Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression

Abstract

The decision to eat is strongly influenced by non-homeostatic factors such as food palatability. Indeed, the rewarding and motivational value of food can override homeostatic signals, leading to increased consumption and hence, obesity. Ghrelin, a gut-derived orexigenic hormone, has a prominent role in homeostatic feeding. Recently, however, it has emerged as a potent modulator of the mesolimbic dopaminergic reward pathway, suggesting a role for ghrelin in food reward. Here, we sought to determine whether ghrelin and its receptors are important for reinforcing motivation for natural sugar reward by examining the role of ghrelin receptor (GHS-R1A) stimulation and blockade for sucrose progressive ratio operant conditioning, a procedure used to measure motivational drive to obtain a reward. Peripherally and centrally administered ghrelin significantly increased operant responding and therefore, incentive motivation for sucrose. Utilizing the GHS-R1A antagonist JMV2959, we demonstrated that blockade of GHS-R1A signaling significantly decreased operant responding for sucrose. We further investigated ghrelin's effects on key mesolimbic reward nodes, the ventral tegmental area (VTA) and nucleus accumbens (NAcc), by evaluating the effects of chronic central ghrelin treatment on the expression of genes encoding major reward neurotransmitter receptors, namely dopamine and acetylcholine. Ghrelin treatment was associated with an increased dopamine receptor D5 and acetylcholine receptor nAChRβ2 gene expression in the VTA and decreased expression of D1, D3, D5 and nAChRα3 in the NAcc. Our data indicate that ghrelin plays an important role in motivation and reinforcement for sucrose and impacts on the expression of dopamine and acetylcholine encoding genes in the mesolimbic reward circuitry. These findings suggest that ghrelin antagonists have therapeutic potential for the treatment of obesity and to suppress the overconsumption of sweet food.

Figure 1

Peripheral ghrelin injection increases the motivation to obtain palatable food in a PR ratio operant conditioning model. The number of responses on the active lever (a) and the number of 45 mg sucrose rewards obtained (b) are significantly increased by 0.33 mg/kg IP ghrelin injection for a 120-minute period of operant testing. Intake of freely available chow is also increased by IP ghrelin injection (c). Data represent the mean ± SEM, n = 15, *P < 0.05, **P < 0.005 from vehicle

Figure 2

CNS (third ICV) ghrelin delivery increases the rewarding value of sucrose in a PR ratio operant conditioning model. The number of responses on the active lever (a) and the number of 45 mg sucrose rewards obtained (b) are significantly increased by third ICV ghrelin injection for the 120-minute period of operant testing. Short-term intake of freely available chow is also increased by IP ghrelin injection (c). Data represent the mean ± SEM, n = 13, *P < 0.05, **P < 0.005 from vehicle, post hoc Tukey analysis

Figure 3

Peripheral delivery of a ghrelin receptor antagonist, JMV2959. decreases the motivation to obtain palatable food in a PR ratio operant conditioning model. The number of responses on the active lever (a) and the number of 45 mg sucrose rewards obtained (b) are significantly decreased by IP JMV2959 injection for the 120-minute period of operant testing. Data represent the mean ± SEM, n = 13, *P < 0.05, **P < 0.005 from vehicle, post hoc Tukey analysis

Figure 4

Central blockade of GHS-R1A with JMV2959 decreases the motivation to obtain food reward in a PR ratio operant conditioning model. The number of responses on the active lever (a) and the number of 45 mg sucrose rewards obtained (b) are significantly decreased by third ICV delivery of the GHS-R1A antagonist for the 120-minute period of operant testing. Short-term intake of freely available chow was not altered by central JMV2959 treatment in this paradigm (c). Data represent the mean ± SEM, n = 15, *P < 0.05, **P < 0.005, ***P < 0.0005 from vehicle, post hoc Tukey analysis

Figure 5

Dopamine and acetylcholine associated gene expression in VTA (a) and NAcc (b) after chronic ICV ghrelin or vehicle treatment. Data represent the mean of fold change relative to saline treatment. D1, dopamine D1 receptor; D2 dopamine D2 receptor; D3, dopamine D3 receptor; D5, dopamine D5 receptor; COMT, catechol-O-methyltransferase, TH tyrosine hydroxylase; and MAOA, monoamine oxidase A; nAChR, nicotinic acetylcholine receptor subunits α3 α6, β2, β3 *P < 0.05, **P < 0.005, ***P < 0.0005 from vehicle