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Cited by 171Neurotransmitter Receptor Influence on BehaviorNeural and Behavioral Psychology StudiesSubstance Abuse Treatment and Outcomes

Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity

Open access
Trifilieff, Pierre, Martinez, Diana·2014·Neuropharmacology
DOI 10.1016/j.neuropharm.2013.06.031PMC PMC4106030
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Abstract

Dependence to drugs of abuse is closely associated with impulsivity, or the propensity to choose a lower, but immediate, reward over a delayed, but more valuable outcome. Here, we review clinical and preclinical studies showing that striatal dopamine signaling and D2 receptor levels - which have been shown to be decreased in addiction - directly impact impulsivity, which is itself predictive of drug self-administration. Based on these studies, we propose that the alterations in D2 receptor binding and dopamine release seen in imaging studies of addiction constitute neurobiological markers of impulsivity. Recent studies in animals also show that higher striatal dopamine signaling at the D2 receptor is associated with a greater willingness to expend effort to reach goals, and we propose that this same relationship applies to humans, particularly with respect to recovery from addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

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Written from the paper’s full text.

TL;DR

This review argues that low striatal D2 receptor binding and blunted presynaptic dopamine release are neurobiological markers of impulsivity shared across addictions, and that higher D2 signaling in the ventral striatum relates to incentive motivation and treatment response. It synthesizes human PET and preclinical studies to propose that increasing D2 signaling may reduce impulsivity and support recovery, though causal direction and treatment implications remain unresolved.

Key findings

Across substance use disorders, PET studies consistently show decreased striatal D2 receptor binding, on the order of about 20% versus controls, and blunted stimulant-induced dopamine release (ΔBPND); exceptions include cannabis abuse and pathological gambling for baseline D2 binding. Low D2 binding and dopamine release correlate with greater impulsivity and drug choice, e.g., methamphetamine abusers with lower caudate/nucleus accumbens D2 binding had higher Barratt Impulsiveness Scale scores, and cocaine abusers with low ventral striatal dopamine release chose cocaine over money. In treatment studies, cocaine- and methamphetamine-dependent subjects with higher ventral striatal D2 binding and dopamine release were more likely to respond to behavioral treatment or maintain abstinence; cocaine treatment responders had higher social status (34.1 ± 9.2 vs. 27.1 ± 4.5, p = 0.01) and did not differ from controls (34.8 ± 7.9, p = 0.8). Preclinical work shows high impulsivity predicts escalation of drug self-administration and relapse, low striatal D2 receptor availability before drug exposure predicts greater cocaine or alcohol self-administration, and D2 overexpression in ventral striatum enhances willingness to work for larger effortful rewards while attenuating alcohol/cocaine self-administration.

Methods

Narrative review of clinical and preclinical studies; no new primary data are reported. Human evidence mainly involves PET imaging of striatal D2 receptor availability (BPND) and stimulant-induced dopamine release (ΔBPND), alongside choice-impulsivity tasks such as delay discounting and the Iowa Gambling Task, and treatment-response measures. Preclinical evidence comes from rodent and non-human primate studies using PET/autoradiography, lesions, D2 receptor manipulations, drug self-administration, 5-choice serial reaction time task, delay discounting, and effort-based choice.

Limitations

Stated by the paper: the precise types of impulsivity affected in addiction are not clearly defined in human imaging studies; impulsive versus compulsive drug taking is not fully separated; the review focuses on striatal dopamine, largely ventral striatum, and does not fully address other systems such as D1 or serotonin or prefrontal contributions; inverted-U dopamine effects are only briefly addressed; and ventral-to-dorsal striatal progression is not fully integrated. Also stated: it is unknown whether increasing motivation in addicted individuals would increase motivation for drug versus non-drug rewards, and the treatment hypothesis has not been tested in animal models of substance abuse. Evident from the text: as a narrative review, it does not use a systematic search or meta-analysis, and human evidence linking dopamine markers, impulsivity, and addiction remains largely correlational.

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Integrity signals

Registry

Crossref · 10.1016/j.neuropharm.2013.06.031

Cites

187 of 187 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Drug dependence is closely linked to impulsivity, understood as preferring a smaller immediate reward over a larger delayed one.

    “Dependence to drugs of abuse is closely associated with impulsivity, or the propensity to choose a lower, but immediate, reward over a delayed, but more valuable outcome.”
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  • Interpretationreasoning

    Animal models are consistent with human imaging studies of striatal dopamine signaling, impulsivity, and addiction.

    “Importantly, these animal models are consistent with the imaging studies investigating striatal dopamine signaling, impulsivity, and addiction.”
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  • Premisecitation

    In the Iowa Gambling Task, substance abuse is associated with choices for high immediate gains despite higher future losses.

    “or the Iowa Gambling Task, in which substance abuse is associated with choices for high immediate gains despite higher future losses (Bechara et al., 2002).”
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  • Interpretationreasoning

    The absence of the biomarker in this subgroup may reflect their ability to exert cognitive control or suppress impulsive responses when alternatives to drug use are available.

    “The fact that this subgroup does not express the biomarker seen so consistently in addiction may reflect their ability to exert cognitive control, or suppress impulsive responses, when presented with alternatives to drug use.”
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  • Premisecitation

    In animals, greater striatal dopamine signaling at the D2 receptor is associated with a greater willingness to expend effort to reach goals.

    “Recent studies in animals also show that higher striatal dopamine signaling at the D2 receptor is associated with a greater willingness to expend effort to reach goals”
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    Premisecitation

    In preclinical studies, increased D2 receptor dopamine signaling in the nucleus accumbens enhances motivation, while impaired D2 signaling reduces it.

    “Preclinical studies show that increased dopamine signaling at the D2 receptor in the nucleus accumbens enhances motivation, whereas impaired D2 signaling lessens it (Salamone et al., 2007).”
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    Premisecitation

    Cocaine abuse is associated with decreased D2 receptor availability in the striatum compared with controls, first reported in 1990 and confirmed by later studies.

    “The first report was in 1990, where a study showed that cocaine abuse was associated with a decrease in D2 receptor availability in the striatum compared to controls (Volkow et al, 1990), and has been followed by a series of studies confirming this observation”
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    Premisecitation

    Blunted stimulant-induced dopamine release has been shown in cocaine abuse, alcohol dependence, opiate dependence, methamphetamine abuse, and cigarette smoking.

    “This finding has been shown in cocaine abuse (Malison et al., 1999; Martinez et al., 2011; Martinez et al., 2007; Volkow et al., 1997), alcohol dependence (Martinez et al., 2005; Volkow et al., 2007b), opiate dependence (Martinez et al., 2012), methamphetamine abuse (Wang et al., 2012), and cigarette smoking (Busto et al., 2009)”
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    Premisecitation

    Alcohol dependence is associated with decreased D2 receptor availability in the striatum, replicated in additional studies, although some groups report no difference.

    “In alcohol dependence, Hietala et al (Hietala et al., 1994) showed a decrease in D2 receptor availability in the striatum and this has now been replicated in additional studies (Heinz et al., 2005; Heinz et al., 2004; Martinez et al., 2005; Volkow et al., 1996; Volkow et al., 2002b; Volkow et al., 2007b), although some groups report a lack of a difference”
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    Premisenone given

    Striatal dopamine signaling and D2 receptor levels are reduced in addiction.

    “striatal dopamine signaling and D2 receptor levels – which have been shown to be decreased in addiction - directly impact impulsivity”
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    Premisereasoning

    Both impulsivity and low striatal dopamine transmission predict drug self-administration.

    “Furthermore, both impulsivity and low striatal dopamine transmission are predictive of drug self-administration.”
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    Interpretationreasoning

    Low D2 receptor binding and dopamine release may occur before drug exposure, alongside impulsivity, and may confer vulnerability to addiction.

    “Increasing data suggests that these biomarkers (low D2 receptor binding and dopamine release) may occur prior to drug exposure, in parallel with impulsivity, which then confer a vulnerability to develop addiction.”
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    Premisecitation

    Addiction involves deficits in inhibitory control, meaning an impaired ability to inhibit thoughts or actions that lead to impulsive behavior.

    “Thus, addiction is characterized by deficits in inhibitory control, which is an impaired capacity to appropriately inhibit thoughts or actions that lead to impulsive behaviors (Groman and Jentsch, 2012).”
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    Premisereasoning

    Increased endogenous dopamine leaves fewer D2 receptors available for radiotracer binding, so PET scans indirectly measure dopamine system responsiveness to a pharmacologic challenge.

    “The increase in endogenous dopamine results in fewer D2 receptors available to bind to the radiotracer (shown in figure 1), such that the PET scans provide an indirect measure of the responsiveness of the dopamine system to a pharmacologic challenge.”
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    Premisecitation

    A consistent finding in addiction imaging is decreased striatal D2 receptor binding, which may be one of the most replicated findings in human imaging research.

    “A consistent finding in imaging studies of addiction is a decrease in striatal D2 receptor binding, which may be one of the most replicated findings in human imaging research.”
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    Premisecitation

    Low striatal D2 receptor binding correlates with metabolism in prefrontal regions implicated in inhibitory control, and the association between D2 receptors and impulsivity may be mediated partly by dopamine's modulation of prefrontal regions.

    “Volkow et al. (Volkow et al., 2008) showed that low striatal D2 receptor binding correlates with metabolism in prefrontal regions that are implicated in inhibitory control, and this group hypothesized that the association between D2 receptors and impulsivity is mediated partly by dopamine’s modulation of prefrontal regions.”
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    Premisecitation

    Cocaine acts directly at the dopamine transporter, but imaging studies of the transporter show little effect.

    “Cocaine acts directly at the dopamine transporter, but imaging studies of the transporter show little effect (Malison et al., 1998; Volkow et al., 1996; Wang et al., 1997a).”
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    Premisecitation

    Attention deficit disorder is associated with decreased D2 receptor binding and stimulant-induced dopamine release.

    “Attention deficit disorder has also been shown to be associated with a decrease in both D2 receptor binding and stimulant-induced dopamine release (Volkow et al., 2007a)”
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    Premisecitation

    Nicotine abuse is associated with upregulation of the nicotinic receptor.

    “Imaging studies of nicotine abuse report upregulation of the nicotinic receptor (Cosgrove et al., 2009; Mukhin et al., 2008; Staley et al., 2006; Wullner et al., 2008)”
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    Premisecitation

    Obesity is associated with low D2 receptor binding, and morbidly obese individuals with the lowest D2 values had the largest body mass index, although one study did not find this.

    “Obesity has been shown to be associated with low D2 receptor binding, and morbidly obese individuals with the lowest D2 values had the largest body mass index (de Weijer et al., 2011; Volkow et al., 2008; Wang et al., 2001), although this was not seen in one study (Steele et al., 2010).”
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    Premisecitation

    Imaging studies of alcohol dependence do not show consistent changes in the GABAA receptor or in serotonin, opioid, or cannabinoid systems.

    “Imaging studies of alcohol dependence do not show a consistent change in the GABAA receptor, although this receptor is the target for treatment for alcohol withdrawal, and no consistent changes have been observed in other neurotransmitter systems (such as the serotonin, opioid, or cannabinoid systems) (for review see (Broft and Martinez, 2012)).”
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    Premisecitation

    Alcohol dependence is associated with reduced VMAT2 compared with controls, but not reduced [18F]DOPA uptake.

    “In alcohol dependence, imaging studies show a reduction in VMAT2 compared to controls (Gilman et al., 1998) although not of [18F]DOPA uptake (Heinz et al., 2005; Tiihonen et al., 1998).”
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    Premisecitation

    The decrease in D2 receptor binding is long lasting, at least 3-4 months in humans and possibly up to a year in non-human primates depending on the individual.

    “On the other hand, the decrease in D2 receptor binding is long lasting, at least 3–4 months in humans (Volkow et al., 1993) and possibly longer, up to a year in non-human primates depending on the individual (Nader et al., 2006).”
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    Interpretationcitation

    Impulsive eating and addiction share the neurobiological marker of low D2/dopamine release, in addition to an inability to restrain behavior despite awareness of negative effects.

    “Together, these findings suggest that impulsive eating and addiction share this neurobiological marker, in addition to the inability to restrain the behavior despite awareness of its negative effects (Volkow et al., 2008).”
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    Premisecitation

    Opiate abusers show upregulation of the mu receptor.

    “and an imaging study of opiate abusers showed upregulation of the mu receptor (Zubieta et al., 2000).”
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    Premisecitation

    Obesity and attention deficit disorder are associated with high impulsivity, measured with tasks similar to those used in addiction.

    “For example, both obesity and attention deficit disorder are associated with high impulsivity, measured with tasks similar to those used in addiction (Bickel et al., 2012b; Carr and Epstein, 2011; Malloy-Diniz et al., 2007).”
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    Premisecitation

    Cocaine abuse is associated with decreased [18F]DOPA uptake and striatal VMAT2 binding.

    “Cocaine abuse is associated with both decreased [18F]DOPA uptake and striatal vesicular monoamine transporter 2 (VMAT2) binding, which provide measures of pre-synaptic dopamine (Narendran et al., 2012; Wu et al., 1997).”
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    Interpretationcitation

    The inverted U model proposes that optimal dopamine transmission, neither too low nor too high, is required for optimal response inhibition, and may explain discrepancies in healthy control studies.

    “One reason for this discrepancy may be explained by the “inverted U” model, which proposes that optimal dopamine transmission, which is neither too low nor too high, is required for optimal response inhibition (Cools and D'Esposito, 2011; Gjedde et al., 2010; Leyton, 2007).”
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    Premisecitation

    Blunted dopamine release in ADHD is associated with greater symptoms of inattention and greater drug liking.

    “and blunted dopamine release was associated with both greater symptoms of inattention and with greater drug liking (Volkow et al., 2007a; although see Rosa-Neto et al., 2005).”
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    Premisecitation

    In healthy controls, dopamine depletion impairs fronto-striatal functional connectivity during set-shifting, suggesting low dopamine may impair prefrontal control over the striatum in cognitive flexibility.

    “In healthy controls, dopamine depletion impairs fronto-striatal functional connectivity during set-shifting, suggesting that low dopamine may impair the control that the prefrontal cortex exhibits over the striatum in governing cognitive flexibility (Nagano-Saito et al., 2008).”
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    Premisecitation

    ADHD subjects show reduced D2 receptor binding in the ventral striatum and caudate, which correlates inversely with attention.

    “A subsequent study of ADHD subjects showed the same finding of reduced D2 receptor binding in the ventral striatum and caudate (Volkow et al., 2009), which correlated inversely with attention.”
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    Interpretationreasoning

    Dysregulation of striatal dopamine transmission affects prefrontal cortical circuits, which act together to modulate drive and impulsivity.

    “Given the role that these pre-frontal cortical brain regions play in modulating inhibitory control these findings suggest that dysregulation of striatal dopamine transmission affects the prefrontal cortical circuits, which act together to modulate drive and impulsivity (Dalley et al., 2011; Groman and Jentsch, 2012).”
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    Premisecitation

    Cognitive deficits have been described in animals chronically exposed to drugs of abuse, indicating these impairments may be due to chronic drug use.

    “Similarly to humans, cognitive deficits have been described in animals chronically exposed to drugs of abuse (Crean et al., 2011; Porter et al., 2011) indicating that these impairments may be due to chronic drug use.”
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    Interpretationcitation

    Decreased dopamine transmission may contribute to motivation and reward deficits in ADHD, which are characterized by poor response inhibition and preference for small immediate rewards over larger delayed rewards.

    “Based on these results, this group hypothesized that decreased dopamine transmission plays a role in the motivation and reward deficits seen in ADHD, which are characterized by poor response inhibition and preference for small immediate rewards over larger delayed rewards (Volkow et al., 2009).”
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    Premisecitation

    Methamphetamine abuse is associated with lower D2 receptor binding compared with controls and higher impulsivity measured with the Barratt Impulsiveness Scale.

    “Methamphetamine abuse is associated with lower D2 receptor binding compared to controls, and higher levels of impulsivity, measured with the Barratt Impulsiveness Scale (Lee et al., 2009).”
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    Premisecitation

    Lesions of the orbitofrontal cortex promote perseverative responding, whereas lesions of the infralimbic cortex enhance premature responding.

    “Lesions of the orbitofrontal cortex promote perseverative responding, whereas lesions of the infralimbic cortex enhance premature responding (Chudasama et al., 2003).”
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    Premisecitation

    High impulsivity predicts the development of compulsive drug-taking, whereas high reactivity to novelty predicts the propensity to initiate cocaine self-administration.

    “Using a similar approach, Belin et al. (Belin et al., 2008) further showed that high impulsivity predicts the development of compulsive drug-taking, whereas high reactivity to novelty predicts the propensity to initiate cocaine self-administration.”
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    Premisecitation

    Although drug exposure could reduce some forms of impulsivity, animal studies aimed at identifying vulnerability factors consistently reveal that impulsivity itself may influence the development of drug dependence.

    “Although there are evidence that drug exposure could reduce some forms of impulsivity (Caprioli et al., 2013), animal studies aimed at identifying vulnerability factors for the development of addiction consistently reveal that impulsivity itself may influence the development of drug dependence.”
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    Premisecitation

    Alcohol-naïve mice or rats selectively bred to prefer ethanol display decreased basal dopamine levels in the nucleus accumbens, and alcohol preference in these animals is reversed by direct dopamine receptor activation.

    “Indeed, alcohol-naïve mice (George et al., 1995) or rats (Gongwer et al., 1989; Quintanilla et al., 2007) selectively bred to prefer ethanol display decreased basal dopamine levels in the nucleus accumbens, and alcohol preference in these animals is reversed by direct dopamine receptor activation (George et al., 1995).”
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    Interpretationcitation

    Subjects with a family history of alcohol or cocaine abuse have higher D2 receptor availability compared with those without this risk factor, suggesting high D2 receptor binding may serve as a marker for resilience.

    “Similar results were seen in a study of subjects with a family history of alcohol or cocaine abuse who have higher D2 receptor availability compared to those without this risk factor, suggesting that high D2 receptor binding may serve as a marker for resilience (Volkow et al., 2006a; Volkow et al., 2006b).”
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    Premisecitation

    Peripheral administration of a D2 receptor antagonist increases impulsivity, as does intra-accumbens shell administration.

    “Moreover, peripheral administration of D2 receptor antagonist increases impulsivity (Wade et al., 2000) as does intra-accumbens shell administration (Besson et al., 2010).”
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    Interpretationreasoning

    Impulsive behavior leads to a preference for small immediate rewards and increased drug self-administration.

    “which leads to a preference for small immediate rewards and increased drug self-administration.”
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    Premisecitation

    Knock-down of D2 receptor in the striatum produces addiction-like compulsive eating in mice, whereas overexpression attenuates alcohol consumption and cocaine self-administration.

    “Finally, knock-down of D2 receptor in the striatum produces addiction-like, compulsive eating in mice (Johnson and Kenny, 2010), whereas its overexpression attenuates alcohol consumption and cocaine self-administration (Thanos et al., 2008; Thanos et al., 2005; Thanos et al., 2004; Thanos et al., 2001).”
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    Premisecitation

    Adolescents with a potential for problematic substance use show greater risk taking and lower striatal activation during a monetary incentive delay reward task than comparison subjects.

    “Similar results have been reported in the IMAGEN trial, which showed that adolescents with the potential for problematic substance use display greater risk taking and lower striatal activation (in response to the monetary incentive delay reward task) relative to comparison subjects (Schneider et al., 2012).”
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    Interpretationreasoning

    Low D2 receptor binding may confer vulnerability to addiction, insofar as pleasurable experience with a drug is a potential risk for addiction.

    “Insofar as pleasurable experience with a drug is a potential risk for addiction (Davidson et al., 1993; Volkow et al., 2002a), these results suggest that low D2 receptor binding may confer vulnerability.”
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    Interpretationcitation

    Low D2 receptor levels and low dopamine signaling correspond with impulsive behavior.

    “Overall, these studies in animals and humans indicate that low D2 receptor levels and low dopamine signaling correspond with impulsive behavior, which leads to a preference for small immediate rewards and increased drug self-administration.”
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    Premisecitation

    Drug exposure itself can further increase impulsive behavior and decrease dopamine release and D2 receptor binding.

    “animal studies have also shown that drug exposure itself can both further increase impulsive behavior and decrease dopamine release and D2 receptor binding, suggesting that a feedback loop may exist”
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    Interpretationcitation

    Non-dependent young adults at high risk for addiction have lower presynaptic dopamine release compared with controls, suggesting this may be associated with increased risk of future addiction.

    “More recently, Casey et al. (Casey et al., In Revision) showed that non-dependent young adults at high risk for addiction (family history of addiction and experience with drugs of abuse) have lower presynaptic dopamine release compared to controls, suggesting that this may be associated with an increased risk of future addiction.”
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    Premisecitation

    Imaging studies of non-addicted individuals show low striatal D2 receptor availability is predictive of a pleasurable response to intravenous stimulant administration, while high binding is associated with an aversive experience.

    “Imaging studies of non-addicted individuals show that low striatal D2 receptor availability is predictive of a pleasurable response to intravenous stimulant administration, while high binding was associated with an aversive experience (Volkow et al., 1999; Volkow et al., 2002a).”
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      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dysfunction of D2 receptor-dependent transmission in the striatum represents a common mechanism underlying impulsivity and addiction, and these alterations are at least partly predictive of the development of addiction.

    “These data support the idea that dysfunction of the D2 receptor dependent transmission in the striatum represents a common mechanism underlying impulsivity and addiction, and that these neurobiological alterations are - at least in part - predictive of the development of addiction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Increasing D2 receptor signaling in the ventral striatum may serve as a treatment strategy for addiction, perhaps by reducing choice impulsivity and enhancing motivation.

    “Thus, we propose that increasing D2 receptor signaling in the ventral striatum may serve as a treatment strategy for addiction, perhaps by reducing choice impulsivity and enhancing motivation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In cocaine abusers, treatment responders had higher socioeconomic status than relapsers and did not differ from controls.

    “the subjects who responded to treatment had a higher socioeconomic status compared to those who relapsed (Barratt Simplified Measure of Social Status: treatment responders 34.1 ± 9.2; non-responders 27.1 ± 4.5, p = 0.01), and actually did not differ from the control group (34.8 ± 7.9, p = 0.8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Martinez et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cocaine-dependent subjects who respond to treatment have better psychosocial function than those who relapse, and may have greater ability or motivation to obtain non-drug rewards.

    “This suggests that the cocaine dependent subjects who respond to treatment have better psychosocial function compared to those who relapse, and may have a greater ability, or motivation, to obtain certain non-drug rewards (such as education and employment).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    A model is proposed in which low D2 receptor signaling coincides with impulsivity, both can be exacerbated by drug exposure, and further drug use progressively increases.

    “Thus, we propose a model where low D2 receptor signaling coincides with impulsivity, both of which can be exacerbated by drug exposure, with a progressive increase in further drug use.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These factors may precede addiction and could serve as a risk factor for substance use disorders.

    “These factors may precede addiction, and could serve as a risk factor for substance use disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Low striatal dopamine transmission, measured as low D2 receptor binding and low presynaptic dopamine release, is associated with increased choice impulsivity, which correlates with a preference for small immediate rewards over larger rewards requiring greater effort.

    “We have reviewed the human and animal data showing that low striatal dopamine transmission, measured as low D2 receptor binding and low pre-synaptic dopamine release, is associated with increased choice impulsivity, which correlates with a preference for small immediate rewards over larger rewards requiring greater effort.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In both the cocaine and methamphetamine studies, subjects with higher D2 binding in the striatum and higher dopamine release showed less impulsive behavior and chose a larger delayed reward over a smaller immediate reward.

    “Thus in both studies, the subjects with the higher D2 binding in the striatum and higher dopamine release showed less impulsive behavior and chose the larger, delayed reward (money and/or treatment) over a smaller, immediate reward (drug).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Increasing D2 receptor signaling may both reduce drug self-administration and increase willingness to work for a non-drug reinforcer, and therefore facilitate treatment.

    “These findings suggest that increasing D2 receptor signaling may both reduce drug-self-administration and increase an individual’s willingness to work for a non-drug reinforcer and therefore facilitate treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    To date, it has not been shown in animal models of substance abuse that increasing D2 receptor signaling reduces drug self-administration and increases willingness to work for non-drug reinforcers.

    “However, to date, this has not been shown in animal models of substance abuse and will require further investigation.”
    Quote in the paperNot a substantial claim
54 of 54

  • The authors state this as an assumption.

    Motivation can be treated as the inverse of impulsivity, namely the ability to resist initiating behavior and to exert greater effort for a more valuable outcome.

    “To an extent, motivation can be thought of as the inverse of impulsivity, as the ability to resist behavior initiation, and exert greater effort in order to obtain a more valuable outcome.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Malison, 1999, Reduced amphetamine-stimulated dopamine release in cocaine addicts as measured by [123I]IBZM SPECT, J. Nucl. Med., 40, 110P
  2. Stefanini, 1992, Alcohol-prefering rats have fewer dopamine D2 receptors in the limbic area, Alcohol Alcohol, 27

Cited by

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Related

Authors
Trifilieff, P., & Martinez, D.
Affiliations
Université de Bordeaux (FR)
ORCID
Trifilieff, Pierre
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2014-01
Volume
76
Issue
B
Pages
498-509
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2013.06.031
PMC
PMC4106030
OpenAlex
W1968417706
Semantic Scholar
b1477600439ed087119417fd7071d572d62c98e4
Cited by
171
References
187
Citations by year
2026: 11 · 2025: 9 · 2024: 16 · 2023: 12 · 2022: 14 · 2021: 15 · 2020: 15 · 2019: 13 · 2018: 15 · 2017: 11 · 2016: 15 · 2015: 13 · 2014: 8 · 2013: 4
FWCI
1.35
Type
journal article
Language
en
Open access
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
Funders
National Institute on Drug Abuse (K02DA026525)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Keywords
impulsivity, drug addiction, dopamine D2 receptor, neuroimaging biomarkers, delayed rewards, effort-based decision making, self-administration, addiction recovery
MeSH terms
Animals, Corpus Striatum, Dopamine, Humans, Radionuclide Imaging, Biomarkers, Receptors, Dopamine D2, Substance-Related Disorders, Neuroimaging

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

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