Abstract
Drugs which agonise the glucagon-like peptide-1 receptor (GLP-1R) system cause reductions in body weight comparable to bariatric surgery. In addition, recent studies using GLP-1R agonists reveal that treated animals will consume less alcohol, nicotine, amphetamines, opiates and cocaine than their untreated conspecifics. It therefore appears that GLP-1R agonists reduce desire to consume, and hence do not act solely through peripheral mechanisms, but by reducing the cognitive motivation to obtain reward. It is therefore important to investigate the neural circuit through which these drugs act. Traditional dopaminergic reward circuitry contains relatively few GLP-1 receptors when compared with the lateral septum (LS). This region richly expresses GLP-1 receptors, and is centrally connected to receive cognitive information from the hippocampus and communicate with these reward regions, making it a candidate region for the cognitive control of reward. We aimed to examine GLP-1R agonist associated changes in reward representation and activity by LS. We next aimed to probe the potential role of GLP-1R agonist driven reductions in consummatory behaviour. We conducted electrophysiological recordings of the LS of male rats (n=3) under the influence of the GLP-1R agonist liraglutide to examine GLP-1R agonist-associated changes in local field potential. Compared to saline, liraglutide increased the frequency of theta rhythm, and significantly reduced the power of highfrequency oscillations in LS. I next investigated GLP-1R agonist-driven behavioural changes in female rats (n=12) in two operant tasks: the progressive ratio (PR) task, and differential reinforcement of low rates task (DRL). The PR task is used as a test of sustained effort: rats must progressively increase their number of lever presses to obtain a reward of constant value. High-dose liraglutide (0.06 mg/kg) produced a dose-dependent reduction in breakpoint (the point at which animals cease responding) compared to low-dose (0.03 mg/kg) liraglutide, but this was not significantly different from control. Next, I tested rats in the DRL-ii 15 task. This task is often used to assess behavioral inhibition, since animals must wait 15 seconds between lever presses to obtain reward. Presses in the wait interval reset the timer. Under acute liraglutide rats shifted their responses to later time periods. Under chronic dosing, liraglutide (0.06mg/kg) caused a significant increase in the time between responses compared to controls. These findings support the growing theory that GLP-1 agonists modulate reward representation and motivation for rewards. Moreover, they provide initial evidence suggesting a neural substrate for their action. With the increasing use of GLP-1 agonists for obesity, weight loss, and the ongoing clinical trials of these drugs for substance use disorders, clarifying their neural mechanism and their effects on motivation and behaviour is of increasing significance.