Ventral Striatum Binding of a Dopamine D2/3 Receptor Agonist But Not Antagonist Predicts Normal Body Mass Index

Abstract

Background Positron emission tomography research has shown that dopamine D2/3 receptor (D2/3R) availability is negatively correlated with body mass index (BMI) in obese but not in healthy subjects. However, previous positron emission tomography studies have not looked specifically at the ventral striatum (VS), which plays an important role in motivation and feeding. Furthermore, these studies have only used antagonist radiotracers. Normal-weight rats given free access to high-fat diets demonstrate behavioral sensitization to D2/3R agonists but not to antagonists. Sensitization is associated with increased D2/3R affinity, which affects binding of agonists but not antagonists. Methods We examined the association between BMI within the nonobese range (18.6–27.8) and D2/3R availability in the VS with the use of the agonist radiotracer [11C]-(+)-PHNO (n = 26) and the antagonist [11C]-raclopride (n = 35) in healthy humans. Results In the VS, we found a positive correlation between BMI and [11C]-(+)-PHNO binding but no relationship with [11C]-raclopride binding. Secondary analyses revealed no relationship between BMI and binding in the dorsal striatum with either radiotracer. Conclusions We propose that in nonobese individuals, higher BMI may be associated with increased D2R affinity in the VS. This increased affinity may potentiate the incentive salience of food cues and counteract the effects of satiety cues, thereby increasing feeding.

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

“…Although debate still exists whether this can be Seeman, 2012;Skinbjerg et al, 2012), in theory, only agonist tracers like [ 11 C](+)PHNO would prefer these sites as D 2/3 R antagonist tracers typically bind with equal preference to both high-and low-affinity forms of the D 2/3 R. Therefore, it is possible that these differential binding characteristics could also help explain our VST findings such that the regulation of 'active' highaffinity forms vs 'inactive' low-affinity forms of the D 2/3 R may be altered in obesity. Our finding in the VST is also consistent with the previous [ 11 C](+)PHNO work in non-OB individuals (Caravaggio et al, 2013) and preclinical research that posits the nucleus accumbens, a central component of the VST, plays a key role in the formation/development of the OB phenotype (Davis et al, 2008;Geiger et al, 2009;Hryhorczuk et al, 2016;Rada et al, 2010;Valenza et al, 2015). This regional specificity, along with tracer properties, may help explain why differences were not found in the dorsal striatum.…”

“…Prior work with [ 11 C](+)PHNO has demonstrated in non-OB individuals a positive linear association between BMI and tracer binding in the VST (Caravaggio et al, 2013). Our work extends those findings into an OB population when BMI categorical cohorts were combined.…”

“…Furthermore, within both severely obese and OB (Haltia et al, 2007) individuals, a negative linear association between D 2/3 R availability and BMI was observed. This relationship did not extend to non-OB individuals, where no associations between striatal D 2/3 R availability and BMI have been found with [ 11 C]raclopride (Caravaggio et al, 2013). Work done with the D 2 -high affinity tracer, [ 11 C]N-methyl-benperidol (NMB), failed to show any striatal D 2/3 R availability alterations between NW and severely obese individuals (Eisenstein et al, 2013 .…”

“…In addition, [ 11 C](+)PHNO has also been shown to bind to high-affinity, presumably 'active', G-protein coupled forms of the D 2 R within the striatum (Shotbolt et al, 2012;Willeit et al, 2006). Prior work done with [ 11 C](+) PHNO has indicated that BMI correlated positively with D 2/3 R availability in the ventral striatum (VST) (Caravaggio et al, 2013), a region of mixed D 2 Rs and D 3 Rs (Tziortzi et al, 2011), in a cohort with a relatively narrow non-OB BMI range (range 18.6-27.8 kg/m 2 , mean 23.4 kg/m 2 ). Further work in a wide-BMI-ranged (range 21.5-36.5 kg/m 2 , mean 27.9 kg/m 2 ) small cohort showed a positive association between D 2/3 R availability and BMI in the right dorsal caudate (Cosgrove et al, 2015).…”

“…Additionally, in regions where D 2/3 R differences were observed, a cohort of 14 overweight (OW) individuals was added to investigate linear associations in a sample representative of the United States population based on BMI (ie,~33% NW,~33% OW, and~33% OB) (Flegal et al, 2012). Based on prior work (Caravaggio et al, 2013) and tracer-binding characteristics (Shotbolt et al, 2012;Tziortzi et al, 2011), we expected to observe higher [ 11 C](+)PHNO tracer binding in important brain reward areas in OB compared with NW individuals in regions populated with D 3 Rs (ie, the SN/VTA) and in mixed striatal regions where high-affinity 'active' forms of the D 2 R may exist (ie, VST) as well as positive linear relationships between tracer binding and BMI in those respective regions after the OW cohort was added. Overall, this work aims to extend the obesity literature by providing useful and informative data contributing to mechanistic understanding of the disease and identify potential novel pharmacologic targets for treatment.…”