A Functional Inhibitory Role of Habenular Glucagon-Like Peptide-1 (GLP-1) in Forebrain Reward Signaling

Abstract

There is emerging evidence implicating glucagon-like peptide-1 (GLP-1) in reward, including palatable food reinforcement and alcohol-based reward circuitry. While recent findings suggest that mesolimbic structures, such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc), are critical anatomical sites mediating the role of GLP-1’s inhibitory actions, the present study focused on the potential novel impact of GLP-1 within the habenula, a region of the forebrain expressing GLP-1 receptors. Given that the habenula has also been implicated in the neural control of reward and reinforcement, we hypothesized that this brain region, like the VTA and NAc, might mediate the anhedonic effects of GLP-1. Rats were stereotaxically implanted with guide cannula targeting the habenula and trained on a progressive ratio 3 (PR3) schedule of reinforcement. Separate rats were trained on an alcohol two-bottle choice paradigm with intermittent access. The GLP-1 agonist exendin-4 (Ex-4) was administered directly into the habenula to determine the effects on operant responding for palatable food as well as alcohol intake. Our results indicated that Ex-4 reliably suppressed PR3 responding and that this effect was dose-dependent. A similar suppressive effect on alcohol consumption was observed. These findings provide initial and compelling evidence that the habenula may mediate the inhibitory action of GLP-1 on reward, including operant and drug reward. Our findings further suggest that GLP-1 receptor mechanisms outside of the midbrain and ventral striatum are critically involved in brain reward neurotransmission.