Striatal dopamine D2/D3 receptor binding in pathological gambling is correlated with mood-related impulsivity

Clark, Luke; Stokes, Paul; Wu, Kit; Michalczuk, Rosanna; Benecke, Aaf; Watson, Ben; Egerton, Alice; Piccini, Paola; Nutt, David; Bowden‐Jones, Henrietta; Lingford‐Hughes, Anne

doi:10.1016/j.neuroimage.2012.06.067

Cited by 175 publications

(106 citation statements)

References 58 publications

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“…Consistent with previous work, we found higher impulsivity scores in individuals with GD compared with HV (Clark et al 2012; Michalczuk et al 2011). Preclinical studies suggest that reductions in or lower levels of GABA are associated with greater impulsivity (Boy et al 2011; Murphy et al 2012; Paine et al 2011).…”

Section: Discussionsupporting

confidence: 93%

“…Consistent with our hypothesis that there would be a positive relationship between impulsivity and [ 11 C]Ro15‐4513 V T , we found such a relationship in subcortical limbic regions in GD but not in HV. The relationship between [ 11 C]Ro15‐4513 V T and ‘NU’ construct of impulsivity adds further support to the idea that mood‐related impulsivity is especially relevant to disordered gambling (Clark et al 2012; Nussbaum et al 2011). It is notable that we have found NU to be associated with our PET studies of dopamine D2, MOR and now GABA‐A receptor in those with GD but not healthy controls suggesting that dysregulation in these systems has particular relevance to impulsivity in gambling (Clark et al 2012; Mick et al 2015).…”

Section: Discussionmentioning

confidence: 61%

“…The relationship between [ 11 C]Ro15‐4513 V T and ‘NU’ construct of impulsivity adds further support to the idea that mood‐related impulsivity is especially relevant to disordered gambling (Clark et al 2012; Nussbaum et al 2011). It is notable that we have found NU to be associated with our PET studies of dopamine D2, MOR and now GABA‐A receptor in those with GD but not healthy controls suggesting that dysregulation in these systems has particular relevance to impulsivity in gambling (Clark et al 2012; Mick et al 2015). Given the association with NU, further exploration revealed a positive relationship between trait anxiety and [ 11 C]Ro15‐4513 V T in the amygdala in the GD group only.…”

Section: Discussionmentioning

confidence: 61%

“…As previous work (Clark et al 2012; Michalczuk et al 2011) has shown that NU, as a mood‐related subgroup of impulsivity, is most strongly associated with GD, we chose to test for correlations between UPPS‐P NU and a priori selected brain regions. Correlations were considered significant at p < 0.05, and for the group comparisons, if ROIs are to be treated as independent, multiple comparison correction adjusts the significance value to p < 0.0125.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously shown that Negative Urgency (NU) derived from the UPPS‐P impulsivity scale is related to dopamine D2/3 receptor availability in GD (Clark et al 2012) and also to MOR availability (Mick et al 2015). As the main inhibitory neurotransmitter in the human brain, the role of GABAergic functioning in impulsivity is attracting attention with growing preclinical evidence supporting its involvement (Hayes et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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Evidence for GABA‐A receptor dysregulation in gambling disorder: correlation with impulsivity

et al. 2016

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As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15‐4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11C]Ro15‐4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of the ‘Negative Urgency’ construct of impulsivity in GD, and these were positively associated with higher [11C]Ro15‐4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11C]Ro15‐4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence for GABA‐A receptor dysregulation in gambling disorder: correlation with impulsivity

et al. 2016

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Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

Eisenstein

Bogdan

Love‐Gregory

et al. 2016

Synapse

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In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are non-selective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N‐[11C]methyl)benperidol ([11C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in 2 independent samples. Sample 1 (n = 39) was composed of obese and non-obese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5-12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1−), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1− was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [11C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states. GRAPHICAL ABSTRACT We investigated the difference in striatal dopamine D2 receptor binding, as measured by PET with (N-[11C]methyl)benperidol ([11C]NMB), between A1 allele carriers (A1+) and individuals homozygous for the A2 allele (A1−) of the DRD2/ANKK1 TaqIA single nucleotide polymorphism. In Study 1, A1+ had 5-12% less striatal [11C]NMB binding than A1−.

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