Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity

Eisenstein, Sarah A.; Gredysa, Danuta M.; Antenor-Dorsey, Jo Ann V.; Green, Leonard; Arbeláez, Ana María; Koller, Jonathan M.; Black, Kevin J.; Perlmutter, Joel S.; Moerlein, Stephen M.; Hershey, Tamara

doi:10.1371/journal.pone.0133621

Cited by 54 publications

(58 citation statements)

References 89 publications

(127 reference statements)

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“…Data from these individuals regarding the relationship between obesity and striatal D2R were previously presented (Eisenstein et al, 2013; Eisenstein et al, 2015b; Eisenstein et al, 2015a). Obese ( n = 24) and non-obese ( n = 20) individuals, aged 18-40 years, were eligible for the study based on strict inclusion and exclusion criteria (Eisenstein et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

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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Section: Methodsmentioning

confidence: 99%

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

Eisenstein

Bogdan

Love‐Gregory

et al. 2016

Synapse

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“…Selected data from these subjects have been reported previously (13–15). Potential subjects completed a comprehensive medical evaluation that included an oral glucose tolerance test (OGTT); those who had diabetes, smoked tobacco, were taking medications that affect dopamine function, had an IQ <80, or had neurological conditions including parkinsonism, lifetime psychosis, mania, substance dependence, major depression, social phobia, or eating disorders and panic disorders determined by neurological examination and psychiatric interview were excluded.…”

Section: Methodsmentioning

confidence: 99%

Sweet Dopamine: Sucrose Preferences Relate Differentially to Striatal D2 Receptor Binding and Age in Obesity

et al. 2016

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Alterations in dopaminergic circuitry play a critical role in food reward and may contribute to susceptibility to obesity. Ingestion of sweets releases dopamine in striatum, and both sweet preferences and striatal D2 receptors (D2R) decline with age and may be altered in obesity. Understanding the relationships between these variables and the impact of obesity on these relationships may reveal insight into the neurobiological basis of sweet preferences. We evaluated sucrose preferences, perception of sweetness intensity, and striatal D2R binding potential (D2R BPND) using positron emission tomography with a D2R-selective radioligand insensitive to endogenous dopamine, (N-[11C] methyl)benperidol, in 20 subjects without obesity (BMI 22.5 ± 2.4 kg/m2; age 28.3 ± 5.4 years) and 24 subjects with obesity (BMI 40.3 ± 5.0 kg/m2; age 31.2 ± 6.3 years). The groups had similar sucrose preferences, sweetness intensity perception, striatal D2R BPND, and age-related D2R BPND declines. However, both striatal D2R BPND and age correlated with sucrose preferences in subjects without obesity, explaining 52% of their variance in sucrose preference. In contrast, these associations were absent in the obese group. In conclusion, the age-related decline in D2R was not linked to the age-related decline in sweetness preferences, suggesting that other, as-yet-unknown mechanisms play a role and that these mechanisms are disrupted in obesity.

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“…In humans, reduced insulin sensitivity is associated with less endogenous dopamine at D2/3 receptors in the NAcc and acute dopamine depletion, in turn, reduces insulin sensitivity [93]. Importantly, a recent PET study has shown that insulin sensitivity is not correlated with D2 receptor binding per se using a non-replaceable tracer [94]. Insulin has been shown to reduce food-cue reactivity in the brain including the striatum [95, 96] and, accordingly, cue-induced appetite [96].…”

Section: Endocrine Modulation Of Dopamine Signalingmentioning

confidence: 99%

Fuel not fun: Reinterpreting attenuated brain responses to reward in obesity

Kroemer

Small

2016

Physiology & Behavior

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There is a well-established literature linking obesity to altered dopamine signaling and brain response to food-related stimuli. Neuroimaging studies frequently report enhanced response in dopaminergic regions during food anticipation and decreased responses during reward receipt. This has been interpreted as reflecting anticipatory “reward surfeit”, and consummatory “reward deficiency”. In particular, attenuated response in the dorsal striatum to primary food rewards is proposed to reflect anhedonia, which leads to overeating in an attempt to compensate for the reward deficit. In this paper, we propose an alternative view. We consider brain response to food-related stimuli in a reinforcement-learning framework, which can be employed to separate the contributions of reward sensitivity and reward-related learning that are typically entangled in the brain response to reward. Consequently, we posit that decreased striatal responses to milkshake receipt reflect reduced reward-related learning rather than reward deficiency or anhedonia because reduced reward sensitivity would translate uniformly into reduced anticipatory and consummatory responses to reward. By re-conceptualizing reward deficiency as a shift in learning about subjective value of rewards, we attempt to reconcile neuroimaging findings with the putative role of dopamine in effort, energy expenditure and exploration and suggest that attenuated brain responses to energy dense foods reflect the “fuel”, not the fun entailed by the reward.

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Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity

Cited by 54 publications

References 89 publications

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

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

Sweet Dopamine: Sucrose Preferences Relate Differentially to Striatal D2 Receptor Binding and Age in Obesity

Fuel not fun: Reinterpreting attenuated brain responses to reward in obesity

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