The GLP-1 agonist exendin-4 attenuates self-administration of sweetened fat on fixed and progressive ratio schedules of reinforcement in rats

Abstract

GLP-1 agonists such as exendin-4 (EX4) are used in the treatment of type 2 diabetes and have the additional benefit of promoting weight loss. GLP-1 agonists decrease feeding through peripheral affects, but recent evidence suggests they may also influence sweet or high fat preference, as well as the motivation to obtain these tastants. Yet it remains unclear how GLP-1 induced alterations in food preference influences the decrease in overall feeding. The current study sought to determine if EX4 affects the reinforcing strength and consumption of a highly palatable sweet/fat reinforcer. Rats were trained to self-administer sweetened vegetable shortening (SVS) under fixed (FR) and progressive ratio (PR) schedules of reinforcement. EX4 (0.3 - 2.4 μg/kg, IP) administered one hour prior to operant sessions significantly reduced responding for SVS under both FR and PR schedules (e.g. total reinforcers and breakpoints, respectively), although the lowest active dose (0.6 μg/kg) significantly suppressed FR responding only. EX4 also dose dependently decreased locomotor activity (0.6-2.4 μg/kg doses), but did not enhance acute kaolin intake, indicating that EX4-induced nausea did not influence the self-administration results. Analysis of ED50 values show that EX4 is more effective at inhibiting FR responding versus PR, indicating that EX4 may have more potent effects on consummatory versus appetitive feeding behaviors. Although EX4 caused generalized behavioral suppression, these results cannot fully explain the decreases in operant responding. For example, the 0.6 μg/kg dose inhibited only FR responding, even though the rats were physically capable of responding at a higher rate during PR sessions. In addition, the rate of intake was constant at the beginning of the sessions in both PR and FR schedules, regardless of the dose. Together these data suggest that EX4 inhibits consumption of a palatable high sweet/high fat reinforcer potentially through altering satiety.

Exendin-4 disrupts responding to reward predictive incentive cues in rats

“…However, it is important to note that we also observed substantial individual variation in the latency to nosepoke and first IC rewarded at the 2.4 g/kg dose. This is similar to results in our previous study in which 2.4 g/kg EX4 increased the latency to the first lever press in a model of sweetened fat self-administration (Bernosky-Smith et al, 2016). Such individual differences should be explored further in future studies of EX4 on motivation.…”

“…Specific to nausea, we have previously reported that EX4 did not induce pica in a kaolin test at any of these doses (Bernosky-Smith et al, 2016). It is possible that the IC task is more sensitive to visceral malaise than the kaolin test, and therefore the decrease in IC responding, particularly at higher doses of EX4 could have a nausea component.…”

“…The most parsimonious explanation for attenuation of responding in our IC task is that EX4 inhibited locomotor activity or reduced appetite via an increase in nausea, two well-known side effects of GLP-1R agonists. However, the rats performed the IC task at the same level as vehicle at the 0.6 dose, and to some extent the 1.2 g/kg EX4 dose, even though these doses have been previously reported to decrease locomotor behavior (Bernosky-Smith et al, 2016). Further, while EX4 inhibited the total number of nosepokes at the 1.2 and 2.4 g/kg doses, only the highest dose, 2.4 g/kg, inhibited reward cup entries (Figure 2), even though both metrics require a similar degree of motor activity.…”

“…For example, systemic, intraventricular (ICV), and targeted EX4 microinfusions into the mesolimbic structures including the nucleus accumbens (NAc) and ventral tegmental area (VTA) decreased lever pressing for food rewards and decreased food intake when highly palatable foods and standard chow were available concurrently (Dickson et al, 2012;Yang et al, 2014). Recently, we demonstrated that EX4 dosedependently attenuated operant responding for a sweetened fat reward under both the fixed ratio 1 and progressive ratio schedules (FR1 and PR, respectively (Bernosky-Smith et al, 2016), with EX4 being more effective in reducing FR1 responding.…”

Ghrelin and Glucagon-Like Peptide-1: A Gut-Brain Axis Battle for Food Reward

“…As opposed to ghrelin, GLP-1 signaling reduces instrumental responding for high fat/sucrose food rewards. Administration of exendin-4 in rats, for example, whether via ip injection [ 66 , 83 , 84 ] or icv infusion [ 66 , 85 ], dampens motivated lever pressing for sucrose. As a primary CNS node in the gut-to-brain axis, it is not surprising that the NTS contributes to the central effects of GLP-1 signaling on food motivated behaviors.…”