Dopamine's role in inhibitory control is well recognized and its disruption may contribute to behavioral disorders of discontrol such as obesity. However, the mechanism by which impaired dopamine neurotransmission interferes with inhibitory control is poorly understood. We had previously documented a reduction in dopamine D2 receptors in morbidly obese subjects. To assess if the reductions in dopamine D2 receptors were associated with activity in prefrontal brain regions implicated in inhibitory control we assessed the relationship between dopamine D2 receptor availability in striatum with brain glucose metabolism (marker of brain function) in ten morbidly obese subjects (BMI>40 kg/m 2 ) and compared it to that in twelve non-obese controls. PET was used with [ 11 C]raclopride to assess D2 receptors and with [ 18 F] FDG to assess regional brain glucose metabolism. In obese subjects striatal D2 receptor availability was lower than controls and was positively correlated with metabolism in dorsolateral prefrontal, medial orbitofrontal, anterior cingulate gyrus and somatosensory cortices. In controls correlations with prefrontal metabolism were not significant but comparisons with those in obese subjects were not significant, which does not permit to ascribe the associations as unique to obesity. The associations between striatal D2 receptors and prefrontal metabolism in obese subjects suggest that decreases in striatal D2 receptors could contribute to overeating via their modulation of striatal prefrontal pathways, which participate in inhibitory control and salience attribution. The association between striatal D2 receptors and metabolism in somatosensory cortices (regions that process palatability) could underlie one of the mechanisms through which dopamine regulates the reinforcing properties of food. KeywordsOrbitofrontal cortex; Cingulate gyrus; Dorsolateral prefrontal; Dopamine transporters; Raclopride, PET The increase in obesity and associated metabolic diseases seen over the past decade has raised concern that if not controlled this may become the number one preventable public health threat for the 21st century (Sturm, 2002 (Berthoud, 2007). The extent to which individuals differ in their ability to inhibit these responses and control how much they eat is likely to modulate their risk for overeating in our current food rich environments (Berthoud, 2007).We had shown that in healthy individuals D2 receptor availability in the striatum modulated eating behavioral patterns (Volkow et al., 2003). Specifically the tendency to eat when exposed to negative emotions was negatively correlated with D2 receptor availability (the lower the D2 receptors the higher the likelihood that an individual would eat if emotionally stressed). In addition, in a different study, we showed that morbidly obese subjects (BMI>40) had lower than normal D2 receptor availability and these reductions were proportional to their BMI (Wang et al., 2001). These findings led us to postulate that low D2 receptor availability could put an...

Overeating in obese individuals shares similarities with the loss of control and compulsive drug taking behavior observed in drug-addicted subjects. The mechanism of these behaviors is not well understood. Our prior studies with positron emission tomography (PET) in drug-addicted subjects documented reductions in striatal dopamine (DA) D2 receptors. In pathologically obese subjects, we found reductions in striatal DA D2 receptors similar to that in drug-addicted subjects. Moreover, DA D2 receptor levels were found to have an inverse relationship to the body mass index of the obese subjects. We postulated that decreased levels of DA D2 receptors predisposed subjects to search for reinforcers; in the case of drug-addicted subjects for the drug and in the case of the obese subjects for food as a means to temporarily compensate for a decreased sensitivity of DA D2 regulated reward circuits. Understanding the mechanism in food intake will help to suggest strategies for the treatment of obesity.

Obesity has been associated with a higher risk for impaired cognitive function, which most likely reflects associated medical complications (i.e., cerebrovascular pathology). However, there is also evidence that in healthy individuals excess weight may adversely affect cognition (executive function, attention, and memory). Here, we measured regional brain glucose metabolism (using positron emission tomography (PET) and 2‐deoxy‐2[18F]fluoro‐d‐glucose (FDG)) to assess the relationship between BMI and brain metabolism (marker of brain function) in 21 healthy controls (BMI range 19–37 kg/m2) studied during baseline (no stimulation) and during cognitive stimulation (numerical calculations). Statistical parametric mapping (SPM) revealed a significant negative correlation between BMI and metabolic activity in prefrontal cortex (Brodmann areas 8, 9, 10, 11, 44) and cingulate gyrus (Brodmann area 32) but not in other regions. Moreover, baseline metabolism in these prefrontal regions was positively associated with performance on tests of memory (California Verbal Learning Test) and executive function (Stroop Interference and Symbol Digit Modality tests). In contrast, the regional brain changes during cognitive stimulation were not associated with BMI nor with neuropsychological performance. The observed association between higher BMI and lower baseline prefrontal metabolism may underlie the impaired performance reported in healthy obese individuals on some cognitive tests of executive function. On the other hand, the lack of an association between BMI and brain metabolic activation during cognitive stimulation indicates that BMI does not influence brain glucose utilization during cognitive performance. These results further highlight the urgency to institute public health interventions to prevent obesity.

The cDNA for the dopamine D 3 receptor was isolated and characterized in 1990. Subsequent studies have indicated that D 3 receptors, as well as D 3 receptor mRNA, are primarily localized in limbic regions in mammals. This finding led to the postulate that D 3 receptors may be involved in drug dependence and addiction. However, this hypothesis has been difficult to test due to the lack of compounds with high selectivity for central D 3 receptors. The interpretation of results from studies using mixed D 2 /D 3 agonists and/or antagonists is problematic because these agents have low selectivity for D 3 over D 2 receptors and it is likely that their actions are primarily related to D 2 receptor antagonism and possibly interaction with other neurotransmitter receptors. Currently, with the synthesis and characterization of new highly selective D 3 receptor antagonists such as SB-277011-A this difficulty has been surmounted. The purpose of the present article is to review, for the first time, the effects of various putative D 3 receptor selective compounds in animal models of drug dependence and addiction. The results obtained with highly selective D 3 receptor antagonists such as SB-277011-A, SB-414796, and NGB-2904 indicate that central D 3 receptors may play an important role in drug-induced reward, drug-taking, and cue-, drug-, and stressinduced reinstatement of drug-seeking behavior. Provided these results can be extrapolated to human drug addicts, they suggest that selective DA D 3 receptor antagonists may prove effective as potential pharmacotherapeutic agents to manage drug dependence and addiction.

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