Dataset Information

Dopamine D_2/3 receptor availability in cocaine use disorder individuals with obesity as measured by [¹¹C]PHNO PET.

ABSTRACT:

Background

Positron emission tomography (PET) work with the dopamine D3 receptor (D₃R) preferring ligand [¹¹C]PHNO in obese individuals has demonstrated higher binding and positive correlations with body mass index (BMI) in otherwise healthy individuals. These findings implicated brain reward areas including the substantia nigra/ventral tegmental area (SN/VTA) and pallidum. In cocaine use disorder (CUD), similar SN/VTA binding profiles have been found compared to healthy control subjects. This study investigates whether BMI-[¹¹C]PHNO relationships are similar in individuals with CUD.

Methods

Non-obese CUD subjects (N = 12) were compared to age-matched obese CUD subjects (N = 14). All subjects underwent [¹¹C]PHNO acquisition using a High Resolution Research Tomograph PET scanner. Parametric images were computed using the simplified reference tissue model with cerebellum as the reference region. [¹¹C]PHNO measures of receptor availability were calculated and expressed as non-displaceable binding potential (BP_ND).

Results

In between-group analyses, D2/3R availability in non-obese and obese CUD groups was not significantly different overall. BMI was inversely correlated withBP_ND in the SN/VTA (r = -0.45, p = 0.02 uncorrected) in all subjects.

Conclusion

These data suggest that obesity in CUD was not associated with significant differences in D_2/3R availability. This in contrast to previous findings in non-CUD individuals that found increased availability of D₃Rs in the SN/VTA associated with obesity. These findings could potentially reflect dysregulation of D₃R in CUD, impacting how affected individuals respond to natural stimuli such as food.

SUBMITTER: Matuskey D

PROVIDER: S-EPMC7889720 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Dopamine D<sub>2/3</sub> receptor availability in cocaine use disorder individuals with obesity as measured by [<sup>11</sup>C]PHNO PET.

Matuskey David D Angarita Gustavo A GA Worhunsky Patrick P Koohsari Sheida S Gravel Paul P Pittman Brian B Gaiser Edward C EC Gallezot Jean-Dominque JD Nabulsi Nabeel N Huang Yiyun Y Carson Richard E RE Potenza Marc N MN Malison Robert T RT

Drug and alcohol dependence 20210108

<h4>Background</h4>Positron emission tomography (PET) work with the dopamine D3 receptor (D<sub>3</sub>R) preferring ligand [<sup>11</sup>C]PHNO in obese individuals has demonstrated higher binding and positive correlations with body mass index (BMI) in otherwise healthy individuals. These findings implicated brain reward areas including the substantia nigra/ventral tegmental area (SN/VTA) and pallidum. In cocaine use disorder (CUD), similar SN/VTA binding profiles have been found compared to he ...[more]

PMID: 33454626

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Project description:Dopamine type 2 and type 3 receptors (D2R/D3R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2R availability and greater D3R availability in regions primarily expressing D2R or D3R concentrations, respectively. However, these CUD-related alterations in D2R and D3R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2R/D3R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2R and D3R availability using regional and source-based analyses of [11C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BPND) in CUD in the midbrain, consistent with prior [11C]-(+)-PHNO research, and lower BPND in CUD in the dorsal striatum, consistent with research using non-selective D2R/D3R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BPND (striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D2R-related proportions of BPND (calculated using independent reports of [11C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D3R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2R/D3R research in CUD, demonstrating both lower BPND in the D2R-rich dorsal striatum and greater BPND in the D3R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11C]-(+)-PHNO BPND that were correlated with regional estimates of D2R-related and D3R-related proportions of BPND, were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D2R/D3R concentration.

Project description:Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D2 and D3 receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (11C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14-30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20-30 min; spleen as reference region) demonstrated a statistically significant reduction (-36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20-30 min) (R 2 = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20-30 min) (R 2 = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20-30 min) (R 2 = 0.57, P = 0.05), nor did mean baseline proinsulin (R 2 = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D3 receptor and dopamine D2 receptor in HCs. No colocalization of the dopamine D3 receptor or dopamine D2 receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D3 receptor, dopamine D2 receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D3 receptor and dopamine D2 receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for 11C-(+)-PHNO, a dopamine D3 receptor-preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.

Project description:Preclinical studies support an important role of dopamine D3 receptors (DRD3s) in alcohol use disorder (AUD). In animals, voluntary alcohol consumption increases DRD3 expression, and pharmacological blockade of DRD3s attenuates alcohol self-administration and reinstatement of alcohol seeking. However, these findings have yet to be translated in humans. This study used positron emission tomography (PET) and [11C]-(+)-PHNO to compare receptor levels in several dopamine D2 receptor (DRD2) and DRD3 regions of interest between AUD subjects in early abstinence (n = 17; 6.59 ± 4.14 days of abstinence) and healthy controls (n = 18). We recruited non-treatment seeking subjects meeting DSM-5 criteria for AUD. We examined the relationship between DRD2/3 levels and both alcohol craving and alcohol motivation/wanting, using a cue reactivity procedure and an intravenous alcohol self-administration (IVASA) paradigm, respectively. [11C]-(+)-PHNO binding levels in AUD subjects were significantly lower than binding in HCs when looking at all DRD2/3 ROIs jointly (Wilk's Λ = .58, F(6,28) =3.33, p = 0.013, η2p = 0.42), however there were no region-specific differences. Binding values demonstrate -12.3% and -16.1% lower [11C]-(+)-PHNO binding in the SMST and SN respectively, though these differences did not withstand Bonferroni corrections. There was a positive association between [11C]-(+)-PHNO binding in the SN (almost exclusively reflective of DRD3) and alpha (lower values reflect higher alcohol demand) in the APT after Bonferroni corrections (r = 0.66, p = 0.0080). This demonstrates that AUD subjects with lower DRD3 levels in the SN exhibit increased demand for alcohol. These results replicate previous findings demonstrating reduced DRD2/3 levels while also supporting a lack of DRD3 upregulation and potential downregulation in early abstinent AUD. Furthermore, the finding that binding in the SN is associated with alcohol demand warrants further examination.

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Project description:Development of medications selective for dopamine D2 or D3 receptors is an active area of research in numerous neuropsychiatric disorders including addiction and Parkinson's disease. The positron emission tomography (PET) radiotracer [11C]-(+)-PHNO, an agonist that binds with high affinity to both D2 and D3 receptors, has been used to estimate relative receptor subtype occupancy by drugs based on a priori knowledge of regional variation in the expression of D2 and D3 receptors. The objective of this work was to use a data-driven independent component analysis (ICA) of receptor blocking scans to separate D2-and D3-related signal in [11C]-(+)-PHNO binding data in order to improve the precision of subtype specific measurements of binding and occupancy. Eight healthy volunteers underwent [11C]-(+)-PHNO PET scans at baseline and at two time points following administration of the D3-preferring antagonist ABT-728 (150-1000 mg). Parametric binding potential (BPND) images were analyzed as four-dimensional image series using ICA to extract two independent sources of variation in [11C]-(+)-PHNO BPND. Spatial source maps for each component were consistent with respective regional patterns of D2-and D3-related binding. ICA-derived occupancy estimates from each component were similar to D2-and D3-specific occupancy estimated from a region-based approach (intraclass correlation coefficients > 0.95). ICA-derived estimates of D3 receptor occupancy improved quality of fit to a single site binding model. Furthermore, ICA-derived estimates of the regional fraction of [11C]-(+)-PHNO binding related to D3 receptors was generated for each subject and values showed good agreement with region-based model estimates and prior literature values. In summary, ICA successfully separated D2-and D3-related components of the [11C]-(+)-PHNO binding signal, establishing this approach as a powerful data-driven method to quantify distinct biological features from PET data composed of mixed data sources.

Dataset Information

Dopamine D_2/3 receptor availability in cocaine use disorder individuals with obesity as measured by [¹¹C]PHNO PET.

Background

Methods

Results

Conclusion

Publications

Dopamine D<sub>2/3</sub> receptor availability in cocaine use disorder individuals with obesity as measured by [<sup>11</sup>C]PHNO PET.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Dopamine D2/3 receptor availability in cocaine use disorder individuals with obesity as measured by [11C]PHNO PET.

Background

Methods

Results

Conclusion

Publications

Dopamine D<sub>2/3</sub> receptor availability in cocaine use disorder individuals with obesity as measured by [<sup>11</sup>C]PHNO PET.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dopamine D_2/3 receptor availability in cocaine use disorder individuals with obesity as measured by [¹¹C]PHNO PET.