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. 2021 Nov;46(12):2112-2120.
doi: 10.1038/s41386-021-01095-2. Epub 2021 Aug 4.

Exploring regulation and function of dopamine D3 receptors in alcohol use disorder. A PET [11C]-(+)-PHNO study

Chidera C Chukwueke  1   2 , Christina N Nona  3 , Matthew D McPhee  4 , Esmaeil Mansouri  5 , Dafna S Rubin-Kahana  6   7 , Diana Martinez  8   9 , Isabelle Boileau  5   7 , Christian S Hendershot  10   11 , Bernard Le Foll  6   12   4   7   13   14
Affiliations

Exploring regulation and function of dopamine D3 receptors in alcohol use disorder. A PET [11C]-(+)-PHNO study

Chidera C Chukwueke et al. Neuropsychopharmacology. 2021 Nov.

Abstract

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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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. This figure compares the [11C]-(+)-PHNO BPND of AUD subjects to those of healthy controls.
A one-way MANOVA revealed significantly lower binding in AUD subjects compared to healthy controls when looking at all ROIs jointly (Wilk’s Λ = .58, F(6,28) =3.33, p = 0.013, η2p = 0.42). There were no region-specific differences in binding levels between groups. BPND nondisplaceable binding potential, AST associate striatum, SMST sensorimotor striatum.
Fig. 2
Fig. 2. This panel of graphs show the main effects of alcohol craving and the correlations between alcohol-cue-induced craving and [11C]-(+)-PHNO BPND.
A compares cue elicited craving in both the neutral and alcohol cue condition, the alcohol cues eliciting greater craving than neutral cues (t (15) =6.612, p < 0.0001). B–D graph the correlation analysis between [11C]-(+)-PHNO BPND in different ROIs and alcohol cue-elicited craving. These ROIs were chosen to depict DRD3-rich (SN), DRD2-rich (SMST) and DRD2/3 mixed areas (LST). There were no statistically significant correlations except for in the LST which showed a significant positive correlation with binding levels (r = 0.513, p = 0.042), though this did not survive Bonferroni corrections (corrected significance level p = 0.0083). AUQ Alcohol Urge Questionnaire. ***= p value < 0.001.
Fig. 3
Fig. 3. This panel of graphs shows IVASA alcohol consumption patterns, the correlation between motivation to consume alcohol and [11C]-(+)-PHNO BPND, and the correlation between [11C]-(+)-PHNO BPND and alcohol demand.
A shows the time course of breath alcohol concentration (BrAC) throughout the intravenous self-administration session. During this session, participants achieved an average BrAC of 0.65 ± 0.39 mg/dL at around the 60-min mark. B–D graph the correlation analysis between [11C]-(+)-PHNO BPND in different ROIs and peak BrAC achieved during the session. These ROIs were chosen to depict DRD3-rich (SN), DRD2-rich (SMST) and DRD2/3 mixed areas (LST). There were no statistically significant correlations between peak BrAC and binding in any ROI. E This graph depicts the correlation between [11C]-(+)-PHNO BPND and the alpha values of the alcohol purchase task (APT). There is a significant positive correlation between these measures such that AUD subjects with lower [11C]-(+)-PHNO BPND in the SN display lower alpha values (r = 0.66, p = 0.0080).
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