Imaging of dopamine D2/3 agonist binding in cocaine dependence: A [11C]NPA positron emission tomography study

Narendran, Rajesh; Martínez, Diana; Mason, N. Scott; Lopresti, Brian J.; Himes, Michael L.; Chen, Chi-Min; May, Maureen A.; Price, Julie C.; Mathis, Chester A.; Frankle, W. Gordon

doi:10.1002/syn.20970

Cited by 29 publications

(28 citation statements)

References 27 publications

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“…Our finding of no differences in striatal [ 11 C]PHNO binding between abstinent ADP and controls with or without DRD3 blockade initially appears therefore inconsistent. However, recent studies using [ 11 C]PHNO (Boileau et al, 2012;Matuskey et al, 2011;Payer et al, 2013) or [ 11 C]NPA (Narendran et al, 2011) reported no significant differences in striatal binding in stimulant-dependent individuals compared with controls. In one, post-hoc analysis showed that heavy, but not moderate, methamphetamine users had slightly decreased [ 11 C]PHNO binding in dorsal striatum (Boileau et al, 2012).…”

Section: Discussionmentioning

confidence: 98%

“…Although we cannot rule out this possibility in the current data set, a recent study does not support this. A study using both the antagonist [ 11 C]raclopride and the agonist [ 11 C]NPA to measure DRD2 HIGH and DRD2 LOW reported no differences in DRD2 HIGH between cocaine addicts and controls (Narendran et al, 2011).…”

Section: D3 Receptors In Alcoholismmentioning

confidence: 99%

“…In four recent imaging studies, the agonist DRD2/3 radioligands [ 11 C]PHNO (Boileau et al, 2012;Matuskey et al, 2011;Payer et al, 2013) and [ 11 C]NPA (Narendran et al, 2011) were used to compare DRD2/3 receptor availability between individuals with stimulant dependence and matched healthy controls. No significant difference between the groups in striatal DRD2/3 availability was found in contrast to evidence from the previous antagonist studies.…”

Section: Introductionmentioning

confidence: 99%

“…No significant difference between the groups in striatal DRD2/3 availability was found in contrast to evidence from the previous antagonist studies. As both [ 11 C]PHNO and [ 11 C]NPA have higher affinity for DRD3 relative to DRD2 compared with the antagonist ligands (Narendran et al, 2006), the authors speculated that the lack of difference could be a consequence of decreased DRD2 HIGH combined with increased DRD3 binding in stimulant dependence compared with healthy controls (Boileau et al, 2012;Narendran et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Erritzoe

Tziortzi

Bargiela

et al. 2014

Neuropsychopharmacol

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Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [ 11 C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [ 11 C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [ 11 C]PHNO binding between the groups at baseline. However, baseline [ 11 C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (V T : 16.5±4 vs 13.7±2.9, p ¼ 0.040), a region in which the [ 11 C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (V T ) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in V T following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [ 11 C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.

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Section: Discussionmentioning

confidence: 98%

Section: D3 Receptors In Alcoholismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Erritzoe

Tziortzi

Bargiela

et al. 2014

Neuropsychopharmacol

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“…For clusters showing a significant relationship between fallypride measures and max DEQ ratings, we extracted mean BPnd or %ΔBPnd data using Marsbar (Brett et al, 2002) and subjected these values to a bootstrapped Pearson correlation (to identify 95% confidence intervals, CI) and multiple regression analyses (to test for the impact of potential confounds on BPnd) in SPSS. We covaried for potential confounds of plasma amphetamine levels, effective dAMPH dose, sex (known to impact DA signaling (Pohjalainen et al, 1998;Riccardi et al, 2006b)), and subject age (found to negatively correlate with BPnd (Mukherjee et al, 2002;Narendran et al, 2011)) in these follow-up regression analyses.…”

Section: Discussionmentioning

confidence: 99%

Variability in paralimbic dopamine signaling correlates with subjective responses to D-amphetamine

Smith¹

2016

Intrinsic Act

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Subjective responses to psychostimulants vary, the basis of which is poorly understood, especially in relation to possible cortical contributions. Here, we tested for relationships between participants' positive subjective responses to oral d-amphetamine (dAMPH) versus placebo and variability in striatal and extrastriatal dopamine (DA) receptor availability and release, measured via positron emission tomography (PET) with the radiotracer 18 F-fallypride. Analyses focused on 35 healthy adult participants showing positive subjective effects to dAMPH measured via the Drug Effects Questionnaire (DEQ) Feel, Like, High, and Want More subscales (Responders), and were repeated after inclusion of 11 subjects who lacked subjective responses. Associations between peak DEQ subscale ratings and both baseline 18 F-fallypride binding potential (BPnd; an index of D2/D3 receptor availability) and the percentage change in BPnd post dAMPH (%ΔBPnd; a measure of DA release) were assessed. Baseline BPnd in ventromedial prefrontal cortex (vmPFC) predicted the peak level of High reported following dAMPH. Furthermore, %ΔBPnd in vmPFC positively correlated with DEQ Want More ratings. DEQ Want More was also positively correlated with %ΔBPnd in right ventral striatum and left insula. This work indicates that characteristics of DA functioning in vmPFC, a cortical area implicated in subjective valuation, are associated with both subjective high and incentive (wanting) responses. The observation that insula %ΔBPnd was associated with drug wanting converges with evidence suggesting its role in drug craving. These findings highlight the importance of variability in DA signaling in specific paralimbic cortical regions in dAMPH's subjective response, which may confer risk for abusing psychostimulants.

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Association of Stimulant Use With Dopaminergic Alterations in Users of Cocaine, Amphetamine, or Methamphetamine

et al. 2017

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Importance Stimulant use disorder is common, affecting between 0.3 to 1.1% of the population, and costs over $85 billion per year globally. There are currently no licensed treatments. Several lines of evidence implicate the dopamine system in the pathophysiology of substance use disorder. Thus understanding the nature of dopamine dysfunction seen in stimulant users has the potential to aid the development of new therapeutics. Objective To comprehensively review the in-vivo imaging evidence for dopaminergic alterations in stimulant (cocaine or amphetamine/methamphetamine) drug abuse or dependence. Data sources The entire PubMed, EMBASE and PsycINFO databases were searched for studies from inception date to May 14, 2016. Study selection A total of 31 studies were identified that compared dopaminergic measures between 519 stimulant users and 512 controls using positron emission tomography or single-photon emission computed tomography to measure striatal dopamine synthesis or release, or dopamine transporter or receptor availability. Data extraction and synthesis Demographic, clinical and imaging measures were extracted from each study and meta-analyses and sensitivity analyses were conducted for stimulants combined and cocaine and amphetamines separately where there were sufficient studies. Main Outcomes and Measures We determined the difference in dopamine release (assessed using change in the D2/3 receptor availability following administration of amphetamine or methylphenidate), transporter and receptor availability in cocaine, amphetamine and methamphetamine users and healthy controls. Results In majority of the studies the duration of abstinence varied from 5 days to 3 weeks. There was a significant decrease in striatal dopamine release (stimulants combined: Hedge’s g= −0.84; cocaine: −0.87, both p<0.001), dopamine transporter availability (stimulants combined: Hedge’s g= −0.91, p<0.01; amphetamine and methamphetamine: Hedge’s g: −1.47, p<0.001) and D2/3 availability (stimulants combined: Hedge’s g= −0.76; cocaine: −0.73; amphetamine and methamphetamine: −0.81, all p<0.001). We did not find consistent alterations in vesicular monoamine transporter, dopamine synthesis or D1 receptor studies. Conclusion and relevance Our data suggest that both pre and post-synaptic aspects of the dopamine system in the striatum are down-regulated in stimulant users. We discuss the commonality and difference between these findings and the discrepancies with the preclinical literature as well as their implications for future drug development.

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Imaging of dopamine D_2/3 agonist binding in cocaine dependence: A [¹¹C]NPA positron emission tomography study

Cited by 29 publications

References 27 publications

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Variability in paralimbic dopamine signaling correlates with subjective responses to D-amphetamine

Association of Stimulant Use With Dopaminergic Alterations in Users of Cocaine, Amphetamine, or Methamphetamine

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