Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens
Introduction
Food intake is controlled by many factors. In order for an organism to survive, its energy intake and output must be closely regulated, and the behaviors that are likely to benefit an organism's survival must be highly motivated. Considering that these primitive systems evolved early in phylogeny, often under conditions of food scarcity, it is not surprising that food intake would be rewarded, and that the reward would be mediated by many factors within multiple brain sites. Reward for feeding is governed by the mesolimbic dopamine (DA) pathway, which consists of dopaminergic cell bodies that reside in the VTA and project to multiple nodes, including the Acb, amygdala, prefrontal cortex, and hippocampus [15]. Food intake is driven not only by reward, however, but also by metabolic forces, primarily mediated by numerous factors within hypothalamic nuclei [26]. Until recently, energy intake and expenditure were thought of as parts of a stable homeostatic process that maintains a constant body weight. However, with the obesity epidemic gaining in severity throughout the world, feeding behavior must now be considered outside of the scope of homeostatic regulation, and the increasing abundance of inexpensive, highly rewarding foods in obese societies suggests an interaction between homeostatic factors and reward processes [2].
One factor originally thought to act only at the hypothalamus to stimulate food intake is ghrelin, a peptide hormone that is released primarily from the stomach but acts anabolically in the brain [5], [17], [31], [33]. The ghrelin receptor is highly expressed in the hypothalamus, particularly in the arcuate nucleus (ARC), as well as in the caudal brainstem, where some gustatory information is processed. It is also expressed in the VTA, hippocampus, substantia nigra, and dorsal and medial raphe nuclei [10], [14]. Expression of the ghrelin receptor in the VTA and hippocampus, two primary nodes of the mesolimbic dopamine pathway, might indicate that ghrelin, normally considered a homeostatic factor, can also act on reward circuitry, perhaps to modulate feeding behavior.
To determine the network of sites that regulate food intake, two-site microinjection studies are often performed, particularly regarding opioid-stimulated feeding [8], [9], [23], [24], [29], which is an important component of reward-related food intake. These studies reveal a complex network of sites for which feeding induced by opioids in one site requires opioid signaling at another site. Generally, an opioid agonist is injected into one site, while an opioid antagonist or saline is injected into another site. In many studies, opioid signaling in one site is required for opioids at the other site to elicit feeding. For example, the μ-opioid agonist, DAMGO, injected into the VTA requires opioid signaling in the Acb to increase feeding, and feeding elicited by DAMGO injected into the Acb requires opioid signaling in the VTA [23]. Two-site microinjections can be used to determine interactions between other factors as well. For example, opioid-induced feeding in the VTA requires DA signaling in the Acb, but opioid-induced feeding in the Acb does not require DA signaling in the VTA [24]. Studies such as these are revealing a much more complex network of feeding sites than originally imagined. Furthermore, they are revealing interactions between factors formerly thought to mediate separate processes of reward and metabolism. One study found that for neuropeptide Y (NPY) to induce feeding when injected into the hypothalamic paraventricular nucleus (PVN), opioid signaling is required in the hindbrain nucleus of the solitary tract (NTS) [20]. Since NPY was initially thought to stimulate food intake via metabolic pathways, rather than via reward, but opioids mediate reward-based feeding, this study shows a direct neural interaction between homeostatic and hedonic pathways. Food intake appears to be regulated by a much more diverse set of processes than the homeostatic theory would indicate.
Because the ghrelin receptor is expressed in portions of the mesolimbic reward pathway, we hypothesized that microinjection of ghrelin into the VTA would increase food intake in rats. However, since there is no evidence of ghrelin receptor expression in the Acb [19], we expected no effect of intra-Acb ghrelin administration on feeding behavior. We also hypothesized that opioids might affect ghrelin-induced feeding in the VTA and Acb, since opioids are involved in many reward-related feeding circuits [21]. We tested our hypotheses by doubly cannulating rats in the VTA and Acb, performing a dose-response feeding study for ghrelin in each site, and finally by pretreing each alternate site with the opioid antagonist, naltrexone (NTX), before injecting ghrelin.
Section snippets
Materials and methods
Male Sprague-Dawley rats (Charles River, Wilmington, MD), weighing 225–250 g were individually housed in wire mesh hanging cages with a 12 h light/12 h dark photoperiod (lights on at 0700 h) in a temperature-controlled room (21–22 °C). Rats were anesthetized with sodium pentobarbital (60 mg/kg) injected intraperitoneally and fitted with unilateral (Acb) and bilateral (VTA, 2 mm apart) 26-gauge stainless steel guide cannulae (Plastics One, Austin, TX). Stereotaxic coordinates taken from the rat brain
Results
Experiment 1: Ghrelin stimulated feeding at the highest dose (0.3 nmol) in both sites, increasing intake after 1 h by 29-fold in the VTA and by eight-fold in the Acb (Fig. 2). After 2 h, intake at the highest dose was 11 times greater than saline in the VTA and six times greater than saline in the Acb. By the 4 h time point, intake at the highest dose remained 11 times greater than saline in the VTA and 3.5 times greater than saline in the Acb. Two-way ANOVA indicated no main effect of site at the
Discussion
We found that the highest dose of ghrelin (0.3 nmol) significantly increased feeding when injected into the VTA or the Acb, and that this effect was not dependent on opioid signaling in the alternate site. Intake stimulated from the VTA, the origin of the mesolimbic DA reward pathway, was at least twice as great as that stimulated from the Acb.
In Experiment 1, we found that there was a significant effect of site at the 0–2 and 0–4 h time points, and a significant interaction of dose and site at
Acknowledgements
This work was supported by the Department of Veterans Affairs, by the National Institute of Drug Abuse Grant DA-03999, P30 DK-50456, the Minnesota Craniofacial Research Training Program grant T32-DE07288, and NIH PO1 DK68384 (to D.E.C.).
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2021, NeuroImageCitation Excerpt :Kroemer et al. (2013) showed that higher fasting ghrelin is associated with greater neural FCR to palatable food images in a bilateral network of visual processing-, reward- and taste-related regions in normal weight adults. In addition to these human studies, many animal studies support the idea that ghrelin acts on mesolimbic reward and motivational pathways to increase FCR (Abizaid et al., 2006; Carlini et al., 2004; Naleid et al., 2005). According to these studies, current knowledge about the relationship between ghrelin levels and FCR is limited to samples including normal weight individuals.