenetic alterations that have been implicated in transgenerational epigenetic inheritance include DNA methylation, histone modifications, and downregulation or upregulation of microRNAs.[24] With respect to addiction, more research is needed to determine the specific heritable epigenetic alterations that arise from various forms of addiction in humans and the corresponding behavioral phenotypes from these epigenetic alterations that occur in human offspring.[24][47] Based upon preclinical evidence from animal research, certain addiction-induced epigenetic alterations in rats can be transmitted from parent to offspring and produce behavioral phenotypes that decrease the offspring's risk of developing an addiction.[note 1][24] More generally, the heritable behavioral phenotypes that are derived from addiction-induced epigenetic alterations and transmitted from parent to offspring may serve to either increase or decrease the offspring's risk of developing an addiction.[24][47]

Mechanisms

Addiction is a disorder of the brain's reward system which arises through transcriptional and epigenetic mechanisms and develops over time from chronically high levels of exposure to an addictive stimulus (e.g., eating food, the use of cocaine, engagement in sexual activity, participation in high-thrill cultural activities such as gambling, etc.).[1][48][18] DeltaFosB (ΔFosB), a gene transcription factor, is a critical component and common factor in the development of virtually all forms of behavioral and drug addictions.[48][18][49][19] 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 ΔFosB in the D1-type medium spiny neurons of the nucleus accumbens.[1][48][18][49] Due to the causal relationship between ΔFosB expression and addictions, it is used preclinically as an addiction biomarker.[1][48][49] ΔFosB expression in these neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement, while decreasing sensitivity to aversion.[note 2][1][48]


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.[50] Cognitive control, and particularly inhibitory control over behavior, is impaired in both addiction and attention deficit hyperactivity disorder.[51][52] 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.[52] Template:Transcription factor glossary Template:Psychostimulant addiction Chronic addictive drug use causes alterations in gene expression in the mesocorticolimbic projection.[19][53][54] The most important transcription factors that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[19] ΔFosB is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB in the D1-type medium 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.[19] ΔFosB expression in nucleus accumbens D1-type medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion.[note 2][1][48] ΔFosB has been implicated in mediating addictions to many different drugs and drug classes, including alcohol, amphetamine and other substituted amphetamines, cannabinoids, cocaine, methylphenidate, nicotine, opiates, phenylcyclidine, and propofol, among others.[48][19][53][55][56] ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function of ΔFosB and inhibit increases in its expression.[1][19][57] Increases in nucleus accumbens ΔJunD expression (via viral vector-mediated gene transfer) or G9a expression (via pharmacological means) reduces, or with a large increase can even block, many of the neural and behavioral alterations that result from chronic high-dose use of addictive drugs (i.e., the alterations mediated by ΔFosB).[49][19]

ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[19][58] 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 overexpression.[18][19][58] Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards (i.e., behavioral addictions) as well;[19][18][58] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.[58] 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.[18][21][22] 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.[18]

ΔFosB inhibitors (drugs or treatments that oppose its action) may be an effective treatment for addiction and addictive disorders.[59]

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.[60][61] Altered dopamine neurotransmission is frequently observed following the development of an addictive state.[18] 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.[18] 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.[62]

Reward system

Template:Expand section

Mesocorticolimbic pathway

Template:Annotated image 4 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 receptors (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.[63] These neurons also project and release DA into the nucleus accumbens,[64] through the mesolimbic pathway. Virtually all drugs causing drug addiction increase the dopamine release in the mesolimbic pathway,[65] 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).[66] The NAcc is associated with acquiring and eliciting conditioned behaviors, and is involved in the increased sensitivity to drugs as addiction progresses.[63] Overexpression of ΔFosB in the nucleus accumbens is a necessary common factor in essentially all known forms of addiction;[1] ΔFosB is a strong positive modulator of positively reinforced behaviors.[1]
  • The prefrontal cortex, including the anterior cingulate and orbitofrontal cortices,[67] 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.[68] 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.[69]

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.[68]
  • 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.[64]

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.[70] 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.[70][71] Nearly all addictive drugs, directly or indirectly, act upon the brain's reward system by heightening dopaminergic activity.[72]

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.[70]

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.[67]

Reward sensitization

Neural and behavioral effects of validated ΔFosB transcriptional targets in the striatum[48][73]
Target
gene 		Target
expression 		Neural effects Behavioral effects
c-Fos ↓ Molecular switch enabling the chronic
induction of ΔFosB[note 3]		 –
dynorphin ↓
[note 4]		 Template:BullDownregulation of κ-opioid feedback loop Template:BullIncreased drug reward
NF-κB ↑ Template:BullExpansion of NAcc dendritic processes
Template:BullNF-κB inflammatory response in the NAcc
Template:BullNF-κB inflammatory response in the CP		 Template:BullIncreased drug reward
Template:BullIncreased drug reward
Template:BullLocomotor sensitization
GluR2 ↑ Template:BullDecreased sensitivity to glutamate Template:BullIncreased drug reward
Cdk5 ↑ Template:BullGluR1 synaptic protein phosphorylation
Template:BullExpansion of NAcc dendritic processes		 Decreased drug reward
(net effect)

Reward sensitization is a process that causes an increase in the amount of reward (specifically, incentive salience[note 5]) 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.[75][74][76] 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.[1][48][49]

"Cue-induced wanting" or "cue-triggered wanting", a form of craving that occurs in addiction, is responsible for most of the compulsive behavior that addicts exhibit.[74][76] During the development of an addiction, the repeated association of otherwise neutral and even non-rewarding stimuli with drug consumption triggers an associative learning process that causes these previously neutral stimuli to act as conditioned positive reinforcers of addictive drug use (i.e., these stimuli start to function as drug cues).[74][77][76] As conditioned positive reinforcers of drug use, these previously neutral stimuli are assigned incentive salience (which manifests as a craving) – sometimes at pathologically high levels due to reward sensitization – which can transfer to the primary reinforcer (e.g., the use of an addictive drug) with which it was originally paired.[74][77][76]

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 a bidirectional reward cross-sensitization effect[note 6] that is mediated through ΔFosB.[18][21][22] 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.[1][78][73]

The set of proteins known as "regulators of G protein signaling" (RGS), particularly RGS4 and RGS9-2, have been implicated in modulating some forms of opioid sensitization, including reward sensitization.[79]

Template:Addiction-related plasticity

Neuroepigenetic mechanisms

Template:Expand section Altered epigenetic regulation of gene expression within the brain's reward system plays a significant and complex role in the development of drug addiction.[57][80] Addictive drugs are associated with three types of epigenetic modifications within neurons.[57] These are (1) histone modifications, (2) epigenetic methylation of DNA at CpG sites at (or adjacent to) particular genes, and (3) epigenetic downregulation or upregulation of microRNAs which have particular target genes.[57][19][80] As an example, while hundreds of genes in the cells of the nucleus accumbens (NAc) exhibit histone modifications following drug exposure – particularly, altered acetylation and methylation states of histone residues[80] – most other genes in the NAc cells do not show such changes.[57]

Diagnosis

Further information: Substance use disorder#Diagnosis

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 drug use-related disorders. 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. These specifiers are determined by the number of diagnostic criteria present in a given case. In the DSM-5, the term drug addiction is synonymous with severe substance use disorder.[81][3]

The DSM-5 introduced a new diagnostic category for behavioral addictions; however, problem gambling is the only condition included in that category in the 5th edition.[16] Internet gaming disorder is listed as a "condition requiring further study" in the DSM-5.[82]

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.[83] 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 body aches, anxiety, irritability, intense cravings for the substance, nausea, hallucinations, headaches, cold sweats, tremors, and seizures.

Medical researchers who actively study addiction have criticized the DSM classification of addiction for being flawed and involving arbitrary diagnostic criteria.[17] Writing in 2013, the director of the United States National Institute of Mental Health discussed the invalidity of the DSM-5's classification of mental disorders:[84]

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.

Given that addiction manifests in structural changes to the brain, it is possible that non-invasive neuroimaging scans obtained via MRI could be used to help diagnose addiction in the future.[85] As a diagnostic biomarker, ΔFosB expression could be used to diagnose an addiction in humans, but this would require a brain biopsy and therefore is not used in clinical practice.

Treatment

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."[6]

Behavioral therapy

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.[86]

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.[18][87][88][89][90] 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.[18][88] 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.[90] 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 (decreased DRD2 density).[18][88] Consequently, consistent aerobic exercise may lead to better treatment outcomes when used as an adjunct treatment for drug addiction.[18][88][89]

Medication

Alcohol 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 simultaneously. Benzodiazepines have the largest and the best evidence base in the treatment of alcohol withdrawal and are considered the gold standard of alcohol detoxification.[91]

Pharmacological treatments for alcohol addiction include drugs like naltrexone (opioid antagonist), disulfiram, acamprosate, and topiramate.[92][93] 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.[94][95] 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.[96]

Behavioral addictions

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Cannabinoid addiction

As of 2010, there are no effective pharmacological interventions for cannabinoid addiction.[97] 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.[98]

Nicotine addiction

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.[99][100] Examples of drugs that act on nicotinic receptors and have been used for treating nicotine addiction include antagonists like bupropion and the partial agonist varenicline.[99][100]

Opioid addiction

Further information: 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.[101][102] 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 addicted individual'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,[103] dihydrocodeine,[104] dihydroetorphine[105] and even heroin[106][107] are used as substitute drugs for illegal street opiates, with different prescriptions being given depending on the needs of the individual patient. Baclofen has 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 therapy.[108] Some studies show the interconnection between opioid drug detoxification and overdose mortality.[109]

Psychostimulant addiction

As of May 2014, there is no effective pharmacotherapy for any form of psychostimulant addiction.[6][110][111][112] Reviews from 2015, 2016, and 2018 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[113][114][115] however, as of 2018, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[113][114][115]

Research

Template:Expand section 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;[116] however, current vaccine-based therapies are only effective in a relatively small subset of individuals.[116][117] As of November 2015, vaccine-based therapies are being tested in human clinical trials as a treatment for addiction and preventive measure against drug overdoses involving nicotine, cocaine, and methamphetamine.[116]

The new study shows, that the vaccine may also save lives during a drug overdose. In this instance, the idea is that the body will respond to the vaccine by quickly producing antibodies to prevent the opioids from accessing the brain.[118]

Since addiction involves abnormalities in glutamate and GABAergic neurotransmission,[119][120] receptors associated with these neurotransmitters (e.g., AMPA receptors, NMDA receptors, and GABAB receptors) are potential therapeutic targets for addictions.[119][120][121][122] 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.[119] It may also be useful as an adjunct therapy for addictions to amphetamine-type stimulants, but more clinical research is required.[119]

Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors[note 7] – 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.[49][57][123][80] 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 8] that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates;[57][80][124][125] however, few 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 regimen.[note 9]

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 brain.[127][128][129][130][131]

Epidemiology

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, etc.).[24]

Asia

The prevalence of alcohol dependence is not as high as is seen in other regions. In Asia, not only socioeconomic factors but also biological factors influence drinking behavior.[132]

The overall prevalence of smartphone ownership is 62%, ranging from 41% in China to 84% in South Korea. Moreover, participation in online gaming ranges from 11% in China to 39% in Japan. Hong Kong has the highest number of adolescents reporting daily or above Internet use (68%). Internet addiction disorder is highest in the Philippines, according to both the IAT (Internet Addiction Test) – 5% and the CIAS-R (Revised Chen Internet Addiction Scale) – 21%.[133]

Australia

The prevalence of substance abuse disorder among Australians was reported at 5.1% in 2009.[134]

Europe

In 2015, the estimated prevalence among the adult population was 18.4% for heavy episodic alcohol use (in the past 30 days); 15.2% for daily tobacco smoking; and 3.8, 0.77, 0.37 and 0.35% in 2017 cannabis, amphetamine, opioid and cocaine use. The mortality rates for alcohol and illicit drugs were highest in Eastern Europe.[135]

United States

Based upon representative samples of the US youth population in 2011, the lifetime prevalence[note 10] of addictions to alcohol and illicit drugs has been estimated to be approximately 8% and 2–3% respectively.[12] Based upon representative samples of the US adult population in 2011, the 12 month prevalence of alcohol and illicit drug addictions were estimated at roughly 12% and 2–3% respectively.[12] The lifetime prevalence of prescription drug addictions is currently around 4.7%.[136]

As of 2016 about 22 million people in the United States need treatment for an addiction to alcohol, nicotine, or other drugs.[13][137] 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.[13][137] 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.[13][137] 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.[13][137]

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.[18] 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.[20]

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.[138]

In 2019, opioid addiction was acknowledged as a national crisis in the United States.[139] A Washington Post article stated that "America’s largest drug companies flooded the country with pain pills from 2006 through 2012, even when it became apparent that they were fueling addiction and overdoses."

South America

The realities of opioid use and abuse in Latin America may be deceptive if observations are limited to epidemiological findings. In the United Nations Office on Drugs and Crime report,[140] although South America produced 3% of the world's morphine and heroin and 0.01% of its opium, prevalence of use is uneven. According to the Inter-American Commission on Drug Abuse Control, consumption of heroin is low in most Latin American countries, although Colombia is the area's largest opium producer. Mexico, because of its border with the United States, has the highest incidence of use.[141]

Personality theories

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. Data analysis demonstrates that there is a significant difference in the psychological profiles of drug users and non-users and the psychological predisposition to using different drugs may be different.[142] 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 impulsiveness.[143][144][145][146][147]

Notes

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 Cite error: Invalid <ref> tag; no text was provided for refs named Cellular basis
  2. ↑ 2.0 2.1 Cite error: Invalid <ref> tag; no text was provided for refs named Nestler Labs Glossary
  3. ↑ 3.0 3.1 Cite error: Invalid <ref> tag; no text was provided for refs named Brain disease
  4. ↑ (October 2008) The disease of addiction: origins, treatment, and recovery. Disease-a-Month 54 (10): 696–721.
  5. ↑ 5.0 5.1 (2009) "Chapter 15: Reinforcement and Addictive Disorders", Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2nd, New York: McGraw-Hill Medical, 364–65, 375. ISBN 978-0-07-148127-4. “The defining feature of addiction is compulsive, out-of-control drug use, despite negative consequences. ...
    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 dopamine system.”     
  6. ↑ 6.0 6.1 6.2 6.3 (February 2013) The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans. Subst. Abuse Rehabil. 4: 29–43.
  7. ↑ [1][2][3][4][5][6]
  8. ↑ American Society for Addiction Medicine (2012). Definition of Addiction.
  9. ↑ (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): 1012–14.
  10. ↑ (1988). Addictive behaviors: etiology and treatment. Annu Rev Psychol 39: 223–52.
  11. ↑ 11.0 11.1 (2009) "Chapter 1: Basic Principles of Neuropharmacology", Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2nd, New York: McGraw-Hill Medical. ISBN 978-0-07-148127-4. “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.” 
  12. ↑ 12.0 12.1 12.2 12.3 (June 2012) Epidemiology of Substance Use Disorders. Hum. Genet. 131 (6): 779–89.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 American Board of Medical Specialties recognizes the new subspecialty of addiction medicine (14 March 2016). Retrieved 3 April 2016.
  14. ↑ (2013) "Economic consequences of drug abuse", International Narcotics Control Board Report: 2013. United Nations – International Narcotics Control Board. ISBN 978-92-1-148274-4. Retrieved 28 September 2018. 
  15. ↑ Meredith E. Gansner, M. D. (2019-09-12). Gaming Addiction in ICD-11: Issues and Implications (in en).
  16. ↑ 16.0 16.1 American Psychiatric Association (2013). Substance-Related and Addictive Disorders pp. 1–2. American Psychiatric Publishing. Archived from the original on 15 August 2015. Retrieved 10 July 2015.
  17. ↑ 17.0 17.1 (2015) "Chapter 16: Reinforcement and Addictive Disorders", Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3rd, New York: McGraw-Hill Medical. ISBN 978-0-07-182770-6. “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.” 
  18. ↑ 18.00 18.01 18.02 18.03 18.04 18.05 18.06 18.07 18.08 18.09 18.10 18.11 18.12 18.13 18.14 18.15 18.16 18.17 18.18 18.19 18.20 18.21 18.22 18.23 18.24 Olsen CM (December 2011). Natural rewards, neuroplasticity, and non-drug addictions. Neuropharmacology 61 (7): 1109–22.
    Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers"
  19. ↑ 19.00 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 19.12 (November 2011) Transcriptional and epigenetic mechanisms of addiction. Nat. Rev. Neurosci. 12 (11): 623–37.
  20. ↑ 20.0 20.1 20.2 20.3 (2014). Sexual addiction or hypersexual disorder: different terms for the same problem? A review of the literature. Curr. Pharm. Des. 20 (25): 4012–20.
  21. ↑ 21.0 21.1 21.2 21.3 21.4 (February 2013) Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator. The Journal of Neuroscience 33 (8): 3434–42.
  22. ↑ 22.0 22.1 22.2 22.3 22.4 (February 2016) Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats. Neuropharmacology 101: 154–64.
  23. ↑ 23.0 23.1 Cite error: Invalid <ref> tag; no text was provided for refs named Behavioral addictions
  24. ↑ 24.00 24.01 24.02 24.03 24.04 24.05 24.06 24.07 24.08 24.09 24.10 24.11 24.12 24.13 24.14 24.15 (2014). Mechanisms of transgenerational inheritance of addictive-like behaviors. Neuroscience 264: 198–206.
  25. ↑ Mayfield RD, Harris RA,1, Schuckit MA (May 2008) "Genetic factors influencing alcohol dependence" PMID 18362899
  26. ↑ 26.0 26.1 (May 1994) A twin-family study of alcoholism in women. Am J Psychiatry 151 (5): 707–15.
  27. ↑ (2013). Low frequency genetic variants in the μ-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine. Neuroscience Letters 542: 71–75.
  28. ↑ (December 2013) Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong?. Pharmacology & Therapeutics 140 (3): 267–79.
  29. ↑ Genetics of alcoholism. Alcohol Health and Research World: 1–11.
  30. ↑ Life, Dr. Steven Melemis, I Want to Change My, "The Genetics of Addiction – Is Addiction a Disease?", I Want to Change My Life.
  31. ↑ Abuse, National Institute on Drug, "Overdose Death Rates", 9 August 2018.
  32. ↑ 32.0 32.1 Abuse, National Institute on Drug, "What are risk factors and protective factors?".
  33. ↑ 33.0 33.1 Adverse Childhood Experiences. Substance Abuse and Mental Health Services Administration. Retrieved 26 September 2016.
  34. ↑ 34.0 34.1 (2011). The role of early life stress as a predictor for alcohol and drug dependence. Psychopharmacology 214 (1): 17–31.
  35. ↑ Environmental Risk Factors.
  36. ↑ (June 2000) The adolescent brain and age-related behavioral manifestations. Neuroscience and Biobehavioral Reviews 24 (4): 417–63.
  37. ↑ (April 2014) Neurobiology of adolescent substance use and addictive behaviors: treatment implications. Adolescent Medicine 25 (1): 15–32.
  38. ↑ (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.
  39. ↑ (November 2008) Practitioner review: adolescent alcohol use disorders: assessment and treatment issues. Journal of Child Psychology and Psychiatry, and Allied Disciplines 49 (11): 1131–54.
  40. ↑ Age and Substance Abuse – Alcohol Rehab.
  41. ↑ 42.0 42.1 "Addiction Statistics – Facts on Drug and Alcohol Addiction", AddictionCenter.
  42. ↑ SAMHSA. Risk and Protective Factors. Substance Abuse and Mental Health Administration.
  43. ↑ Infographic – Risk Factors of Addiction | Recovery Research Institute.
  44. ↑ Drug addiction Risk factors – Mayo Clinic.
  45. ↑ "The Connection Between Mental Illness and Substance Abuse | Dual Diagnosis", Dual Diagnosis.
  46. ↑ 47.0 47.1 47.2 (2015). Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism. Mol. Neurobiol. 53 (9): 6367–76.
  47. ↑ 48.0 48.1 48.2 48.3 48.4 48.5 48.6 48.7 48.8 48.9 Ruffle JK (November 2014). Molecular neurobiology of addiction: what's all the (Δ)FosB about?. Am. J. Drug Alcohol Abuse 40 (6): 428–37.
  48. ↑ 49.0 49.1 49.2 49.3 49.4 49.5 (2012). Epigenetic regulation in drug addiction. Ann. Agric. Environ. Med. 19 (3): 491–96.
  49. ↑ (2016). The Stroop effect at 80: The competition between stimulus control and cognitive control. J Exp Anal Behav 105 (1): 3–13.
  50. ↑ Diamond A (2013). Executive functions. Annu Rev Psychol 64: 135–68.
  51. ↑ 52.0 52.1 (2009) "Chapter 13: Higher Cognitive Function and Behavioral Control", Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2nd, New York: McGraw-Hill Medical, 313–21. ISBN 978-0-07-148127-4. “Template:Bull Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.
    Template:Bull 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.”     
  52. ↑ 53.0 53.1 (2006). Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29: 565–98.
  53. ↑ (January 2013) Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants. Prog. Neurobiol. 100: 60–80.
  54. ↑ Kanehisa Laboratories (2 August 2013). Alcoholism – Homo sapiens (human). KEGG Pathway. Retrieved 10 April 2014.
  55. ↑ (February 2009) Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens. Proc. Natl. Acad. Sci. USA 106 (8): 2915–20.
  56. ↑ 57.0 57.1 57.2 57.3 57.4 57.5 57.6 57.7 (January 2014) Epigenetic mechanisms of drug addiction. Neuropharmacology 76 Pt B: 259–68.
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  58. ↑ (2009) "Chapter 15: Reinforcement and addictive disorders", Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2nd, New York: McGraw-Hill Medical, 384–85. ISBN 978-0-07-148127-4. 
  59. ↑ Salamone, J.D. (1992). Complex motor and sensorimotor function of striatal and accumbens dopamine: Involvement in instrumental behavior processes. Psychopharmacology 107 (2–3): 160–74.
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  63. ↑ 64.0 64.1 (2006). Opiates, psychostimulants, and adult hippocampal neurogenesis: Insights for addiction and stem cell biology. Hippocampus 16 (3): 271–86.
  64. ↑ Rang, H.P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4. 
  65. ↑ (2007). Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens. J. Neurosci. 27 (30): 7921–28.
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  68. ↑ (October 2014) Role of cues and contexts on drug-seeking behaviour. British Journal of Pharmacology 171 (20): 4636–72.
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    Table 3
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  74. ↑ 75.0 75.1 (2009) Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2nd, New York: McGraw-Hill Medical, 147–48, 366–67, 375–76. 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 contact. 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 partner. ...
    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.”     
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