Changes in dopamine release and dopamine D2/3 receptor levels with the development of mild obesity

Dopamine (DA) neurotransmission is an important modulator of both homeostatic food consumption mediated by the hypothalamus, and reward-related/ hedonic food consumption mediated by the brain reward circuit (Lutter and Nestler, 2009; Schwartz et al., 2000; Wise, 2008). Although there are monogenetic mutations that affect the regulation of body weight, the majority of cases of human obesity appear to result from the interaction of polygenetic predispositions to obesity with an environment in which highly palatable foods are readily available leading to excessive consumption of such foods (Walley et al. 2009). There have been two major hypotheses regarding the role of DA neurotransmission in the development of obesity. The first postulates a rewarddeficient state leading to compensatory overeating to remedy an anhedonic state; decreased brain reward circuit DA neurotransmission is hypothesized to be a significant factor in this reward-deficient state (Blum et al., 2000; Geiger et al., 2008). The second hypothesis postulates that increased behavioral salience of food produces excessive intake of highly palatable foods leading to obesity; this increased behavioral salience is believed to be mediated by increased ventral striatal DA release (Berridge et al., 2009). Although studies of obese animals and obesity prone animals have consistently shown decreased striatal DA release and DA D2/3 receptor levels (DA D2r), to date there have been no published data in humans on changes in DA release in the evolution of obesity and varying results on changes in DA D2r with the development of obesity (Eisenstein et al., 2013; Geiger et al., 2008; Haltia et al., 2007; Johnson and Kenny, 2010; Wang et al., 2001). The purpose of this study was to evaluate the changes in DA release and DA D2r with the development of mild obesity. Baseline [F]fallypride PET studies were performed in 33 healthy subjects (M5 18, F515, mean age5 25.8, range 18–35; mean BMI5 24.8, range 19–35) as previously described to determine regional DA D2r (Kessler, 2009). To evaluate regional DA release, 16 of the 33 subjects having the baseline [F]fallypride positron emission tomography (PET) study (8M, 8F; mean age5 24.3, age range5 21–32; mean BMI5 25.2, body mass index (BMI) range of 19–35) had a second [F]fallypride PET study 3 h following oral administration of 0.43 mg/kg d-amphetamine.(Riccardi et al., 2006). Regions believed to be involved in the development of obesity including ventral striatum, ventral midbrain/substantia nigra, amygdala, caudate, and putamen were specifically examined. High-resolution T1-weighted MRI scans and PET scans of the brain were performed and coregistered to each other. Regions of interest were delineated on the coregistered MRI, and regional estimates of DA D2r (BPND’s) and amphetamine-induced DA release were calculated as previously described (Kessler, 2009; Riccardi et al., 2006). Correlations of regional DA D2r and DA release with BMI were performed using a Pearson product moment correlation covaried for age. Correlations of DA D2r with BMI covaried for age demonstrated small negative correlations in the regions examined (Table 1). Correlations in the right