|• addiction – a state characterized by compulsive engagement in rewarding stimuli 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|
|• dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)|
|• 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)|
|(edit | history)|
Addiction is a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences. It can be thought of as a disease or biological process leading to such behaviors. The two properties that characterize all addictive stimuli are that they are (positively) reinforcing (i.e., they increase the likelihood that a person will seek repeated exposure to them) and intrinsically rewarding (i.e., they activate the brain's "reward pathways", and are therefore perceived as being something positive or desirable). 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.
Addiction exacts a high toll on individuals and society as a whole through the direct adverse effects of drugs and associated healthcare costs, the functional consequences of altered neuroplasticity in the brain, and the loss of productivity. Classic hallmarks of addiction include impaired control over substances or behavior, preoccupation with substance or behavior, continued use despite consequences, and denial. Habits and patterns associated with addiction are typically characterized by immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs).
Potential addictions can include, but are not limited to, exercise addiction, food addiction, drug addiction, computer addiction, sex addiction, shopping addiction, and gambling addiction. Currently, only substance addictions and gambling addiction are recognized by the DSM-5, which uses physical dependence and the associated withdrawal syndrome to identify an addictive state. Physical dependence occurs when the body has adjusted by incorporating the substance into its "normal" functioning – i.e., attains homeostasis – and therefore physical withdrawal symptoms occur upon cessation of use. Tolerance is the process by which the body continually adapts to the substance and requires increasingly larger amounts to achieve the original effects. Withdrawal refers to physical and psychological symptoms experienced when reducing or discontinuing a substance that the body has become dependent on. Symptoms of withdrawal generally include but are not limited to anxiety, irritability, intense cravings for the substance, nausea, hallucinations, headaches, cold sweats, and tremors.
- 1 Behavioral addiction
- 2 Risk factors
- 3 Biomolecular mechanisms
- 4 DSM diagnosis of addiction
- 5 Addiction treatment and management
- 6 Personality theories of addiction
- 7 References
- 8 Further reading
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, video game addiction, and computer addiction. 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, and social life.
It has long been established that genetic factors along with social and psychological factors are contributors to addiction. A common theory along these lines is the self-medication hypotheses. Epidemiological studies estimate that genetic factors account for 40–60% of the risk factors for alcoholism. Similar rates of heritability for other types of drug addiction have been indicated by other studies. Knestler hypothesized in 1964 that a gene or group of genes might contribute to predisposition to addiction in several ways. For example, altered levels of a normal protein due to environmental factors could then change the structure or functioning of specific brain neurons during development. These altered brain neurons could change the susceptibility of an individual to an initial drug use experience. In support of this hypothesis, animal studies have shown that environmental factors such as stress can affect an animal's genotype.
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. On the other hand, the rare variant hypothesis states that genes with low frequencies in the population (<1%) confer much greater additional risk in the development of disease.
Genome-wide association studies (GWAS) are a recently developed research method which are used to examine genetic associations with dependence, addiction, and drug use. These studies employ an unbiased approach to finding genetic associations with specific phenotypes and give equal weight to all regions of DNA, including those with no ostensible relationship to drug metabolism or response. These studies rarely identify genes from proteins previously described via animal knockout models and candidate gene analysis. Instead, large percentages of genes involved in processes such as cell adhesion are commonly identified. This is not to say that previous findings, or the GWAS findings, are erroneous. The important effects of endophenotypes are typically not capable of being captured by these methods. Furthermore, genes identified in GWAS for drug addiction may be involved either in adjusting brain behavior prior to drug experiences, subsequent to them, or both. 
Current models of addiction from chronic addictive drug use involve alterations in gene expression in the mesocorticolimbic projection. 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). 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; it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, opiates, and substituted amphetamines. ΔJunD is the transcription factor which directly opposes ΔFosB. 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).
ΔFosB also plays an important role in regulating behavioral responses to natural (non-drug) rewards, such as palatable food, sex, and exercise. Natural rewards, like drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression. Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards (i.e., behavioral addictions) as well; in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward. Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional cross-sensitization effects that are mediated through ΔFosB. This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications.
The release of dopamine in the nucleus accumbens plays a role in the reinforcing qualities of many forms of stimuli, including naturally reinforcing stimuli like palatable food and sex. Altered dopamine neurotransmission is frequently observed following the development of an addictive state. In humans and lab animals that have developed an addiction, alterations in dopamine or opiate neurotransmission in the nucleus accumbens and other parts of the striatum are evident. 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.
|Form of neural or behavioral plasticity||Type of reinforcer||Sources|
|Opiates||Psychostimulants||High fat or sugar food||Sexual reward||Physical exercise
|ΔFosB expression in
nucleus accumbens D1-type MSNs
|Escalation of intake||Yes||Yes||Yes|||
conditioned place preference
|Reinstatement of drug-seeking behavior||↑||↑||↓||↓|||
in the nucleus accumbens
|Sensitized dopamine response
in the nucleus accumbens
|Altered striatal dopamine signaling||↓DRD2, ↑DRD3||↑DRD1, ↓DRD2, ↑DRD3||↑DRD1, ↓DRD2, ↑DRD3||↑DRD2||↑DRD2|||
|Altered striatal opioid signaling||↑μ-opioid receptors||↑μ-opioid receptors
|↑μ-opioid receptors||↑μ-opioid receptors||No change||No change|||
|Changes in striatal opioid peptides||↑dynorphin||↑dynorphin||↓enkephalin||↑dynorphin||↑dynorphin|||
|Mesocorticolimbic synaptic plasticity|
|Number of dendrites in the nucleus accumbens||↓||↑||↑|||
|Dendritic spine density in
the nucleus accumbens
Dopamine binds to the D1 receptor, a postsynaptic dopamine receptor, triggering a signaling cascade within the cell. cAMP-dependent protein kinase (protein kinase A) phosphorylates cAMP response element binding protein (CREB), a transcription factor, which induces the transcription of certain genes including c-Fos.
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. These neurons also project and release DA into the nucleus accumbens, through the mesolimbic pathway. Virtually all drugs causing drug addiction increase the dopamine release in the mesolimbic pathway, in addition to their specific effects.
- The nucleus accumbens (NAcc) is one output of the VTA projections. The nucleus accumbens itself consists mainly of GABAergic medium spiny neurons (MSNs). The NAcc is associated with acquiring and eliciting conditioned behaviors, and is involved in the increased sensitivity to drugs as addiction progresses. Overexpression of ΔFosB in the nucleus accumbens is a necessary common factor in essentially all known forms of addiction; ΔFosB is a strong positive modulator of positively reinforced behaviors.
- The prefrontal cortex, more specifically the anterior cingulate and orbitofrontal cortices, is the other VTA output in the mesocorticolimbic pathway; it is important for the integration of information which helps determine whether a behavior will be elicited.
Other brain structures that are involved in addiction include:
- The basolateral amygdala projects into the NAcc and is thought to also be important for motivation.
- The hippocampus is involved in drug addiction, because of its role in learning and memory. Much of this evidence stems from investigations showing that manipulating cells in the hippocampus alters dopamine levels in NAcc and firing rates of VTA dopaminergic cells.
Role of dopamine and glutamate
Dopamine is the primary neurotransmitter of the reward system in the brain. It plays a role in regulating movement, emotion, cognition, motivation, and feelings of pleasure. Natural rewards, like eating, as well as recreational drug use cause a release of DA, and are associated with the reinforcing nature of these stimuli. Nearly all addictive drugs, directly or indirectly, act upon the brain’s reward system by heightening dopaminergic activity.
Excessive intake of many types of addictive drugs results in repeated release of high amounts of DA, which in turn affects the reward pathway directly through heightened dopamine receptor activation. Prolonged and abnormally high levels of DA in the synaptic cleft can induce receptor downregulation in along the neural pathway. Downregulation of mesolimbic DA receptors can result in a decrease in the sensitivity to natural reinforcers.
Drug seeking behavior is induced by glutamatergic projections from the prefrontal cortex to the NAc. 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 NAc.
Sensitization, or reverse tolerance, is the increase in sensitivity to a drug after repeated use. The protein ΔFosB (Delta-FosB) is known to be involved in drug and behavioral sensitization. The ΔFosB transcription factor activates genes that, counter to the effects of CREB, actually increase the user's sensitivity to the effects of the substance. A stable form of ΔFosB slowly builds up with each exposure to the drug and remains activated for 1–2 months after the last exposure—long after the effects of CREB have faded. The hypersensitivity that it causes is thought to be responsible for the intense cravings associated with drug addiction, and is often extended to even the peripheral cues of drug use, such as related behaviors or the sight of drug paraphernalia. There is also very significant evidence that ΔFosB causes behavioral plasticity and structural changes within the nucleus accumbens, which helps to perpetuate cravings and relapses in addicts.
The regulator of G-protein signaling 9-2 (RGS9-2) is also thought to be involved in sensitization. Regulator of G-protein Signaling 9-2 (RGS9-2) has recently been the subject of several animal knockout studies. Animals lacking RGS9-2 appear to have increased sensitivity to dopamine receptor agonists such as cocaine and amphetamines; over-expression of RGS9-2 causes a lack of responsiveness to these same agonists. RGS9-2 is believed to catalyze inactivation of the G-protein coupled D2 receptor by enhancing the rate of GTP hydrolysis of the G alpha subunit which transmits signals into the interior of the cell.
DSM diagnosis of addiction
- 303.90 Alcohol dependence
- 304.00 Opioid dependence
- 304.10 Sedative, hypnotic, or anxiolytic dependence (including benzodiazepine dependence and barbiturate dependence)
- 304.20 Cocaine dependence
- 304.30 Cannabis dependence
- 304.40 Amphetamine dependence (or amphetamine-like)
- 304.50 Hallucinogen dependence
- 304.60 Inhalant dependence
- 304.80 Polysubstance dependence
- 304.90 Phencyclidine (or phencyclidine-like) dependence
- 304.90 Other (or unknown) substance dependence
- 305.10 Nicotine dependence
Forms of dependence that are not mentioned in DSM-5 include:
- Sugar addiction - sucrose, glucose, fructose, etc.
- Information addiction - television, newspaper, Facebook, Twitter, etc.
- Video game addiction - console games, computer games, Handheld game, etc.
- Sexual addiction - sex or sexual activity
Addiction treatment and management
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. 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.
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. 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.
Other forms of treatment include replacement drugs such as suboxone or subutex (both containing the active ingredient buprenorphine) and methadone; these are used as substitutes for illicit opiate drugs. Although these drugs perpetuate physical dependence, the goal of opiate maintenance is to provide a clinically supervised, stable dose of a particular opioid in order to provide a measure of control to both pain and cravings. This provides a chance for the addict to function normally and to reduce the negative consequences associated with obtaining sufficient quantities of controlled substances illicitly, by both reducing opioid cravings and withdrawal symptomology. Once a prescribed dosage is stabilized, treatment enters maintenance or tapering phases. In the United States, opiate replacement therapy is tightly regulated in methadone clinics and under the DATA 2000 legislation. In some countries, other opioid derivatives such as levomethadyl acetate, dihydrocodeine, dihydroetorphine and even heroin are used as substitute drugs for illegal street opiates, with different drugs being used depending on the needs of the individual patient. Baclofen has been shown successful in attenuating cravings for most drugs of abuse – stimulants, ethanol, and opioids – and also attenuates the actual withdrawal syndrome of ethanol. Many patients have stated they "became indifferent to alcohol" or "indifferent to cocaine" overnight after starting baclofen therapy. It is possible that one of the best, albeit relatively unexplored, treatment modalities for opioid addiction – notoriously the most difficult addiction to treat (and to recover from), having relapse rates of around 23% at four weeks and 57% at twelve months if not on maintenance therapy with a mu-opioid agonist – would be to combine an opioid maintenance agent, such as methadone or buprenorphine, to block withdrawal symptomology, with baclofen, to attenuate cravings and the desire to use, in people who find that they are still using or still craving drugs while on methadone or buprenorphine maintenance.
Substitute drugs for other forms of drug addiction have historically been less successful than opioid substitute treatment, but some limited success has been seen with drugs such as dextroamphetamine to treat stimulant addiction, and clomethiazole to treat alcohol addiction. Bromocriptine and desipramine have been reported to be effective for treatment of cocaine but not amphetamine addiction.
Other pharmacological treatments for alcohol addiction include drugs like naltrexone, disulfiram, acamprosate and topiramate, but rather than substituting for alcohol, these drugs are intended to reduce 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. Additional drugs acting on glutamate neurotransmission such as modafinil, lamotrigine, gabapentin and memantine have also been proposed for use in treating addiction to alcohol and other drugs.
Opioid antagonists such as naltrexone and nalmefene have also been used successfully in the treatment of alcohol addiction, which is often particularly challenging to treat. Some have also attempted to use these drugs for maintenance treatment of former opiate addicts with little success. They cannot be started until the patient has been abstinent for an extended period – unlikely with opioid addicts who are not on maintenance with a full or partial mu-opioid agonist – or they will trigger acute opioid withdrawal symptoms. No study has found them to be efficacious treatments in preventing relapse. They do nothing to block craving, and block endorphin and enkephalin, two natural neurotransmitters that regulate one's sense of well-being. An addict must discontinue the drug for just eighteen hours in order to use again.
Treatment of stimulant addiction can often be difficult, with substitute drugs often being ineffective, although newer drugs such as nocaine, vanoxerine and modafinil may have more promise in this area, as well as the GABAB agonist baclofen. Another strategy that has recently been successfully trialled used a combination of the benzodiazepine antagonist flumazenil with hydroxyzine and gabapentin for the treatment of methamphetamine addiction.
Another area in which drug treatment has been widely used is in the treatment of nicotine addiction. Various drugs have been used for this purpose such as bupropion, mecamylamine and the more recently developed varenicline. The cannaboinoid antagonist rimonabant has also been trialled for treatment of nicotine addiction but has not been widely adopted for this purpose.
Ibogaine is a hallucinogen (psychotomimetic) that some claim interrupts addiction and reduces or eliminates withdrawal syndromes, specifically in regards to opioids. Its mechanism of action is unknown, but likely linked to nAchR α3ß4 antagonism. In one animal trial, it was shown to slightly reduce self-administration of cocaine. Another uncontrolled trial showed it reduced tremor by a mild to moderate degree during morphine withdrawal in rats. These finding can not be extrapolated to human beings with any certainty. Research is complicated by the fact that ibogaine is illegal in many developed countries, and a Schedule I substance in the US, and as a result no controlled human trials have ever been performed. A semi-synthetic analogue of ibogaine, 18-methoxycoronaridine was developed, in an attempt to reduce the toxic (ibogaine is significantly cardiotoxic, and several deaths have been reported from its use; because of its illegal, underground nature, it is impossible to know how toxic the drug is) and psychotomimetic effects of the drug.
Personality theories of addiction
Role of affect dysregulation in addiction
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. 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. 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. Emotion-motivated reasoning has been shown to influence addictive behaviours via selecting outcomes that minimize negative affective states while maximizing positive affective states.
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. 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. 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.
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. 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. 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.
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. Early individual differences in emotional differences in reactivity and regulation underlie the later emergence of the trait 'negative urgency'.
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.
Extensive personality research has been done that links positive emotional states to individual differences in risky behaviour. 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. 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. 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. 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. 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. 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. According to this model, the experience of the positive mood enhances implicit attention to substance cues and implicit associations between reward and substance use.
Interestingly, many addicts report symptoms of anhedonia (i.e., the inability to experience pleasure). 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. 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.
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. Dysregulation in reflection results in the inability to override impulsivity, thus resulting in addiction. 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.
Temperamental effortful control is defined as the ability to suppress a dominant response in order to perform a subdominant response. 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. 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.
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. 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. For example, high positive affect may interact with low effortful control in increasing risk of addiction amongst vulnerable populations.
Gray's reinforcement sensitivity theory
Gray's Reinforcement sensitivity theory (RST) consists of two motivational systems: the Behaviour Inhibition System (BIS) and the Behaviour Activation System (BAS). 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). 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. For instance, it has been postulated that high BIS is related to anxiety, while high BAS is related to conduct disorders or impulsivity.
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. 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
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:
- Reward Drive (RD) - reflects individual differences in sensitivities to incentive motivation and engagement of addictive behaviour when reward cues are detected.
- Rash Impulsiveness (RI) - reflecting individual differences in the ability to modify the addictive behaviour due to negative consequences. Individuals high in RI are oblivious or insensitive to the negative consequences as a result of addictive behaviour when engagement is craved.
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. Some moderators of RD and RI on the severity of addiction are stress and negative affect (such as feeling depressed). 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. High RI for individual without a family history of addiction has been related to poor decision-making.
Cloninger's tri-dimensional personality theory
Cloninger's Tri-Dimensional Personality Theory states that personality comprises three genetically independent dimensions:
- Novelty seeking (NS) - tendency towards exploration and intense exhilaration in response to novel stimuli
- Harm avoidance (HA) - intense response to adverse stimuli and learned inhibited behaviour to avoid punishment
- Reward dependence (RD) - resistance to extinction of previously rewarded behaviour.
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.
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). This model proposes that alcoholics can be classified in two groups based on the combinations of their three personality dimensions:
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. 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.
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. These individuals are high in NS, and low in HA and RD, which means they may be typically aggressive, impulsive, active, talkative, and impatient.
- Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410.
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
- "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.
- American Society for Addiction Medicine (2012). "Definition of Addiction".
- Yoshida T (1997). Klee H, ed. Amphetamine Misuse: International Perspectives on Current Trends. Amsterdam, Netherlands: Harwood Academic Publishers. p. 5. ISBN 9789057020810. Retrieved 1 December 2014.
In summary, the essential component of [drug addiction] is a strong desire or a sense of compulsion (craving) to take the drug as manifested by drug-seeking behaviour which is difficult to control. Withdrawal syndrome and tolerance (a reduction in the sensitivity to a drug following its repeated administration) are both considered merely as consequences of drug exposure which, alone, are not sufficient evidence for a positive diagnosis of [drug addiction].
In pharmacology, when a drug is a reinforcer, it makes the desire for the drug stronger as the subject continues using the drug. Therefore repeated use of drugs having marked reinforcing efficacy can easily lead to a state of [drug addiction].
- 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.
- 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.
- 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"
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 1: Basic Principles of Neuropharmacology". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 4. ISBN 9780071481274.
Drug abuse and addiction exact an astoundingly high financial and human toll on society through direct adverse effects, such as lung cancer and hepatic cirrhosis, and indirect adverse effects—for example, accidents and AIDS—on health and productivity.
- 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.
- 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.
- 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.
- 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.
- Kendler KS, Neale MC, Heath AC, Kessler RC, Eaves LJ (May 1994). "A twin-family study of alcoholism in women". Am J Psychiatry 151 (5): 707–15. PMID 8166312.
- Clarke, Toni-Kim; Crist, Richard C.; Kampman, Kyle M.; Dackis, Charles A.; Pettinati, Helen M.; O’Brien, Charles P.; Oslin, David W.; Ferraro, Thomas N.; Lohoff, Falk W.; Berrettini, Wade H. (May 2013). "Low frequency genetic variants in the μ-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine". Neuroscience Letters 542: 71–75. doi:10.1016/j.neulet.2013.02.018.
- Hall, F. Scott; Drgonova, Jana; Jain, Siddharth; Uhl, George R. (December 2013). "Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong?". Pharmacology & Therapeutics 140 (3): 267–279. doi:10.1016/j.pharmthera.2013.07.006.
- Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". J. Gen. Physiol. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950.
- Descarries L, Berube-Carriere N, Riad M, Bo GD, Mendez JA, Trudeau LE (August 2008). "Glutamate in dopamine neurons: synaptic versus diffuse transmission". Brain Res. Rev. 58 (2): 290–302. doi:10.1016/j.brainresrev.2007.10.005. PMID 18042492.
- Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
- Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues Clin. Neurosci. 11 (3): 257–268. PMC 2834246. PMID 19877494. Retrieved 21 July 2014.
- Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Mol. Neurobiol. 51 (2): 696–717. doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.
- Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924.
- 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.
- 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
- 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.
- 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.
- Kanehisa Laboratories (2 August 2013). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 10 April 2014.
- 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
- 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.
- 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.
- Kauer, J.A.; R.C. Malenka (2007). "Synaptic plasticity and addiction". Nature Reviews Neuroscience 8 (11): 844–858. doi:10.1038/nrn2234. PMID 17948030.
- Witten, I; S.-C. Lin; M Brodsky (2010). "Cholinergic interneurons control local circuit activity and cocaine conditioning". Science 330: 1677–1681. doi:10.1126/science.1193771.
- Kalivas PW, Volkow ND (2005). "The neural basis of addiction: a pathology of motivation and choice". Am J Psychiatry 162 (8): 1403–13. doi:10.1176/appi.ajp.162.8.1403. PMID 16055761.
- Jones S, Bonci A (2005). "Synaptic plasticity and drug addiction". Current Opinion in Pharmacology 5 (1): 20–5. doi:10.1016/j.coph.2004.08.011. PMID 15661621.
- Eisch AJ, Harburg GC (2006). "Opiates, psychostimulants, and adult hippocampal neurogenesis: Insights for addiction and stem cell biology". Hippocampus 16 (3): 271–86. doi:10.1002/hipo.20161. PMID 16411230.
- Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 596. ISBN 0-443-07145-4.
- Kourrich S, Rothwell PE, Klug JR, Thomas MJ (2007). "Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens". J. Neurosci. 27 (30): 7921–8. doi:10.1523/JNEUROSCI.1859-07.2007. PMID 17652583.
- Floresco SB, Ghods-Sharifi S (2007). "Amygdala-prefrontal cortical circuitry regulates effort-based decision making". Cereb. Cortex 17 (2): 251–60. doi:10.1093/cercor/bhj143. PMID 16495432.
- "Dopamine in Drug Abuse and Addiction: Results of Imaging Studies and Treatment Implications".
- "Drugs, Brains, and Behavior: The Science of Addiction".
- "Understanding Drug Abuse and Addiction".
- Nestler EJ, Barrot M, Self DW (September 2001). "ΔFosB: A sustained molecular switch for addiction". Proceedings of the National Academy of Sciences of the United States of America 98 (20): 11042–6. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966.
- Chao J, Nestler EJ (2004). "Molecular neurobiology of drug addiction". Annual Review of Medicine 55: 113–32. doi:10.1146/annurev.med.55.091902.103730. PMID 14746512.
- Nestler EJ (December 2005). "The Neurobiology of Cocaine Addiction". Science & Practice Perspectives / a Publication of the National Institute on Drug Abuse, National Institutes of Health 3 (1): 4–10. PMC 2851032. PMID 18552739.
- Conversi D, Bonito-Oliva A, Orsini C, Colelli V, Cabib S (January 2008). "DeltaFosB accumulation in ventro-medial caudate underlies the induction but not the expression of behavioral sensitization by both repeated amphetamine and stress". The European Journal of Neuroscience 27 (1): 191–201. doi:10.1111/j.1460-9568.2007.06003.x. PMID 18184321.
- Perrotti LI, Weaver RR, Robison B, Renthal W, Maze I, Yazdani S, Elmore RG, Knapp DJ, Selley DE, Martin BR, Sim-Selley L, Bachtell RK, Self DW, Nestler EJ (May 2008). "Distinct Patterns of ΔFosB Induction in Brain by Drugs of Abuse". Synapse 62 (5): 358–69. doi:10.1002/syn.20500. PMC 2667282. PMID 18293355.
- Nikulina EM, Arrillaga-Romany I, Miczek KA, Hammer RP (May 2008). "Long-lasting alteration in mesocorticolimbic structures after repeated social defeat stress in rats: time course of μ-opioid receptor mRNA and FosB/ΔFosB immunoreactivity". The European Journal of Neuroscience 27 (9): 2272–84. doi:10.1111/j.1460-9568.2008.06176.x. PMC 2442756. PMID 18445218.
- Wallace DL, Vialou V, Rios L, Carle-Florence TL, Chakravarty S, Kumar A, Graham DL, Green TA, Kirk A, Iñiguez SD, Perrotti LI, Barrot M, DiLeone RJ, Nestler EJ, Bolaños-Guzmán CA (October 2008). "The influence of ΔFOSB in the Nucleus Accumbens on natural reward-related behavior". Journal of Neuroscience 28 (41): 10272–7. doi:10.1523/JNEUROSCI.1531-08.2008. PMC 2653197. PMID 18842886.
- Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: role of ΔFosB". Philosophical Transactions of the Royal Society B 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924.
- Ulery-Reynolds PG, Castillo MA, Vialou V, Russo SJ, Nestler EJ (January 2009). "PHOSPHORYLATION OF ΔFosB MEDIATES ITS STABILITY IN VIVO". Neuroscience 158 (2): 369–72. doi:10.1016/j.neuroscience.2008.10.059. PMC 2734485. PMID 19041372.
- Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine formation and ΔFosB expression in nucleus accumbens". Proceedings of the National Academy of Sciences of the United States of America 106 (8): 2915–20. doi:10.1073/pnas.0813179106. PMC 2650365. PMID 19202072.
- Chen JC, Chen PC, Chiang YC (2009). "Molecular mechanisms of psychostimulant addiction". Chang Gung Medical Journal 32 (2): 148–54. PMID 19403004.
- Teegarden SL, Scott AN, Bale TL (May 2009). "Early life exposure to a high fat diet promotes long-term changes in dietary preferences and central reward signaling". Neuroscience 162 (4): 924–32. doi:10.1016/j.neuroscience.2009.05.029. PMC 2723193. PMID 19465087.
- Watanabe H, Henriksson R, Ohnishi YN, Ohnishi YH, Harper C, Sheedy D, Garrick T, Nyberg F, Nestler EJ, Bakalkin G, Yakovleva T (July 2009). "FOSB proteins in the orbitofrontal and dorsolateral prefrontal cortices of human alcoholics". Addiction Biology 14 (3): 294–7. doi:10.1111/j.1369-1600.2009.00155.x. PMC 2828493. PMID 19523044.
- Garzón J, Rodríguez-Muñoz M, López-Fando A, Sánchez-Blázquez P (March 2005). "Activation of mu-opioid receptors transfers control of Galpha subunits to the regulator of G-protein signaling RGS9-2: role in receptor desensitization". The Journal of Biological Chemistry 280 (10): 8951–60. doi:10.1074/jbc.M407005200. PMID 15632124.
- Kovoor A, Seyffarth P, Ebert J, Barghshoon S, Chen CK, Schwarz S, Axelrod JD, Cheyette BN, Simon MI, Lester HA, Schwarz J (February 2005). "D2 dopamine receptors colocalize regulator of G-protein signaling 9-2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways". The Journal of Neuroscience 25 (8): 2157–65. doi:10.1523/JNEUROSCI.2840-04.2005. PMID 15728856.
- Garzón J, Rodríguez-Muñoz M, Sánchez-Blázquez P (May 2005). "Morphine alters the selective association between mu-opioid receptors and specific RGS proteins in mouse periaqueductal gray matter". Neuropharmacology 48 (6): 853–68. doi:10.1016/j.neuropharm.2005.01.004. PMID 15829256.
- Bouhamdan M, Yan HD, Yan XH, Bannon MJ, Andrade R (March 2006). "Brain-specific regulator of G-protein signaling 9-2 selectively interacts with alpha-actinin-2 to regulate calcium-dependent inactivation of NMDA receptors". Journal of Neuroscience 26 (9): 2522–30. doi:10.1523/JNEUROSCI.4083-05.2006. PMID 16510730.
- Silverman JL, Koenig JI (August 2007). "Evidence for Involvement of ERβ and RGS9-2 in 17-β Estradiol Enhancement of Amphetamine-Induced Place Preference Behavior". Hormones and Behavior 52 (2): 146–55. doi:10.1016/j.yhbeh.2007.03.017. PMC 2096711. PMID 17493623.
- Hooks SB, Martemyanov K, Zachariou V (January 2008). "A role of RGS proteins in drug addiction". Biochemical Pharmacology 75 (1): 76–84. doi:10.1016/j.bcp.2007.07.045. PMID 17880927.
- Martemyanov KA, Krispel CM, Lishko PV, Burns ME, Arshavsky VY (December 2008). "Functional comparison of RGS9 splice isoforms in a living cell". Proceedings of the National Academy of Sciences of the United States of America 105 (52): 20988–93. doi:10.1073/pnas.0808941106. PMC 2634932. PMID 19098104.
- Traynor JR, Terzi D, Caldarone BJ, Zachariou V (March 2009). "RGS9-2: probing an intracellular modulator of behavior as a drug target". Trends in Pharmacological Sciences 30 (3): 105–11. doi:10.1016/j.tips.2008.11.006. PMC 3394094. PMID 19211160.
- 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.
- Cerny, E. H.; T. Cerny (2009). "Vaccines against nicotine". Human Vaccines 5: 200–205. doi:10.4161/hv.5.4.7310.
- 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. doi:10.1021/jm2004943.
- Luigjes, J.; W. van den Brink; M. Feenstra (2011). "Deep brain stimulation in addiction: a review of potential brain targets". Molecular Psychiatry 17 (6): 572. doi:10.1038/mp.2011.114.
- 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. doi:10.1227/01.neu.0000360570.40339.64.
- Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE (2000). "A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence". N. Engl. J. Med. 343 (18): 1290–7. doi:10.1056/NEJM200011023431802. PMID 11058673.
- Connock M, Juarez-Garcia A, Jowett S et al. (2007). "Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation". Health Technol Assess 11 (9): 1–171, iii–iv. PMID 17313907.
- Marsch LA, Stephens MA, Mudric T, Strain EC, Bigelow GE, Johnson RE (2005). "Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence". Exp Clin Psychopharmacol 13 (4): 293–302. doi:10.1037/1064-12184.108.40.2063. PMID 16366759.
- Robertson JR, Raab GM, Bruce M, McKenzie JS, Storkey HR, Salter A (2006). "Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial". Addiction 101 (12): 1752–9. doi:10.1111/j.1360-0443.2006.01603.x. PMID 17156174.
- Qin Bo-Yi (1998). "Advances in dihydroetorphine: From analgesia to detoxification". Drug Development Research 39 (2): 131–134. doi:10.1002/(SICI)1098-2299(199610)39:2<131::AID-DDR3>3.0.CO;2-Q. Link
- Metrebian N, Shanahan W, Wells B, Stimson GV (1998). "Feasibility of prescribing injectable heroin and methadone to opiate-dependent drug users: associated health gains and harm reductions". Med. J. Aust. 168 (12): 596–600. PMID 9673620.
- Metrebian N, Mott J, Carnwath Z, Carnwath T, Stimson GV, Sell L (2007). "Pathways into receiving a prescription for diamorphine (heroin) for the treatment of opiate dependence in the United kingdom". Eur Addict Res 13 (3): 144–7. doi:10.1159/000101550. PMID 17570910.
- Kenna GA, Nielsen DM, Mello P, Schiesl A, Swift RM (2007). "Pharmacotherapy of dual substance abuse and dependence". CNS Drugs 21 (3): 213–37. doi:10.2165/00023210-200721030-00003. PMID 17338593.
- Mattick RP, Darke S (1995). "Drug replacement treatments: is amphetamine substitution a horse of a different colour?". Drug Alcohol Rev 14 (4): 389–94. doi:10.1080/09595239500185531. PMID 16203339.
- White R (2000). "Dexamphetamine substitution in the treatment of amphetamine abuse: an initial investigation". Addiction 95 (2): 229–38. doi:10.1046/j.1360-0443.2000.9522299.x. PMID 10723851.
- Majumdar SK (1991). "Chlormethiazole: current status in the treatment of the acute ethanol withdrawal syndrome". Drug Alcohol Depend 27 (3): 201–7. doi:10.1016/0376-8716(91)90001-F. PMID 1884662.
- Giannini AJ, Billett W (August 1987). "Bromocriptine-desipramine protocol in treatment of cocaine addiction". J Clin Pharmacol 27 (8): 549–54. doi:10.1002/j.1552-4604.1987.tb03065.x. PMID 3308977.
- Soyka M, Roesner S (2006). "New pharmacological approaches for the treatment of alcoholism". Expert Opin Pharmacother 7 (17): 2341–53. doi:10.1517/146565220.127.116.111. PMID 17109610.
- Pettinati HM, Rabinowitz AR (2006). "Choosing the right medication for the treatment of alcoholism". Curr Psychiatry Rep 8 (5): 383–8. doi:10.1007/s11920-006-0040-0. PMID 16968619.
- Bouza C, Angeles M, Magro A, Muñoz A, Amate JM (2004). "Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review". Addiction 99 (7): 811–28. doi:10.1111/j.1360-0443.2004.00763.x. PMID 15200577.
- Williams SH (2005). "Medications for treating alcohol dependence". Am Fam Physician 72 (9): 1775–80. PMID 16300039.
- Gass JT, Olive MF (2008). "Glutamatergic substrates of drug addiction and alcoholism". Biochem. Pharmacol. 75 (1): 218–65. doi:10.1016/j.bcp.2007.06.039. PMC 2239014. PMID 17706608.
- Srisurapanont M, Jarusuraisin N (2005). Srisurapanont, Manit, ed. "Opioid antagonists for alcohol dependence". Cochrane Database Syst Rev (1): CD001867. doi:10.1002/14651858.CD001867.pub2. PMID 15674887.
- Karhuvaara S, Simojoki K, Virta A et al. (2007). "Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study". Alcohol. Clin. Exp. Res. 31 (7): 1179–87. doi:10.1111/j.1530-0277.2007.00401.x. PMID 17451401.
- Comer SD, Sullivan MA, Hulse GK (2007). "Sustained-release naltrexone: novel treatment for opioid dependence". Expert Opin Investig Drugs 16 (8): 1285–94. doi:10.1517/13543718.104.22.1685. PMID 17685876.
- Ling W, Rawson R, Shoptaw S, Ling W (2006). "Management of methamphetamine abuse and dependence". Curr Psychiatry Rep 8 (5): 345–54. doi:10.1007/s11920-006-0035-x. PMID 16968614.
- Preti A (2007). "New developments in the pharmacotherapy of cocaine abuse". Addict Biol 12 (2): 133–51. doi:10.1111/j.1369-1600.2007.00061.x. PMID 17508985.
- Urschel HC, Hanselka LL, Gromov I, White L, Baron M (2007). "Open-label study of a proprietary treatment program targeting type A gamma-aminobutyric acid receptor dysregulation in methamphetamine dependence". Mayo Clin. Proc. 82 (10): 1170–8. doi:10.4065/82.10.1170. PMID 17908523.
- Garwood CL, Potts LA (2007). "Emerging pharmacotherapies for smoking cessation". Am J Health Syst Pharm 64 (16): 1693–8. doi:10.2146/ajhp060427. PMID 17687057.
- Frishman WH (2007). "Smoking cessation pharmacotherapy—nicotine and non-nicotine preparations". Prev Cardiol 10 (2 Suppl 1): 10–22. doi:10.1111/j.1520-037X.2007.05963.x. PMID 17396063.
- Siu EC, Tyndale RF (2007). "Non-nicotinic therapies for smoking cessation". Annu. Rev. Pharmacol. Toxicol. 47: 541–64. doi:10.1146/annurev.pharmtox.47.120505.105354. PMID 17209799.
- K.R. Alper, H.S. Lotsof, G.M. Frenken, D.J. Luciano, J. Bastiaans (1999). "Treatment of Acute Opioid Withdrawal with Ibogaine" (PDF). The American Journal on Addictions 8 (3): 234–242. doi:10.1080/105504999305848. PMID 10506904. Retrieved 16 June 2009.
- S.L.T. Cappendijk, M.R. Dzoljic (1993). "Inhibitory effects of ibogaine on cocaine self-administration in rats". European Journal of Pharmacology 241 (2–3): 261–265. doi:10.1016/0014-2999(93)90212-Z. PMID 8243561.
- S.D. Glick, K. Rossman, N.C. Rao, I.M. Maisonneuve and J.N. Carlson (1992). "Effects of ibogaine on acute signs of morphine withdrawal in rats: Independence from tremor". Neuropharmacology 31 (5): 497–500. doi:10.1016/0028-3908(92)90089-8. PMID 1528400.
- 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.
- Gross JJ (September 1998). "The emerging field of emotion regulation: An integrative review". Review of General Psychology 2 (3): 271–299. doi:10.1037/1089-2622.214.171.1241.
- 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.
- Quirk SW (May 2009). "Emotion concepts in models of substance abuse". Drug and Alcohol Review 20 (1): 95–104. doi:10.1080/09595230125185.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Robinson TE, Berridge KC (2003). "Addiction". Annu Rev Psychol 54: 25–53. doi:10.1146/annurev.psych.54.101601.145237. PMID 12185211.
- 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.
- 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:10.1037/1040-35126.96.36.199. PMID 17371126.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Bechara A (2003). "Risky business: emotion, decision-making, and addiction". J Gambl Stud 19 (1): 23–51. doi:10.1023/A:1021223113233. PMID 12635539.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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:10.1037/1040-35188.8.131.52. PMID 15456380.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Image legend
|Look up addiction or -holism in Wiktionary, the free dictionary.|
- Lemonick MD (July 16, 2007). "How We Get Addicted". Time 170 (38). Archived from the original on 2 September 2010. Retrieved 7 September 2010. Cover July 16, 2007 (note: cover provided to clarify date discrepancy from article link)
- Martin P (2008). "Sex, Drugs & Chocolate: The Science of Pleasure". London: Fourth Estate. ISBN 978-0-00-712708-5.
- Nash-Alice MJ (May 5, 1997). "Addicted: Why do people get hooked?". Time (18): 52–58.
Cellular_basiswas invoked but never defined (see the help page).
Cite error: The named reference
Nestler_Labs_Glossarywas invoked but never defined (see the help page).
Cite error: The named reference
- 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.
NHM_addiction-reward-reinforcementwas invoked but never defined (see the help page).
Cite error: The named reference
Addiction-drug_reinforcerswas invoked but never defined (see the help page).
Cite error: The named reference