Abstract
Glucagon-like-peptide-1 (GLP-1) is a gut- and neuro-peptide with an important role in the regulation of food intake and glucose metabolism. Interestingly, GLP-1 receptors (GLP-1R) are expressed in key mesolimbic reward areas (including the ventral tegmental area, VTA), innervated by hindbrain GLP-1 neurons. Recently GLP-1 has emerged as a potential regulator of food reward behavior, an effect driven by the mesolimbic GLP-1Rs. Its role in other reward behaviors remains largely unexplored. Since a considerable overlap has been suggested for circuitry controlling reward behavior derived from food and alcohol we hypothesized that GLP-1 and GLP-1Rs could regulate alcohol intake and alcohol reward. We sought to determine whether GLP-1 or its clinically safe stable analogue, Exendin-4, reduce alcohol intake and reward. To determine the potential role of the endogenous GLP-1 in alcohol intake we evaluated whether GLP-1R antagonist, Exendin 9-39, can increase alcohol intake. Furthermore, we set out to evaluate whether VTA GLP-1R activation is sufficient to reduce alcohol intake. Male Wistar rats injected peripherally with GLP-1 or Exendin-4 reduced their alcohol intake in an intermittent access two bottle free choice drinking model. Importantly, a contribution of endogenously released GLP-1 is highlighted by our observation that blockade of GLP-1 receptors alone resulted in an increased alcohol intake. Furthermore, GLP-1 injection reduced alcohol reward in the alcohol conditioned place preference test in mice. To evaluate the neuroanatomical substrate linking GLP-1 with alcohol intake/reward, we selectively microinjected GLP-1 or Exendin 4 into the VTA. This direct stimulation of the VTA GLP-1 receptors potently reduced alcohol intake. Our findings implicate GLP-1R signaling as a novel modulator of alcohol intake and reward. We show for the first time that VTA GLP-1R stimulation leads to reduced alcohol intake. Considering that GLP-1 analogues are already approved for clinical use, this places the GLP system as an exciting new potential therapeutic target for alcohol use disorders.
Highlights
Glucagon-like peptide-1 (GLP-1), released after meals and in association with gastric distension [1], is a potent anorexigenic peptide [2,3], produced both in the periphery and in discrete CNS sites
When the vehicle baseline drinking was used to separate the rats into high and low drinking groups, an interesting interaction emerged between this baseline alcohol consumption and the efficacy of GLP-1 to reduce alcohol intake (two-way ANOVA baseline drinking vs. drug treatment; interaction F(1,12) = 32.5, p,0.005)
The present studies reveal an important role for GLP-1 in alcohol consumption and reward
Summary
Glucagon-like peptide-1 (GLP-1), released after meals and in association with gastric distension [1], is a potent anorexigenic peptide [2,3], produced both in the periphery (pancreas, gut) and in discrete CNS sites. Therapeutic interest in the GLP-1 signaling system has focused largely on its incretin (insulin-releasing) properties, and has culminated in the discovery of a novel diabetes therapy, Exendin-4 (EX4), a long-acting GLP-1 analogue [7]. The observation that diabetic patients receiving EX4 therapy lose body weight [8] has intensified efforts to discover the neurobiological mechanisms/substrates downstream of GLP-1 signaling that mediate the weight loss effects of GLP-1. Several studies have linked central GLP-1 receptor signaling to feeding control at the level of the mesolimbic reward system [9,10,11]. Given that common mesolimbic pathways confer reward from natural rewards (e.g. food) and drugs of abuse (e.g. alcohol)[12], we sought to determine whether the GLP-1 signaling system plays a role in alcohol intake and alcohol reward
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