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

Abstract

Exendin-4 (EX4) is a GLP-1 receptor agonist used clinically to control glycemia in Type-2 Diabetes Mellitus (T2DM), with the additional effect of promoting weight loss. The weight loss seen with EX4 is attributable to the varied peripheral and central effects of GLP-1, with contributions from the mesolimbic dopamine pathway that are implicated in cue-induced reward seeking. GLP-1 receptor agonists reduce preference for palatable foods (i.e. sweet and fat) as well as the motivation to obtain and consume these foods. Accumulating evidence suggest that GLP-1 receptor activity can attenuate cue-induced reward seeking behaviors. In the present study, we tested the effects of EX4 (0.6, 1.2, and 2.4 {micro}g/kg i.p.) on incentive cue (IC) responding. This rat model required rats to emit a nosepoke response during an intermittent audiovisual cue to obtain a sucrose reward (10% solution). EX4 dose-dependently attenuated responding to reward predictive cues, and increased latencies of the cue response and reward cup entry to consume the sucrose reward. Moreover, EX4 dose-dependently decreased the number of nosepokes relative to the number of cue presentations during the session. There was no drug effect on the number of reward cup entries per reward earned during the session, a related reward-seeking behavior with similar locomotor demand. Interestingly, there was a dose-dependent effect of time on the responding to reward predictive cues and nosepoke response latency, such that 2.4 {micro}g/kg of EX4 delayed responding to the initial IC of the behavioral session. Together, these findings suggest that agonism of the GLP-1 receptor with EX4 modulates the incentive properties of cues attributed with motivational significance.