Reward, dopamine and the control of food intake: implications for obesity

Abstract

The ability to resist the urge to eat requires the proper functioning of neuronal circuits involved in top-down control to oppose the conditioned responses that predict reward from eating the food and the desire to eat the food. Imaging studies show that obese subjects might have impairments in dopaminergic pathways that regulate neuronal systems associated with reward sensitivity, conditioning and control. It is known that the neuropeptides that regulate energy balance (homeostatic processes) through the hypothalamus also modulate the activity of dopamine cells and their projections into regions involved in the rewarding processes underlying food intake. It is postulated that this could also be a mechanism by which overeating and the resultant resistance to homoeostatic signals impairs the function of circuits involved in reward sensitivity, conditioning and cognitive control.

Published by Elsevier Ltd.

Figures

Figure 1

Regulation of food intake relies on multichannel communication between overlapping reward and homeostatic neurocircuits. (a) Schematic diagram of the crosstalk between the homeostatic (hypothalamus, HYP) and reward circuits that control food intake. The HYP is central to energy balance and several of its nuclei are involved in energy regulation [arcuate (ARC), dorsomedial (DMH) ventromedial (VMH) and lateral HYP (LH)] integrating orexigenic and anorexigenic signals from the periphery and the CNS and communicating these to regions from the reward circuitry. For example, orexin neurons in LH are influenced by leptin and ghrelin and, in turn, project to reward regions via OX1 and OX2 receptors. Several key neuropeptides produced in various hypothalamic nuclei are indicated: corticotrophin-releasing hormone (CRH), tyrotrophin-releasing hormone (TRH), oxytocin (OT), vasopressin (AVP), cocaine- and amphetamine-regulated transcript (CART), NPY, agouti-related protein (AgRP), proopiomelanocortin (POMC), galanin (GAL), neurotensin (NT), leptin, orexin, luteinizing hormone-releasing hormone (LHRH) and melanin-concentrating hormone (MCH). By contrast, top-down inhibition of feeding depends heavily on the PFC, including OFC and ACC. The amygdala ascribes emotional attributes and, together with memory and learning circuitry, generates conditioned responses. This circuit is subject to strong influence coming from cortical and mesolimbic input. Many of the orexigenic and anorexigenic peripheral signals directly influence neural computations not only in hypothalamus, but also in mesocorticolimbic structures (amygdala, OFC and hippocampus). Conversely, many classic neurotransmitters (DA, CB, opioids, GABA and serotonin) are produced as a result of mesocorticolimbic activity and influence the HYP. For comprehensive reviews, see [26,105]. (b) Expression of orexigenic and anorexigenic genes in the central circuitry (data derived from the Allen Brain Atlas; http://www.brain-map.org). Each box represents a brain region and the circles indicate expression levels of genes in the region. Circle sizes represent expression density (‘+’ expression is sparse to ‘+++’ expression throughout the entire area). Colors represent expression levels (dark blue < light blue < turquoise < light green < orange < red). The location of each gene symbol in the boxes does not correlate with the distribution of that gene within the brain region it represents. Gene symbols without circles are mentioned when only expression density or level is >0. POMC is a precursor for an orexigen, β-endorphin, and for an anorexigen, α-melanocyte-stimulating hormone. Reproduced, with permission, from [106].

Figure 2

Leptin decreases whereas ghrelin increases reactivity to food stimuli in brain reward areas. (a, b) Brain images showing areas where leptin reduced the activation (NAc-caudate) in two subjects with leptin deficiency. (b) Histogram for the activation response to food stimuli in subjects with leptin deficiency before and after leptin treatment. (c) Ghrelin increases reactivity to food stimuli in brain reward areas, as indicated by SPM images showing brain areas where activation by food stimuli was greater with ghrelin than with saline; and (d) a histogram of limbic areas for the response to food stimuli after saline (controls; red bars) and after ghrelin (blue bars). Modified, with permission, from [19] (a, b) and [55] (c, d).

Figure 3

Hyperphagia could result from a drive to compensate for a weakened reward circuit (processed through dopamine regulated corticostriatal circuits) combined with a heightened sensitivity to palatability (hedonic properties of food processed in part through the somatosensory cortex). (a) Averaged images for DA D2 receptor (D2R) availability in controls (n=10) and in morbidly obese subjects (n=10). (b) Results from SPM identifying the areas in the brain where D2R was associated with glucose metabolism, these included the medial OFC, ACC and the dorsolateral PFC (region not shown). (c) Regression slope between striatal D2R and metabolic activity in ACC in obese subjects. (d) Three-dimensionally rendered SPM images showing the areas with higher metabolism in obese than in lean subjects (P <0.003, uncorrected). (e) Color-coded SPM results displayed in a coronal plane with a superimposed diagram of the somatosensory homunculus. The results (z value) are presented using the rainbow scale where red > yellow > green. When compared with lean subjects, obese subjects had higher baseline metabolism in the somatosensory areas where the mouth, lips and tongue are represented and which are involved with processing food palatability. Modified, with permission, from [22] (a–c) and [68] (d,e).

Figure 4

Obese subjects have a decreased response in DA target regions when given food compared with that recorded in lean subjects. (a) Coronal section of weaker activation in the left caudate nucleus in response to receiving a milkshake versus a tasteless solution; (b) Correlation between the difference in activation and BMI of the subjects. Modified, with permission, from [67].