Addiction

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For other uses, see Addiction (disambiguation).
Addiction glossary
addiction – a state characterized by compulsive engagement in rewarding behavior or compulsive drug use, despite adverse consequences
reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached.
addictive drug – a drug that is both rewarding and reinforcing
addictive behavior – a behavior that is both rewarding and reinforcing
sensitization - an amplified response to a stimulus resulting from repeated exposure to it
drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
drug dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated drug intake
physical dependence – dependence that involves physical–somatic withdrawal symptoms (e.g., fatigue)
psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
(edit | history)

Addiction is a state defined by compulsive engagement in naturally rewarding behavior or compulsive drug use, despite adverse consequences;[4] it can be thought of as a disease or biological process leading to such behaviors.[6]

According to many addiction specialists, potential non-drug addictions can include, but are not limited to, exercise addiction, food addiction, computer addiction and gambling. Currently, only substance addictions and gambling addiction are recognized by the DSM-5. ΔFosB, a gene transcription factor, is now known to be a critical component and common factor in the development of virtually all forms of behavioral and drug addictions.[7][8][9] Classic hallmarks of addiction include impaired control over substances or behavior, preoccupation with substance or behavior, continued use despite consequences, and denial.[10] Habits and patterns associated with addiction are typically characterized by immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs).[11]

Physiological dependence occurs when the body has to adjust to the substance by incorporating the substance into its "normal" functioning.[12] This state creates the conditions of tolerance and withdrawal. 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 tremors.

Substance dependence[edit]

Main article: Substance dependence

Substance dependence can be diagnosed with physiological dependence, evidence of tolerance or withdrawal, or without physiological dependence. DSM-5 substance dependencies include:

Forms of dependence that are not mentioned in DSM-5 include:

Withdrawal[edit]

Main article: Drug withdrawal

Withdrawal is the body's reaction to abstaining from an addictive substance of which it has become dependant and tolerant. Without the substance, physiological functions that were dependent on the substance will react because of the body's tolerance and dependence of the substance. Chemical and hormonal imbalances may arise if the substance is not introduced. Physiological and psychological stress is to be expected if the substance is not re-introduced.

Recovery and interventions[edit]

In addition to the traditional behavioral self-help groups and programs available for rehabilitation, there is a varied array of preventive and therapeutic approaches to combating addiction. For example, a common treatment option for opiate addiction is methadone maintenance. This process consists of administering the drug, a potent opiate with some potential for abuse, as a drink in a supervised clinical setting. In this way, the brain opiate levels increase slowly without producing the high but remain in the system long enough to deter addicts from injecting heroin.

Another form of drug therapy involves buprenorphine, a drug which seems to be even more promising than methadone.[13] A partial agonist for certain opiate receptors, this treatment blocks the effects of opiates but produces only mild reactions itself. Moreover, this method of detoxification has little value in the drug market.

New research indicates that it may even be possible to develop antibodies which combat a particular drug's effect on the brain, rendering the pleasurable effects null. Recently, vaccines have been developed against cocaine, heroin, methamphetamine, and nicotine. These advances are already being tested in human clinical trials and show serious promise as a preventive and recovery measure for addicts or those prone to addiction.[14][15]

Furthermore, another method of treatment for addiction that is being studied is deep brain stimulation. A serious procedure, DBS targets several brain regions including the nucleus accumbens, subthalamic nucleus, dorsal striatum, and medial prefrontal cortex among others.[16] Other studies have concurred and demonstrated that stimulation of the nucleus accumbens, an area that is apparently one of the most promising regions, allowed a seventy-year-old man to stop smoking without issue and attain a normal weight.[17]

Behavioral addiction[edit]

The term addiction is also sometimes applied to compulsions that are not substance-related, such as compulsive shopping, sex addiction/compulsive sex, overeating, problem gambling, exercise/sport, compulsive or binge travel, and computer addiction.[3][9] In these kinds of common usages, the term addiction is used to describe a recurring compulsion by an individual to engage in some rewarding activity, despite harmful consequences, as deemed by the user themselves to their individual health, mental state, or social life.[9]

Biomolecular mechanisms[edit]

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction

The signaling cascade involved in psychostimulant addiction
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, methylphenidate, phenethylamine, and cocaine. Following presynaptic dopamine and glutamate co-release by such psychostimulants, postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[18][19] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-fos gene with the help of corepressors.[19] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated exposure to stimulants through this process.[20][21] 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 addictive state.[20][21]
Part of this section is transcluded from FOSB. (edit | history)

Current models of addiction from chronic addictive drug use involve alterations in gene expression in the mesocorticolimbic projection.[7][22][23] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB).[7] ΔFosB is the most significant gene transcription factor in addiction since its viral or genetic overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction;[7] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, opiates, and substituted amphetamines.[7][22][24] ΔJunD is the transcription factor which directly opposes ΔFosB.[7] Increases in nucleus accumbens ΔJunD expression using viral vectors (a genetically engineered virus) can reduce or, with a large increase, even block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[7]

ΔFosB also plays an important role in regulating behavioral responses to natural (non-drug) rewards, such as palatable food, sex, and exercise.[7][8] 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.[7][8][9] Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards (i.e., behavioral addictions) as well;[7][8][9] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.[8] 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.[25][9] 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.[9]

ΔFosB inhibitors (drugs or treatments that oppose its action) may be an effective treatment for addiction and addictive disorders.[26]

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.[27][28] Altered dopamine neurotransmission is frequently observed following the development of an addictive state.[9] In humans and lab animals that have developed an addiction, alterations in dopamine or opiate neurotransmission in the nucleus accumbens and other parts of the striatum are evident.[9] Studies have found that use of certain drugs (e.g., nicotine) affect cholinergic neurons that innervate the reward system, in turn affecting dopamine signaling in this region.[29]

Summary of addiction-related plasticity
Form of neural or behavioral plasticityType of reinforcerSources
OpiatesPsychostimulantsHigh fat or sugar foodSexual rewardExerciseEnvironmental enrichment
ΔFosB expression
in the nucleus accumbens
[9]
Behavioral Plasticity
Escalation of intakeYesYesYes[9]
Psychostimulant
cross-sensitization
YesNot applicableYesYesAttenuatedAttenuated[9]
Psychostimulant
self-administration
[9]
Psychostimulant
conditioned place preference
[9]
Reinstatement of drug-seeking behavior[9]
Neurochemical Plasticity
CREB phosphorylation
in the nucleus accumbens
[9]
Sensitized dopamine response
in the nucleus accumbens
NoYesNoYes[9]
Altered striatal dopamine signalingDRD2, ↑DRD3DRD1, ↓DRD2, ↑DRD3DRD1, ↓DRD2, ↑DRD3DRD2DRD2[9]
Altered striatal opioid signalingμ-opioid receptorsμ-opioid receptors
κ-opioid receptors
μ-opioid receptorsμ-opioid receptorsNo changeNo change[9]
Changes in striatal opioid peptidesdynorphindynorphinenkephalindynorphindynorphin[9]
Mesocorticolimbic Synaptic Plasticity
Number of dendrites in the nucleus accumbens[9]
Dendritic spine density in
the nucleus accumbens
No change[9]

Personality theories of addiction[edit]

Role of affect dysregulation in addiction[edit]

Research has consistently shown strong associations between affective disorders and substance use disorders. Specifically, people with mood disorders are at increased risk of substance use disorders.[30] Affect and addiction can be related in a variety of ways as they play a crucial role in influencing motivated behaviours. For instance, affect facilitates action, directs attention, prepares the individual for a physical response, and guides behaviour to meet particular needs.[31] Moreover, affect is implicated in a range of concepts relevant to addiction: negative reinforcement and positive reinforcement, behaviour motivation, regulation of cognition and mood, and reasoning and decision making.[32][33] Emotion-motivated reasoning has been shown to influence addictive behaviours via selecting outcomes that minimize negative affective states while maximizing positive affective states.[34]

Negative affect[edit]

The relationship between negative affect and substance use disorders has been the most widely studied model of addiction. It proposes that individuals who experience the greatest levels of negative affect are at the greatest risk of using substances or behaviours as a coping (psychology) mechanism.[35][36] Here, substances and behaviours are used to improve mood and distract from unpleasant feelings. Once physical dependence has been established, substance abuse is primarily motivated by a desire to avoid negative affective states associated with withdrawal. Individuals high in affective mood disorders (anxiety) most commonly report high levels of negative affect associated with cravings.[37][38][39] The relationship between negative affect and addiction is not unidirectional. That is, while positive affect increases the likelihood of initiation of substance use, the negative affective states produced by withdrawal are the most commonly reported factors for continued use.[30]

Key to this concept is the Hedonic Hypothesis, which states that individuals initiate use of the substance or behaviour for their pleasurable effects, but then take it compulsively to avoid withdrawal symptoms, resulting in dependence.[40] Based on this hypothesis, some researchers believe that individuals engaging in risky use of substances or behaviours may be over-responsing to negative stimuli, which leads to addiction.

Negative affect has also been a powerful predictor in terms of vulnerability to addiction in adolescents. High-risk adolescents have been found to be highly reactive to negative stimuli, which increases their motivation to engage in substance use following a negative emotion-arousing situation.[41] Moreover, it has been established that adolescents high in negative affect are at increased risk for moving from recreational use to problematic use despite a family history of addiction.[41]

Furthermore, the trait negative urgency, the propensity to engage in risky behaviour in response to distress, is highly predictive of certain aspects of substance abuse in adolescents.[42] Early individual differences in emotional differences in reactivity and regulation underlie the later emergence of the trait 'negative urgency'.[43]

Positive affect[edit]

Unlike negative affect, positive affect is related to addiction in both high and low forms. For example, individuals high in positive affect are more likely to engage in risky behaviour, such as drug use. Individuals with high positive affect in response to use are more likely to seek out substances for hedonic reasons. Conversely, low positive affect may prompt initial use due to lack of responsiveness to natural rewards.[30]

Extensive personality research has been done that links positive emotional states to individual differences in risky behaviour.[30] The trait positive urgency, defined as the tendency to engage in risky behaviour under conditions of extreme positive affect, is predictive of substance or behavioural problems that lead to addiction.[44] This trait represents an underlying dysregulation in response to extreme affective states and has a direct impact on behaviour. The trait 'positive urgency' has been shown to have a predictive relationship with increases in drinking quantity and alcohol-related problems in college, as well as drug use in college.[42][45] Furthermore, this trait provides important information on how positive affect can increase the likelihood of engaging in substance abuse.

Another important factor to consider is the individual differences in the experience of pleasurable effects brought on by the substance or behaviour. It is reasoned that certain individuals may be more sensitive to the pleasurable effects and thus experience them with greater intensity, resulting in addiction.[30] For example, over-responsiveness to substance affects has been found in cocaine addicts - an increased response to methylphenidate in the brain regions associated with emotional reactivity and mood.[46][47][48] Thus, strong emotional responses that addicted individuals show in response to substances or behaviours might be results of enhanced sensitivity to their effects.

Individuals differ in the way by which they metabolize substances, such as alcohol; these positive reinforcing effects are partly predetermined.[30] Individual reactivity to the effects of substances may affect motivation to use. For example, if a person experiences strong positive (and weak negative) effects from a substance, due to their biochemical profile, their expectations of the positive effects from the substance will be heightened, therefore increasing their desire for continued use, resulting in dependence.[30] According to this model, the experience of the positive mood enhances implicit attention to substance cues and implicit associations between reward and substance use.[49]

Interestingly, many addicts report symptoms of anhedonia (i.e., the inability to experience pleasure).[50] Results of chronic deviation of the brain's reward set point, which follow a prolonged intoxication, diminish responsiveness to natural positive stimuli. This may result in an over-responsiveness to substance-related cues, coupled with an impaired capacity to initiate behaviours in response to natural rewards.[51] Thus, low positive affect inhibits the individual's ability to replace drug-taking with other rewarding activities. It has also been proposed that during substance dependence the somatic states that guide decision-making are weakened in relation to natural rewards, while at the same time they enhance the emotional response to drug-related stimuli.[52]

Compulsive behaviours characterized by addiction are underpinned by two interacting systems: (a) impulsivity, and (b) reflection. Impulsivity is responsible for the rapid signalling of the affective importance of a stimuli. Reflection cognitively evaluates the signal before altering the behavioural response. Dysfunction in impulsivity exaggerates the emotional impact of the drug-related stimuli and attenuates the impact of natural reinforcement.[30] Dysregulation in reflection results in the inability to override impulsivity, thus resulting in addiction.[30] Under-responsiveness to naturally occurring positive stimuli is a crucial element that biases the individual towards the use of substances or behaviours and away from non-drug alternatives.

Effortful control[edit]

Temperamental effortful control is defined as the ability to suppress a dominant response in order to perform a subdominant response.[53] In other words, it is the degree of control the individual has over impulses and emotions, which includes the ability to focus or shift attention. Temperamental effortful control can influence addiction in a number of ways.

Low levels of effortful control can render the individual less able to distract themselves from unpleasant feelings or overcome strong affective impulses, resulting in maladaptive responses to distress - such as continued substance use.[30] Low effortful control may also interact with negative and positive affect, predisposing individuals to substance or behavioural use, and impair their ability to control use.[30]

A general inability to control affective states may impair the conditioning of behaviour associated with rewards and punishment, may increase susceptibility to biasing by substance-related cues, and could tax self-regulatory capacity.[30] Such conditions may render individuals unable to interrupt automatic drug-seeking behaviours. Abnormal levels of positive and negative affect can be increased by low effortful control.[54][55] For example, high positive affect may interact with low effortful control in increasing risk of addiction amongst vulnerable populations.

Gray's reinforcement sensitivity theory[edit]

Gray's Reinforcement sensitivity theory (RST) consists of two motivational systems: the Behaviour Inhibition System (BIS) and the Behaviour Activation System (BAS).[56][57] The BIS is responsible for organizing behaviour in response to adverse stimuli. In other words, stimuli associated with punishment or the omission/termination of reward, are believed to underlie anxiety. The purpose of the BIS is to initiate behaviour inhibition, or interrupt ongoing behaviour, while the BAS is sensitive to stimuli that signal reward and/or relief from punishment (impusivity).[56][57] In accordance with the RST, an association was found between people with extreme scores in BIS/BAS and adjustment problems. BIS and BAS reactivity correspond with individual trait differences in positive affect and negative affect - The BAS is associated with trait impulsivity and positive affect, while the BIS is associated with trait negative affect.[58][59] For instance, it has been postulated that high BIS is related to anxiety, while high BAS is related to conduct disorders or impulsivity.[57][60]

According to this model substance abuse problems may arise under two different personality traits: low BIS and high BAS. Since the BAS promotes the individual to pursue actions that may result in reward, BAS sensitivity is involved in the initiation of addiction. Significant associations have been found between high BAS such as alcohol misuse in school girls, hazardous drinking in men, illicit drug abuse, and tobacco use. BAS sensitivity is a significant predictor of reactivity to substance cues, or cravings.[61][62][63][64][65][66][67][68] Conversely, BIS sensitivity is involved in avoiding negative situations or affect (such as withdrawal). Low BIS has been positively associated with continuing the addiction to relieve feelings of withdrawal, or for continued use to alleviate negative affect.

Model of impulsivity[edit]

The model of impulsivity states that individuals high in impulsivity are at greater risk of addictive behaviours. The model proposes a two dimensional trait characteristic for the initiation and continuation of substance/behavioural abuse:

Both high RD and RI individuals are found to have difficulty in making decisions that have future consequences. Individuals high in RD experience greater reinforcement when initially engaging in the addictive behaviour, and experience stronger conditioned associations with continued use. Individuals high in RI experience greater difficulty resisting cravings even in the face of negative consequences.[69] Some moderators of RD and RI on the severity of addiction are stress and negative affect (such as feeling depressed).[70] That is, individuals high in RD/RI who also experience high levels of negative affect or stress, present more severe addictive behaviours. For example, if an individual is experiencing emotional distress, the distress experienced may lessen impulse control if they believe that engaging in addictive behaviour will decrease negative affect. According to this model, adolescents who are high in RI are at greater risk for developing addictions. Interestingly, low RI has been shown to moderate some of the risk of addiction due to family history.[71][72][73][74] High RI for individual without a family history of addiction has been related to poor decision-making.

Cloninger's tri-dimensional personality theory[edit]

Cloninger's Tri-Dimensional Personality Theory states that personality comprises three genetically independent dimensions:[75]

Each personality dimension lies on a spectrum ranging from low to high. For example, individuals high in NS are impulsive, while individual's low in NS are reflective. Interactions between each of these three personality dimensions lead to different responses to novelty, punishment and rewards.[75]

This model was extended to alcohol use disorders proposing that individuals with alcohol use disorders have extreme temperaments (i.e. are very high or very low in NS, HA, and RD).[76] This model proposes that alcoholics can be classified in two groups based on the combinations of their three personality dimensions:[75]

Type I alcoholics have a late onset of alcohol-related problems, experience guilt and fear associated with consumption, lose control once drinking is initiated, engage in alcohol-related antisocial conduct, and rarely exhibit spontaneous alcohol-seeking behaviour.[77] Type I alcoholics are thought to be low in NS and high in HA and RD, exhibiting behaviors that are motionally dependent, rigid, perfectionistic, anxious, quiet, patient, and introverted.[77]

Type II alcoholics have an earlier onset of alcohol-related problems, less ability to abstain from alcohol, more frequent alcohol-related antisocial behaviour, less loss of control once drinking commenced, and less guilt or fear associated with drinking.[77] These individuals are high in NS, and low in HA and RD, which means they may be typically aggressive, impulsive, active, talkative, and impatient.[77]

Criticism of the addiction model[edit]

In the mid-20th century critics of the addiction model, notably Thomas Szasz, claimed that the concept of addiction was not normatively neutral, but inherently included a normative component that was arguably out of place in scientific discourse. Szasz cited, for example, Goodman and Gilman's The Pharmacological Basis of Therapeutics, which defined "drug abuse" as "the use, usually by self-administration, of any drug in a manner that deviates from the approved medical or social patterns within a given culture."[78] In investigating the history of the word "addiction," Szasz found that until the 20th century, the term meant "simply a strong inclination toward certain kinds of conduct, with little or no pejorative meaning attached to it."[79] The Oxford English Dictionary included examples of addiction "to civil affairs" and "to useful reading."[79] Szasz observed that the term transformed over time into a "stigmatizing label" with "pejorative meaning."[80] Szasz drew an analogy between this stigmatization of minority psychopharmacological habits and the stigmatization of minority sexual habits

Just as socially disapproved pharmacological behavior constitutes "drug abuse," and is officially recognized as an illness by a medical profession that is a licensed agency of the state, so socially disapproved sexual behavior constitutes a "perversion" and is also officially recognized as an illness; and so, more generally, socially disapproved personal behavior of any kind constitutes "mental illnesses."[78]

Szasz's views were criticized for failing to account for the effect of physiological dependence.[81]

References[edit]

  1. ^ a b Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin Neurosci 15 (4): 431–43. 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 ΔFosB induction in D1-type NAc 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 [emphasis in original]" 
  2. ^ Angres DH, Bettinardi-Angres K (October 2008). "The disease of addiction: origins, treatment, and recovery". Dis Mon 54 (10): 696–721. doi:10.1016/j.disamonth.2008.07.002. PMID 18790142. 
  3. ^ 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 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."
     
  4. ^ [1][2][3]
  5. ^ American Society for Addiction Medicine (2012). "Definition of Addiction". 
  6. ^ [1][5]
  7. ^ a b c d e f g h i j 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 of 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." 
  8. ^ a b c d e 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 deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB 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, DeltaFosB 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 DeltaFosB 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 DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB 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." 
  9. ^ a b c d e f g h i j k l m n o p q r s t u v Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. "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 in delta 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"
  10. ^ 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. PMID 1501306. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ Vocci, F. J.; J. Acri; A. Elkashef (2005). "A Medication development for addictive disorders: The state of the science". American Journal of Psychiatry (162): 1431–1440. 
  14. ^ Cerny, E. H.; T. Cerny (2009). "Vaccines against nicotine". Human Vaccines (5): 200–205. 
  15. ^ Carroll, F. L.; B.E. Blouch; R.R. Pidaparthi (2011). "Synthesis of mercapto-(+)-methamphetamine haptens and their use for obtaining improved epitope density on (+)-methamphetamine conjugate vaccines". Journal of Medical Chemistry (54): 5221–5228. 
  16. ^ Luigjes, J.; W. van den Brink; M. Feenstra (2011). "Deep brain stimulation in addiction: a review of potential brain targets". Molecular Psychiatry. 
  17. ^ Mantione, M.; W. van den Brink, P.R. Schuurman, D. Denys (2010). "Smoking cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: Therapeutic and research implications: Case report". Neurosurgery (66): E218. 
  18. ^ Kanehisa Laboratories (27 February 2012). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 21 July 2014. 
  19. ^ a b Renthal W, Nestler EJ (2009). "Chromatin regulation in drug addiction and depression". Dialogues Clin. Neurosci. 11 (3): 257–268. PMC 2834246. PMID 19877494. Retrieved 21 July 2014. 
  20. ^ a b 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 serves as one of the master control proteins governing this structural plasticity." 
  21. ^ a b 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 ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB" 
  22. ^ 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. PMID 16776597. 
  23. ^ 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. PMID 23085425. 
  24. ^ Kanehisa Laboratories (2 August 2013). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 10 April 2014. 
  25. ^ 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". J. Neurosci. 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 plasticity" 
  26. ^ 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. ISBN 9780071481274. 
  27. ^ Salamone, J.D. (1992). "Complex motor and sensorimotor function of striatal and accumbens dopamine: Involvement in instrumental behavior processes". Psychopharmacology 107: 160–174. doi:10.1007/bf02245133. 
  28. ^ Kauer, J.A.; R.C. Malenka (2007). "Synaptic plasticity and addiction". Nature Reviews Neuroscience (8): 844–858. doi:10.1038/nrn2234. 
  29. ^ 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. 
  30. ^ a b c d e f g h i j k l Cheetham A, Allen NB, Yücel M, Lubman DI (August 2010). "The role of affective dysregulation in drug addiction". Clin Psychol Rev 30 (6): 621–34. doi:10.1016/j.cpr.2010.04.005. PMID 20546986. 
  31. ^ Gross JJ (September 1998). "The emerging field of emotion regulation: An integrative review". Review of General Psychology 2 (3): 271–299. doi:10.1037/1089-2680.2.3.271. 
  32. ^ Bechara A, Damasio H (2002). "Decision-making and addiction (part I): impaired activation of somatic states in substance dependent individuals when pondering decisions with negative future consequences". Neuropsychologia 40 (10): 1675–89. doi:10.1016/S0028-3932(02)00015-5. PMID 11992656. 
  33. ^ Quirk SW (May 2009). "Emotion concepts in models of substance abuse". Drug and Alcohol Review 20 (1): 95–104. doi:10.1080/09595230125185. 
  34. ^ Westen D, Blagov PS, Harenski K, Kilts C, Hamann S (November 2006). "Neural bases of motivated reasoning: an FMRI study of emotional constraints on partisan political judgment in the 2004 U.S. Presidential election". J Cogn Neurosci 18 (11): 1947–58. doi:10.1162/jocn.2006.18.11.1947. PMID 17069484. 
  35. ^ McCollam JB, Burish TG, Maisto SA, Sobell MB (April 1980). "Alcohol's effects on physiological arousal and self-reported affect and sensations". J Abnorm Psychol 89 (2): 224–33. doi:10.1037/0021-843X.89.2.224. PMID 7365134. 
  36. ^ Measelle JR, Stice E, Springer DW (September 2006). "A prospective test of the negative affect model of substance abuse: moderating effects of social support". Psychol Addict Behav 20 (3): 225–33. doi:10.1037/0893-164X.20.3.225. PMC 1560098. PMID 16938060. 
  37. ^ Childress AR, Ehrman R, McLellan AT, MacRae J, Natale M, O'Brien CP (1994). "Can induced moods trigger drug-related responses in opiate abuse patients?". J Subst Abuse Treat 11 (1): 17–23. doi:10.1016/0740-5472(94)90060-4. PMID 8201629. 
  38. ^ Cooney NL, Litt MD, Morse PA, Bauer LO, Gaupp L (May 1997). "Alcohol cue reactivity, negative-mood reactivity, and relapse in treated alcoholic men". J Abnorm Psychol 106 (2): 243–50. doi:10.1037/0021-843X.106.2.243. PMID 9131844. 
  39. ^ Fox HC, Bergquist KL, Hong KI, Sinha R (March 2007). "Stress-induced and alcohol cue-induced craving in recently abstinent alcohol-dependent individuals". Alcohol. Clin. Exp. Res. 31 (3): 395–403. doi:10.1111/j.1530-0277.2006.00320.x. PMID 17295723. 
  40. ^ Robinson TE, Berridge KC (2003). "Addiction". Annu Rev Psychol 54: 25–53. doi:10.1146/annurev.psych.54.101601.145237. PMID 12185211. 
  41. ^ a b Randall DM, Cox WM (February 2001). "Experimental mood inductions in persons at high and low risk for alcohol problems". Am J Drug Alcohol Abuse 27 (1): 183–7. doi:10.1081/ADA-100103126. PMID 11373034. 
  42. ^ a b Cyders MA, Smith GT, Spillane NS, Fischer S, Annus AM, Peterson C (March 2007). "Integration of impulsivity and positive mood to predict risky behavior: development and validation of a measure of positive urgency". Psychol Assess 19 (1): 107–18. doi:10.1037/1040-3590.19.1.107. PMID 17371126. 
  43. ^ Whiteside SP, Lynam DR (March 2001). "The Five Factor Model and impulsivity: using a structural model of personality to understand impulsivity". Personality and Individual Differences 30 (4): 669–689. doi:10.1016/S0191-8869(00)00064-7. 
  44. ^ Cyders MA, Smith GT (November 2008). "Emotion-based dispositions to rash action: positive and negative urgency". Psychol Bull 134 (6): 807–28. doi:10.1037/a0013341. PMC 2705930. PMID 18954158. 
  45. ^ Zapolski TC, Cyders MA, Smith GT (June 2009). "Positive urgency predicts illegal drug use and risky sexual behavior". Psychol Addict Behav 23 (2): 348–54. doi:10.1037/a0014684. PMC 2709762. PMID 19586152. 
  46. ^ Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Gifford A, Hitzemann R, Ding YS, Pappas N (September 1999). "Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels". Am J Psychiatry 156 (9): 1440–3. PMID 10484959. 
  47. ^ Volkow ND (November 2004). "The reality of comorbidity: depression and drug abuse". Biol. Psychiatry 56 (10): 714–7. doi:10.1016/j.biopsych.2004.07.007. PMID 15556111. 
  48. ^ Volkow ND, Wang GJ, Ma Y, Fowler JS, Wong C, Ding YS, Hitzemann R, Swanson JM, Kalivas P (April 2005). "Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction". J. Neurosci. 25 (15): 3932–9. doi:10.1523/JNEUROSCI.0433-05.2005. PMID 15829645. 
  49. ^ Cox WM, Klinger E (May 1988). "A motivational model of alcohol use". J Abnorm Psychol 97 (2): 168–80. doi:10.1037/0021-843X.97.2.168. PMID 3290306. 
  50. ^ Janiri L, Martinotti G, Dario T, Reina D, Paparello F, Pozzi G, Addolorato G, Di Giannantonio M, De Risio S (2005). "Anhedonia and substance-related symptoms in detoxified substance-dependent subjects: a correlation study". Neuropsychobiology 52 (1): 37–44. doi:10.1159/000086176. PMID 15942262. 
  51. ^ Koob GF, Le Moal M (October 1997). "Drug abuse: hedonic homeostatic dysregulation". Science 278 (5335): 52–8. doi:10.1126/science.278.5335.52. PMID 9311926. 
  52. ^ Bechara A (2003). "Risky business: emotion, decision-making, and addiction". J Gambl Stud 19 (1): 23–51. doi:10.1023/A:1021223113233. PMID 12635539. 
  53. ^ Rothbart MK, Ellis LK, Rueda MR, Posner MI (December 2003). "Developing mechanisms of temperamental effortful control". J Pers 71 (6): 1113–43. doi:10.1111/1467-6494.7106009. PMID 14633060. 
  54. ^ Colder CR, Chassin L (June 1997). "Affectivity and impulsivity: Temperament risk for adolescent alcohol involvement". Psychology of Addictive Behaviors 11 (2): 83–97. doi:10.1037/0893-164X.11.2.83. 
  55. ^ Hussong AM, Chassin L (November 1994). "The stress-negative affect model of adolescent alcohol use: disaggregating negative affect". J. Stud. Alcohol 55 (6): 707–18. PMID 7861800. 
  56. ^ a b Gray JA (August 1970). "The psychophysiological basis of introversion-extraversion". Behav Res Ther 8 (3): 249–66. doi:10.1016/0005-7967(70)90069-0. PMID 5470377. 
  57. ^ a b c McNaughton N, Gray ,JA (2000). The neuropsychology of anxiety: an enquiry into the function of the septo-hippocampal system. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-852270-3. 
  58. ^ Campbell-Sills L, Liverant GI, Brown TA (September 2004). "Psychometric evaluation of the behavioral inhibition/behavioral activation scales in a large sample of outpatients with anxiety and mood disorders". Psychol Assess 16 (3): 244–54. doi:10.1037/1040-3590.16.3.244. PMID 15456380. 
  59. ^ Jorm AR, Christensen H, Henderson AS, Jacomb PA, Korten AE, Rodgers B (January 1998). "Using the BIS/BAS scales to measure behavioural inhibition and behavioural activation: Factor structure, validity and norms in a large community sample". Personality and Individual Differences 26 (1): 49–58. doi:10.1016/S0191-8869(98)00143-3. 
  60. ^ Quay HC (February 1997). "Inhibition and attention deficit hyperactivity disorder". J Abnorm Child Psychol 25 (1): 7–13. doi:10.1023/A:1025799122529. PMID 9093895. 
  61. ^ Franken IHA, Muris P (2006). "BIS/BAS personality characteristics and college students' substance use". Personality and Individual Differences 40 (7): 1497–1503. doi:10.1016/j.paid.2005.12.005. 
  62. ^ Genovese JE, Wallace D (December 2007). "Reward sensitivity and substance abuse in middle school and high school students". J Genet Psychol 168 (4): 465–9. doi:10.3200/GNTP.168.4.465-469. PMID 18232522. 
  63. ^ Kimbrel NA, Nelson-Gray RO, Mitchell JT (April 2007). "Reinforcement sensitivity and maternal style as predictors of psychopathology". Personality and Individual Differences 42 (6): 1139–1149. doi:10.1016/j.paid.2006.06.028. 
  64. ^ Knyazev GG (September 2004). "Behavioural activation as predictor of substance use: mediating and moderating role of attitudes and social relationships". Drug Alcohol Depend 75 (3): 309–21. doi:10.1016/j.drugalcdep.2004.03.007. PMID 15283952. 
  65. ^ Loxton NJ, Dawe S (November 2006). "Reward and punishment sensitivity in dysfunctional eating and hazardous drinking women: associations with family risk". Appetite 47 (3): 361–71. doi:10.1016/j.appet.2006.05.014. PMID 16846665. 
  66. ^ Loxton NJ, Dawe S (April 2007). "How do dysfunctional eating and hazardous drinking women perform on behavioural measures of reward and punishment sensitivity?". Personality and Individual Differences 42 (6): 1163–1172. doi:10.1016/j.paid.2006.09.031. 
  67. ^ O’Connor RM, Stewart SH, Watt MC (March 2009). "Distinguishing BAS risk for university students' drinking, smoking, and gambling behaviors". Personality and Individual Differences 46 (4): 514–519. doi:10.1016/j.paid.2008.12.002. 
  68. ^ Pardo Y, Aguilar R, Molinuevo B, Torrubia R (October 2007). "Alcohol use as a behavioural sign of disinhibition: evidence from J.A. Gray's model of personality". Addict Behav 32 (10): 2398–403. doi:10.1016/j.addbeh.2007.02.010. PMID 17407802. 
  69. ^ a b c Dawe S, Loxton NJ (May 2004). "The role of impulsivity in the development of substance use and eating disorders". Neurosci Biobehav Rev 28 (3): 343–51. doi:10.1016/j.neubiorev.2004.03.007. PMID 15225976. 
  70. ^ Koob GF, Le Moal M (February 2001). "Drug addiction, dysregulation of reward, and allostasis". Neuropsychopharmacology 24 (2): 97–129. doi:10.1016/S0893-133X(00)00195-0. PMID 11120394. 
  71. ^ Brook JS, Kessler RC, Cohen P (1999). "The onset of marijuana use from preadolescence and early adolescence to young adulthood". Dev. Psychopathol. 11 (4): 901–14. doi:10.1017/S0954579499002370. PMID 10624731. 
  72. ^ Lynskey MT, Fergusson DM, Horwood LJ (October 1998). "The origins of the correlations between tobacco, alcohol, and cannabis use during adolescence". J Child Psychol Psychiatry 39 (7): 995–1005. doi:10.1111/1469-7610.00402. PMID 9804032. 
  73. ^ King KM, Chassin L (September 2004). "Mediating and moderated effects of adolescent behavioral undercontrol and parenting in the prediction of drug use disorders in emerging adulthood". Psychol Addict Behav 18 (3): 239–49. doi:10.1037/0893-164X.18.3.239. PMID 15482079. 
  74. ^ Tarter RE, Kirisci L, Habeych M, Reynolds M, Vanyukov M (February 2004). "Neurobehavior disinhibition in childhood predisposes boys to substance use disorder by young adulthood: direct and mediated etiologic pathways". Drug Alcohol Depend 73 (2): 121–32. doi:10.1016/j.drugalcdep.2003.07.004. PMID 14725951. 
  75. ^ a b c Cloninger CR (June 1987). "A systematic method for clinical description and classification of personality variants. A proposal". Arch. Gen. Psychiatry 44 (6): 573–88. doi:10.1001/archpsyc.1987.01800180093014. PMID 3579504. 
  76. ^ Howard MO, Kivlahan D, Walker RD (January 1997). "Cloninger's tridimensional theory of personality and psychopathology: applications to substance use disorders". J. Stud. Alcohol 58 (1): 48–66. PMID 8979213. 
  77. ^ a b c d Cloninger CR (April 1987). "Neurogenetic adaptive mechanisms in alcoholism". Science 236 (4800): 410–6. Bibcode:1987Sci...236..410C. doi:10.1126/science.2882604. PMID 2882604. 
  78. ^ a b Thomas Szasz, Ceremonial Chemistry (1974), p. 9
  79. ^ a b Thomas Szasz, Ceremonial Chemistry (1974), p. 6
  80. ^ Thomas Szasz, Ceremonial Chemistry (1974), p. 7
  81. ^ See, for example, David M. Warburton, Addiction Controversies (1992).
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