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Anticipatory Dopamine Response in Addiction
Anticipatory Dopamine Response in Addiction
Jakob Linnet
PII: S0278-5846(19)30527-5
DOI: https://doi.org/10.1016/j.pnpbp.2019.109802
Reference: PNP 109802
Please cite this article as: J. Linnet, The anticipatory dopamine response in addiction: A
common neurobiological underpinning of gambling disorder and substance use disorder?,
Progress in Neuropsychopharmacology & Biological Psychiatry(2018), https://doi.org/
10.1016/j.pnpbp.2019.109802
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The anticipatory dopamine response in addiction: A common
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neurobiological underpinning of gambling disorder and substance
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use disorder?
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Jakob Linnet1*
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Clinic for Gambling- and Binge Eating Disorder, Department of Occupational and
*
Correspondence should be addressed to: Jakob Linnet (jlinnet@mac.com)
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Abstract
The dopamine system is associated with reward processes in both gambling disorder and
substance use disorder, and may constitute a common neurobiological underpinning in addiction.
The present review examines differences and similarities of dopaminergic reward processes in
gambling disorder and substance use disorder. First, it is suggested that baseline binding poten-
tials of the dopamine system may not be a common pathway, since substance use disorder is as-
sociated with reduced binding potentials, whereas gambling disorder is not. Second, it is sug-
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gested that dopaminergic reward response may be not a common pathway, since substance use
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disorder is associated with a blunted dopamine response toward drugs, while conflicting findings
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of reward response has been reported in gambling disorder. Instead, it is suggested that the an-
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ticpatory dopamine response may constitute a common underpinning of gambling disorder and
substance use disorder, which may be associated with increased dopamine activity in both types
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of disorder, and does not involve the intake of substances. The notion of the anticipatory dopa-
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mine response as a common underpinning of gambling disorder and substance use disorder is
consistent with dopaminergic models of addictions such as the incentive-sensitization model, the
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ingrative neurodevelopmental model of vulnerability towards addiction and the reward predic-
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Introduction.
The dopamine system is associated with addictive behavior both with regard to drug addic-
tion and behavioral addictions such as gambling disorder [1]. While the role of the dopamine
system in gambling disorder is currently not fully understood [2] there are several parallels of
dopaminergic dysfunctions in gambling disorder and substance use disorder including reward
anticipation, reward response, reward uncertainty and motivational aspects of gambling [1, 3, 4] .
For instance, Linnet [4] suggested that the distinction between reward anticipation, defined as
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dopaminergic processes occurring prior to reward or omission/loss, and reward response, defined
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as dopaminergic processes occurring after reward or omission/loss, may have important implica-
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tions for the understanding of dopaminergic dysfunctions in gambling disorder and addiction.
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The distinction between reward anticipation and reward response is consistent with dopaminer-
gic models of reward prediction (reward prediction vs. reward prediction error) [5] and incentive
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The present review aims at investigating similarities and differences in dopaminergic dys-
functions in gambling disorder and substance use disorder. Specifically, it is proposed that do-
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pinning of gambling disorder and substance use disorder. Other common underpinnings may
exist as well. The review first examines evidence from positron emission tomography (PET)
studies of gambling disorder, then evidence from functional Magnetic Resonance Imaging
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The dopamine system is sensitive to behavioral stimulation related to monetary reward [11-13].
While the use of substances such as cocaine is associated with a dopamine increase throughout
the striatum, the ventral striatum is specifically involved in reward expectation and monitoring of
reward [14, 15], and this region appears to be central to gambling disorder [16-19]. Evidence
from the animal literature also supports the involvement of the ventral striatum in reward seeking
behavior [20-22].
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Dopaminergic dysfunctions in gambling disorder differ from the substance use disorder liter-
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ature in at least three important ways. Firstly, substance use disorder sufferers have significantly
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lower baseline binding potentials than healthy controls [23, 24]. These findings are inconsistent
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with PET studies of gambling disorder, meaning that there are no significant differences in base-
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line binding potentials between gambling disorder sufferers and healthy controls [18, 19, 25].
Secondly, evidence from PET studies show that substance use disorder sufferers have a
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“blunted” dopamine response to drugs [24, 26-28]. These findings are inconsistent with PET
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during gambling between gambling disorder sufferers and healthy controls [16, 29].
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Thirdly, PET-studies on dopaminergic changes when winning report mixed results with re-
gard to gambling disorder. Steeves et al. [17] found a significantly higher dopamine increase
from winning in Parkinson’s disease patients with gambling disorder compared to Parkinson’s
Disease patients without gambling disorder. Joutsa et al. [16] found no differences in dopamine
increase from winning between gambling disorder sufferers and healthy controls. And Linnet et
al. [18] found that gambling disorder sufferers had a significantly higher dopamine increase
when losing compared with healthy controls. While lower baseline binding potentials, as well as
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other factors, may have confounded the dopamine increase of Parkinson’s disease patients with
gambling disorder in the Steeves et al. study [17], the implications of dopamine increase when
It has been suggested that reward uncertainty is a key factor in gambling disorder [1, 3].
Therefore, it is possible that dopaminergic coding of uncertainty could account for neurobiologi-
cal dysfunctions in gambling disorder. For instance, Linnet et al. [30] found an increased dopa-
mine response associated with decision-making uncertainty in Gambling Disorder on the Iowa
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Gambling Task (IGT). Gambling disorder sufferers who made an equal number of “good” and
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“bad” decisions had higher dopamine increase than gambling disorder sufferers who consistently
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made good or bad decisions. In other words, uncertainty of gains or losses was associated with
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dopamine increase in gambling disorder, while certainty of gains and losses were not.
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Dopaminergic coding of reward uncertainty, rather than actual reward (i.e., overall winning
or losing), could possibly account for the differences in results reported by Steeves et al. [17] and
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Linnet et al. [18]. Steeves et al. [17] used a rigged task, which randomly resulted in either a win
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or a loss, but always produced an overall gain. Linnet et al. [18] used the IGT, where uncertainty
in outcome varied depending on card selections. In both studies, it is possible that the variation
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(i.e., uncertainty of gains and losses) rather than the overall outcome (i.e., winning or losing),
reinforced the dopamine response in gambling disorder sufferers. Therefore, reward anticipation
associated with dopaminergic coding of uncertainty could explain the reinforcement of continued
gambling despite losses (‘chasing one’s losses’) often seen in gambling disorder. Conversely, it
may be less likely that the dopamine response toward of reward receipt can explain the rein-
forcement of continued gambling despite losses, since reward receipt (as well as omission or
losses) is associated with a blunted dopamine response. Furthermore, since losses are much for
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frequent than gains in gambling, it seems unlikely that the dopamine response to reward receipt
could reinforce the behavior. However, in order to compare reward anticipation in gambling dis-
order and substance use disorder, it is necessary to consider important methodological differ-
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PET studies have used drug challenge paradigms to investigate dopaminergic reward re-
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sponses in substance use disorder. Here, the reaction to drug intake is measured. Drug challenge
paradigms show a blunted dopamine increase in substance use disorder sufferers compared to
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healthy controls [24]. The reduced dopamine response toward reward receipt has been demon-
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strated across different types of drug addictions (e.g., alcohol use disorder, cocaine use disorder
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and amphetamine use disorder) [31]. However, it might not relate to all types of drug addiction.
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In contrast, PET studies of reward anticipation in substance use disorder have used cue expo-
sure or cue-elicited paradigms that compare binding potentials toward drug related cues with
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binding potentials toward neutral cues without association to drugs. Evidence from cue exposure
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paradigms suggest that cocaine use disorder sufferers have a significant dopamine increase to-
ward exposure to drug cues compared with exposure to neutral stimuli [32, 33]. These findings
are consistent with the hypothesis of an increased anticipatory dopamine response toward reward
A limitation in the PET studies of gambling disorder is that they might fall somewhere be-
tween a drug challenge paradigm and a cue exposure paradigm. Methodologically, gambling
studies may resemble drug challenge paradigms (because they investigate the response to gam-
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bling), but neurobiologically they may involve both reward anticipation and reward response,
due to the immediacy of uncertainty and outcome in gambling. Therefore, a possibly “blunted”
dopamine increase related to reward response may be confounded by a possibly higher dopamine
increase related to reward anticipation. Such an immediate interaction between reward anticipa-
tion and reward response is not detectable with the temporal resolution of PET, and it is therefore
important to include evidence from functional Magnetic Resonance Imaging (fMRI) studies to
elucidate the temporal relation between reward anticipation and reward response in gambling
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disorder.
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Evidence from fMRI studies
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The evidence from fMRI studies support the involvement of reward anticipation in gambling
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and gambling disorder. [34-37]. Abler et al. [34] found increased Blood Oxygen Level Depend-
ent (BOLD) activation in the nucleus accumbens of healthy controls in anticipation of reward in
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a gambling task. Preuschoff et al. [38] found that reward probability was linearly associated with
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immediate anticipatory BOLD activation in in the ventral striatum of healthy controls, while un-
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certainty was quardratically associated with late anticipatory BOLD activation. In other words:
the late anticipatory BOLD activation was largest toward stimuli with maximum uncertainty (P =
0.5) and smallest toward stimuli with maximum certainty (P = 0.0 and P = 1.0).
Looking at gambling disorder Reuter et al. [36] found a significantly lower BOLD response
in the ventral striatum toward winning in gambling disorder sufferers compared to healthy con-
trols. Furthermore, gambling disorder sufferers showed a significant negative correlation be-
tween the BOLD activation and severity in gambling symptoms. Van Holst et al. [37] found that
gambling disorder sufferers had a significantly increased anticipatory BOLD activation in the
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bilateral ventral striatum and left orbitofrontal cortex toward gain-related expected value com-
pared to healthy controls. There were no differences in BOLD activation toward reward re-
sponse.
A meta review by Luijten et al. [39], however, found significantly decreased anticipatory
BOLD activation in the ventral striatum of substance dependence sufferers during performance
on the Monetary Incentive Delay Task (MIDT). Similar findings are reported by Balodis et al.
[40] in gambling disorder sufferers. The differences in findings between van Holst et al. [37] and
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Balodis et al. [40] are complex and may relate to anticipatory differences of guessing in contrast
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to formulation of prospects. The study by van Holst et al. [37] used a modified version of a
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guessing task, and the anticipatory processes could therefore be associated with outcome uncer-
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tainty. The object of the MIDT [40] is to identify winning and losing cues, and to win (or avoid
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losing money) by pressing a button before the disappearance of a target. The anticipatory process
in the MIDT task could therefore be more related to the formulation of prospects and whether or
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not the target was hit than to the anticipation of gains. These differences in task objectives, as
The anticipatory dopamine response toward guessing wins and losses could be associated
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with reinforcement of addiction behavior, and could in important ways resemble real life gam-
bling situations. Indeed Clark et al. [3] in a recent review concluded that “…studies using more
realistic gambling games have indicated hyper-reactivity of striatal, dopaminergic midbrain, and
medial/PFC in GD” (p. 682). While the anticipatory dopamine in realistic games may be associ-
ated with reinforcement of gambling behavior in gambling disorder, the findings from the MIDT
literature may identify important anticipatory cognitive deficits in prospect formulation of gam-
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bling disorder and substance use disorder. By this account there may be several anticipatory pro-
disorder and substance use disorder has, at least, two important implications. First, gambling
disorder and substance use disorder may be influenced by similar dopamine processes associated
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with reward anticipation, since reward anticipation is endogenous and does not involve the intake
of substances. Such similarities in anticipatory dopamine responses may be associated with simi-
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larities in clinical behavior, like craving and preoccupation with stimuli associated with addictive
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Second, gambling disorder and substance use disorder may be influenced by different dopa-
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mine processes associated with reward response. For instance, amphetamine and cocaine are
dopamine release, while cocaine inhibits dopamine reuptake) [42]. Gambling disorder, on the
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other hand, is associated with endogenous dopamine processes. Although these are distinct pro-
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cesses that alter the dopamine system in different ways, they may result in similar patterns of
dopamine response and clinical behavior, such as a “blunted” dopamine response toward reward
receipt or tolerance.
Here, it is suggested that the endogenous dopaminergic reward anticipation in gambling dis-
order, amphetamine use disorder and cocaine use disorder is similar across disorders, since there
anticipation may thus represent a common basis of addiction. In contrast, gambling disorder,
amphetamine use disorder and cocaine use disorder may differ in dopaminergic reward response,
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nous stimulation of dopamine release, and cocaine use by exogenous stimulation of dopamine
reuptake inhibition. These three distinct types of dopamine responses may be associated with
different forms of neural adaptation. Several models of dopamine dysfunctions in addiction have
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Terry E. Robinson and Kent C. Berridge [6-10] have proposed an incentive-sensitization the-
ory, which distinguishes between hedonic aspects (“liking”) and motivational aspects (“want-
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ing”) of stimuli in addiction. The model focuses on the dopamine system as a core neurobiologi-
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cal basis of addiction. The ventral striatum and its main component the nucleus accumbens
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(NAcc) are associated with addiction in the theory. Robinson and Berridge argue that behavior
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most reinforced behavior is not associated with addiction (e.g., learning how to drive a car), and
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the majority of people using drugs never develop an addiction. Instead, they suggest that changes
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in the dopamine system associated with drug exposure render the brain circuits hypersensitive or
“sensitized” to drugs or drug cues, and that this sensitization may explain addictive behavior.
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Sensitization from repeated drug exposure may also occur at the level of psychomotor or loco-
motor activity.
The sensitization is linked with increased incentive salience, which is the cognitive process
associated with drug seeking and drug taking behavior. Incentive salience (“wanting”) refers to a
motivational state, which is not necessarily associated with declarative goals or conscious pro-
cesses. Incentive salience must be coupled with sensitization to account for addictive behavior:
an increase in dopamine binding does not define incentive-sensitization, but an increase in do-
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pamine binding in relation to particular drug cues does; locomotor activity does not indicate in-
centive-sensitization, but running around to get drugs does; psychomotor preoccupation does not
indicate incentive-sensitization, but an obsession with taking drugs does. Therefore, simple rein-
The incentive-sensitization theory suggests that “Many potentially addictive drugs initially
produce feelings of pleasure (euphoria), encouraging users to take drugs again. However, with
the transition to addiction, there appears to be a decrease in the role of drug pleasure. How can it
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be that drugs come to be wanted more even if they become ‘liked’ less? According to incentive
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sensitization theory, the reason for this paradox is because repeated drug use sensitizes only the
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neural systems that mediate the motivational process of incentive salience (wanting), but not
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neural systems that mediate the pleasurable effects of drugs (liking)” [9]. The notion that drugs
come to be ‘wanted’ more but ‘liked’ less in addiction is consistent with the blunted dopamine
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reward response in substance use disorder and gambling disorder [see e.g., 24, 36],and with the
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increased anticipatory dopamine response in substance use disorder and gambling disorder [see
Incentive sensitization theory was originally developed with a focus on drug use and sub-
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stance use disorder, but Berridge and Robinson [10] have recently expanded the theory to in-
clude behavioral addictions such as gambling disorder. However, it is currently not clear which
mechanisms of neuroadaptation might account for the sensitization seen in gambling disorder:
produce these addictions without the need of drugs, through mechanisms not yet understood”,
[10, p. 678].
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towards addiction [43, 44], which proposes that in addiction drug cues are sensitized, i.e. associ-
ated with increased dopamine response, while non-drug cues may be associated with inhibitory
processes. Critically, the dopamine response is cue-driven, which has several important implica-
tions: First, drug-cues alone can increase the dopamine activity in addiction, consistent with the
notion that behavior (or behavioral addiction) in itself may be associated with sensitization. Sec-
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ond, increased dopamine response to drug cues relative to non-drug cues in addiction could help
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explain the process of increased attention and preoccupation toward drugs relative to other cues.
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The relative increase of dopamine activation to drug cues versus non-drug cues has been shown
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in exposure studies in substance use disorder [33, 45]. Third, ingestion of drugs without drug-
cues in substance use disorder may be associated with blunted dopamine activation. This is con-
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sistent with the proposed blunted dopamine response toward reward receipt. For instance, an
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association between blunted dopamine response and decreased feelings of “rush” and “high” was
Leyton and Vezina [43, 44] further suggests that individual differences may account for vul-
nerability toward engaging in drug use and developing addictive behavior. These preexisting
drugs or exposure to drug cues. Hence, there may be neurodevelopmental vulnerability factors of
addiction, which can protect against or exacerbate the risk of developing addiction.
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The dopamine system plays a key role in reward learning: stimuli with higher reward proba-
bilities (i.e., stimuli that are more likely than not to be followed by a reward) are associated with
an increased anticipatory phasic dopamine activation prior to the outcome (reward or reward
omission). In contrast, stimuli with lower reward probabilities are associated with a reduced an-
ticipatory phasic dopamine activation. This mechanism is referred to as reward prediction [5],
because the dopaminergic signal is associated with the predictive value of the stimuli prior to
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reward or omission. Reward prediction error [5] refers to a phasic dopamine activation, which
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occurs after the reward or omission, where the stimulus prediction differs from the outcome. For
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instance, there is an increased phasic dopamine activation when stimuli with low reward proba-
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bilities are followed by reward, and there is a reduced phasic dopamine activation when stimuli
with high reward probabilities are no longer followed by reward. This way, the interaction be-
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tween reward prediction and reward prediction error updates the reward information of stimuli.
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In random binary outcome conditions, e.g., reward vs. omission, the expected value (EV) is
the average value that can be expected from a given stimulus, which is a linear function of re-
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ward probability (Figure 1A). In contrast, uncertainty, which can be defined as the variance (2)
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of a probability distribution [47], is the mean squared deviation from the expected value. Vari-
where P is the probability of reward represented by the value 1 and no reward represented by the
value 0. Maximum variance is found in P = 0.5 (2 = 0.5(1-0.5) = 0.25), and the variance de-
clines toward higher and lower probabilities (e.g., P = 0.25, 2 = 0.25(1-0.25) = 0.1875; P =
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Midbrain and striatal dopamine coding of expected value and uncertainty follow linear and
quadratic functions of reward similar to their mathematical expressions [30, 38, 48]. For in-
stance, Fiorillo, Tobler and Schultz [48] investigated dopamine activation in relation to expected
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value and uncertainty in monkeys exposed to stimuli with varying reward probabilities (P = 0, P
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= 0.25, P = 0.5, P = 0.75 and P = 1.0). The authors found phasic dopamine reward prediction
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and reward prediction error signals associated with reward probability, consistent with the notion
of a linear relation between expected value and dopaminergic coding of reward (Figure 1A). Fur-
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thermore, they found a sustained phasic dopamine signal associated with reward uncertainty,
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consistent with the notion of a quadratic relation between reward anticipation and dopaminergic
coding of uncertainty (Figure 1B).The sustained dopamine response toward uncertainty was a
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distinct response from dopaminergic reward prediction and reward prediction error, which acti-
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vated separate dopamine neurons in the midbrain (although some overlap was seen between the
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two signals). Fiorillo et al. [48] suggest that this dopaminergic coding of uncertainty and risk
taking could be associated with advantageous behaviors in natural environments such as learning
and risk taking may represent a risk factor for maladaptive behavior. Therefore, the sustained
dopaminergic reward anticipation associated with the coding of uncertainty could offer a rein-
forcement model for explaining why gambling disorder sufferers often: (1) are drawn toward the
risk and uncertainty of gambling; (2) continue gambling despite losses; and (3) do not adapt ad-
vantageous strategies despite negative feedback. This is consistent with a recent review by Clark
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et al. [3] which suggests that uncertainty in itself can have reinforcing properties in gambling
disorder.
In a PET study Linnet et al. [30] tested competing hypotheses of dopamine increase of gam-
bling disorder sufferers playing the IGT. The hypothesis of expected value assumed a linear rela-
tion between IGT performance and dopamine increase (Figure 1C), suggesting that gambling
disorder sufferers who performed better on the IGT had higher dopamine release. In contrast, the
uncertainty hypothesis assumed a quadratic relation between IGT performance and dopamine
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increase (Figure 1D), suggesting that gambling disorder sufferers with maximum uncertainty of
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outcome had higher dopamine release . The results showed a significant quadratic relation of
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dopamine release in gambling disorder, while no support was found for the linear relation, sug-
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gesting that the dopamine release in gambling disorder was reinforced by uncertainty of out-
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come. Uncertainty is a key component in all forms of gambling, and the most addictive forms of
gambling such as slot machines, casino games and sports betting are characterized by maximized
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uncertainty (variance) and high play frequencies (plays per minute). These games typically have
high payback percentages around 80–99% (e.g., slot machines often have payback percentages
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around 82–90%, and black jack has payback percentages as high as 99%).
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Therefore, game properties that maximize uncertainty and variance may constitute an inher-
ent risk for gambling disorder sufferers and individuals at risk for developing gambling disorder.
may reinforce maladaptive and erratic gambling behavior, and preclude the individual from in-
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Several parallels of dopaminergic dysfunctions in gambling disorder and substance use dis-
order have been proposed. Evidence from PET and fMRI studies suggest that dysfunctions in
disorder and substance use disorder. In particular, the anticipatory dopamine toward reward cues
may reinforce addictive behaviors, and might constitute a common neurobiological pathway of
gambling disorder and substance use disorder. Such dysfunctions in anticipatory dopamine re-
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sponse is consistent with theories of incentive sensitization, vulnerability of neurodevelopment
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of addiction, and reward prediction.
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Dysfunctions in anticipatory dopamine response may involve similar neurobiological mecha-
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nisms across gambling disorder and substance use disorder, since reward anticipation is not asso-
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ciated with exogenous intake of substances. Yet, it is not clear if dysfunctions in anticipatory
dopamine responses are associated with different types of neuroadaptation related to, e.g., type
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ior may guide future directions of treatment of addiction both with regard to understanding neu-
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robiological deficits in addiction, predictive measures of treatment outcome, and possible neuro-
biological mechanisms associated with cognitive restructuring of addictive behavior. For in-
stance, reward anticipation may be associated with motivational processes, cognitive biases and
impulsiveness in gambling disorder and substance use disorder and may affect the treatment out-
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While much of the early research on substance use disorder have focused on how the brain re-
sponds to drugs, a focus on reward anticipation could broaden this focus to also include the neu-
Clark et al. [3] this could frame addiction as a “learning disorder” rather than a “substance disor-
der”.
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Figure 1. Expected value and uncertainty as functions of reward probability and dopamine
changes (BPND).
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A. Expected value is a linear function of reward probability, where the expected value is minimal
at P = 0.0 and maximal at P = 1.0. B. Uncertainty, defined as variance, is a quadratic function of
reward probability, where uncertainty is maximal at P = 0.5 and minimal at P = 0.0 and P = 1.0.
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C. Hypothetical relation between expected value and dopamine changes (BPND) in relation to
IGT performance, where higher dopamine increase is associated with higher probability of re-
ward. D. Hypothetical relation between uncertainty and dopamine changes (BPND), where do-
pamine increase is highest when probability of reward is maximally uncertain (P = 0.5) and de-
clines as probability increases or decreases. Reprint with permission from Psychiatry Research:
Neuroimaging 204 (2012) 55–60 © 2012.
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• Dopamine is associated with reward in gambling disorder and substance use disorder.
• Dopaminergic reward anticipation may be dysfunctional in gambling- and drug addiction.
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Figure 1