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

Abstract

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.

The relationship between subcortical brain volume and striatal dopamine D2/3 receptor availability in healthy humans assessed with [11C]‐raclopride and [11C]‐(+)‐PHNO PET

“…This finding is generally important for [ 11 C]‐(+)‐PHNO studies using cross‐sectional or between group designs. For example, it will be important to determine whether increased [ 11 C]‐(+)‐PHNO BP ND in obese persons corresponds with concordant increases in striatal volumes [Caravaggio et al, ; Gaiser et al, ].…”

“…Elucidating the relationship between metabolic health and striatal D 2/3 R availability remains an on‐going and exciting field of exploration in PET [Caravaggio et al, ; Dang et al, ; Gaiser et al, ; Horstmann, ]. It is beyond the scope of the current manuscript to review all these conflicting PET findings; considering all the different radioligands used for D 2/3 R, each with their own unique in vivo binding characteristics.…”

Striatal dopamine transporter changes after glucose loading in humans

“…Therefore, molecular neuroimaging using dopamine receptor (DR) radiopharmaceuticals was adopted in order to understand the dopaminergic pathway in the brain. When compared with lean controls, DR availability in individuals with moderate obesity was observed to be higher than that in individuals with severe obesity . However, results among studies are inconsistent, and the role of DR in obesity is uncertain.…”

“…When compared with lean controls, DR availability in individuals with moderate obesity was observed to be higher than that in individuals with severe obesity. 6,7 However, results among studies are inconsistent, and the role of DR in obesity is uncertain. In addition, DR availability acquired by positron emission tomography (PET) is sensitive to the endogenous concentrations of dopamine, 8 which can complicate interpretation of results.…”

Dopamine Adaptations as a Common Pathway for Neurocognitive Impairment in Diabetes and Obesity: A Neuropsychological Perspective

“…There are consistent findings in the animal literature that HFD, and adiposity alter DA signaling at the cellular, and molecular levels (Anderzhanova et al, 2007; Johnson and Kenny, 2010; van de Giessen et al, 2012, 2013; Sharma and Fulton, 2013; Tellez et al, 2013; Cansell et al, 2014; Adams et al, 2015; Woods et al, 2016), as well as mounting evidence for altered DA signaling in human obesity, especially reflected in changes in DA receptor density, (Wang et al, 2001, 2011; Dunn et al, 2010; Steele et al, 2010; Eisenstein et al, 2013, 2015; Guo et al, 2014; Cosgrove et al, 2015; Horstmann et al, 2015; Karlsson et al, 2015; Caravaggio et al, 2015b; Dang et al, 2016; Gaiser et al, 2016). Additionally, there is evidence that central and peripheral insulin resistance might impact DA function.…”