Lack of Age-Dependent Decrease in Dopamine D3 Receptor Availability: A [11C]-(+)-PHNO and [11C]-Raclopride Positron Emission Tomography Study

Nakajima, Shinichiro; Caravaggio, Fernando; Boileau, Isabelle; Chung, Jun Ku; Plitman, Eric; Gerretsen, Philip; Wilson, Alan A.; Houle, Sylvain; Mamo, David C.; Graff‐Guerrero, Ariel

doi:10.1038/jcbfm.2015.129

Cited by 24 publications

(28 citation statements)

References 38 publications

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“…These findings were confirmed in a whole-brain voxel-wise analysis and are largely consistent with previous studies finding age-related differences in the striatum (Nakajima et al, 2015). ROI analysis did not find age-related changes in in the high-binding extrastriatial areas of the SN/VTA and hypothalamus; however, whole-brain analysis identified regions of the midbrain where BP ND was positively associated with age.…”

Section: Discussionsupporting

confidence: 92%

“…Despite these tracer dissimilarities, the current results of receptor availability decline with age show no differences in the net measurement of age effects when compared to previously studied ligands. This suggests a D 2 R specific mechanism in the dorsal striatum, similar to previous findings with [ 18 F]NMB and [ 11 C](+)PHNO (Eisenstein et al, 2012; Nakajima et al, 2015). …”

Section: Discussionsupporting

confidence: 90%

“…A recent paper focused on the relationship of [ 11 C](+)PHNO and [ 11 C]raclopride (Nakajima et al, 2015) with aging, finding decreases in D 2 R, but not D 3 R rich regions such as the SN/VTA. The current work extends upon those findings by investigating whether receptor availability measured with [ 11 C](+)PHNO is associated with age-related decreases in subcortical brain regions of interest (ROI) and whole-brain voxel-wise analyses in a completely independent cohort.…”

Section: Introductionmentioning

confidence: 99%

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Age-related changes in binding of the D2/3 receptor radioligand [11C](+)PHNO in healthy volunteers

et al. 2016

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Objective Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D2/3R (D2R family) in the striatum using antagonist radiotracers that are largely nonselective for D2R vs. D3R subtypes. Therefore, less is known about any possible age effects in D3-rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [11C](+)PHNO, a D3R-preferring agonist radiotracer, also declines with age. Methods Forty-two healthy control subjects (9 females, 33 males; age range 19-55 years) were scanned with [11C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials (BPND) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images. Results Regional [11C](+)PHNO BPND displayed a negative correlation between receptor availability and age in the caudate (r=−0.56, corrected p = 0.0008) and putamen (r=−0.45, corrected p = 0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions. Conclusion In accordance with previous studies, the striatum (an area rich in D2R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D3R signal as measured with [11C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D2R receptor availability decreases with age while D3R availability stays unchanged or is increased.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Age-related changes in binding of the D2/3 receptor radioligand [11C](+)PHNO in healthy volunteers

et al. 2016

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“…Specifically, this work demonstrated that OB individuals exhibited higher D 2/3 Rs in both extrastriatal (ie, SN/VTA and pallidum) and striatal (ie, VST) regions associated with reward and motivation with the latter finding being the first published difference in any addiction-like condition with [ 11 C](+)PHNO in the striatum. These results were unaffected by adjustment for potential confounding factors such as age (Ishibashi et al, 2009;Kim et al, 2011;Matuskey et al, 2016;Nakajima et al, 2015;Volkow et al, 2000) or tracer injection parameters, and were confirmed with a whole-brain voxel-wise analysis. Moreover, after adding a cohort of OW individuals, we observed a positive linear association between BMI and D 2/3 R availability in the aforementioned regions that also persisted after adjusting for age, gender, and tracer injection parameters.…”

Section: Discussionmentioning

confidence: 61%

Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO

Gaiser

Gallezot

Worhunsky

et al. 2016

Neuropsychopharmacol

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Most prior work with positron emission tomography (PET) dopamine subtype 2/3 receptor (D 2/3 R) non-selective antagonist tracers suggests that obese (OB) individuals exhibit lower D 2/3 Rs when compared with normal weight (NW) individuals. A D 3 -preferring D 2/3 R agonist tracer, [ 11 C](+)PHNO, has demonstrated that body mass index (BMI) was positively associated with D 2/3 R availability within striatal reward regions. To date, OB individuals have not been studied with [ 11 C](+)PHNO. We assessed D 2/3 R availability in striatal and extrastriatal reward regions in 14 OB and 14 age-and gender-matched NW individuals with [ 11 C](+)PHNO PET utilizing a high-resolution research tomograph. Additionally, in regions where group D 2/3 R differences were observed, secondary analyses of 42 individuals that constituted an overweight cohort was done to study the linear association between BMI and D 2/3 R availability in those respective regions. A group-by-brain region interaction effect (F 7, 182 = 2.08, p= 0.047) was observed. Post hoc analyses revealed that OB individuals exhibited higher tracer binding in D 3 -rich regions: the substantia nigra/ventral tegmental area (SN/VTA) (+20%; p = 0.02), ventral striatum (VST) (+14%; po0.01), and pallidum (+11%; p = 0.02). BMI was also positively associated with D 2/3 R availability in the SN/VTA (r = 0.34, p = 0.03), VST (r = 0.36, p = 0.02), and pallidum (r = 0.30, p = 0.05) across all subjects. These data suggest that individuals who are obese have higher D 2/3 R availability in brain reward regions densely populated with D 3 Rs, potentially identifying a novel pharmacologic target for the treatment of obesity.

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“…Notably, BP ND in the GP appears distinct from other regions. For example, [ 11 C]-raclopride BP ND in the GP was not found to be related to age, as it is for the other striatal ROIs (Nakajima et al, 2015). We contend that this is a valid ROI with [ 11 C]-raclopride and note that for the current investigation, GP BP ND was found to be differentially related to personality traits compared to nearby structures, such as the putamen.…”

Section: Discussionmentioning

confidence: 89%

Exploring personality traits related to dopamine D2/3 receptor availability in striatal subregions of humans

Caravaggio

Fervaha

Chung

et al. 2016

European Neuropsychopharmacology

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While several studies have examined how particular personality traits are related to dopamine D2/3 receptor (D2/3R) availability in the striatum of humans, few studies have reported how multiple traits measured in the same persons are differentially related to D2/3R availability in different striatal sub-regions. We examined how personality traits measured with the Karolinska Scales of Personality are related to striatal D2/3R availability measured with [11C]-raclopride in 30 healthy humans. Based on previous literature, five personality traits were hypothesized to be most likely related to D2/3R availability: impulsiveness, monotony avoidance, detachment, social desirability, and socialization. We found self-reported impulsiveness was negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. After controlling for age and gender, monotony avoidance was also negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. Socialization was positively correlated with D2/3R availability in the ventral striatum and putamen. After controlling for age and gender, the relationship between socialization and D2/3R availability in these regions survived correction for multiple comparisons (p-threshold=.003). Thus, within the same persons, different personality traits are differentially related to in vivo D2/3R availability in different striatal sub-regions.

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Lack of Age-Dependent Decrease in Dopamine D₃ Receptor Availability: A [¹¹C]-(+)-PHNO and [¹¹C]-Raclopride Positron Emission Tomography Study

Cited by 24 publications

References 38 publications

Age-related changes in binding of the D2/3 receptor radioligand [11C](+)PHNO in healthy volunteers

Age-related changes in binding of the D2/3 receptor radioligand [11C](+)PHNO in healthy volunteers

Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO

Exploring personality traits related to dopamine D2/3 receptor availability in striatal subregions of humans

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