Elsevier

Physiology & Behavior

Volume 161, 1 July 2016, Pages 140-144
Physiology & Behavior

Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors

https://doi.org/10.1016/j.physbeh.2016.04.013Get rights and content

Highlights

  • Mice received (Ex-4, a GLP-1 analog) following disruption of CNS GLP-1R signaling.

  • Amphetamine reward, alcohol intake and hedonic feeding were examined thereafter.

  • Ex-4 failed to reduce amphetamine reinforcement behavior and alcohol consumption.

  • Hedonic feeding behavior was partially attenuated following Ex-4 pretreatment.

  • Data elucidate mechanisms whereby GLP-1 signaling regulates reinforced behaviors.

Abstract

Recent data implicate glucagon-like peptide-1 (GLP-1), a potent anorexigenic peptide released in response to nutrient intake, as a regulator for the reinforcing properties of food, alcohol and psychostimulants. While, both central and peripheral mechanisms mediate effects of GLP-1R signaling on food intake, the extent to which central or peripheral GLP-1R signaling regulates reinforcing properties of drugs of abuse is unknown. Here, we examined amphetamine reinforcement, alcohol intake and hedonic feeding following peripheral administration of EX-4 (a GLP-1 analog) in FLOX and GLP-1R KDNestin (GLP-1R selectively ablated from the central nervous system) mice (n = 13/group). First, the effect of EX-4 pretreatment on the expression of amphetamine-induced conditioned place preference (Amp-CPP) was examined in the FLOX and GLP-1R KDNestin mice. Next, alcohol intake (10% v/v) was evaluated in FLOX and GLP-1R KDNestin mice following saline or EX-4 injections. Finally, we assessed the effects of EX-4 pretreatment on hedonic feeding behavior. Results indicate that Amp-CPP was completely blocked in the FLOX mice, but not in the GLP-1R KDNestin mice following EX-4 pretreatment. Ex-4 pretreatment selectively blocked alcohol consumption in the FLOX mice, but was ineffective in altering alcohol intake in the GLP-1R KDNestin mice. Notably, hedonic feeding was partially blocked in the GLP-1R KDNestin mice, whereas it was abolished in the FLOX mice. The present study provides critical insights regarding the nature by which GLP-1 signaling controls reinforced behaviors and underscores the importance of both peripheral and central GLP-1R signaling for the regulation of addictive disorders.

Introduction

Glucagon-like peptide-1 (GLP-1), a feeding peptide with anorectic properties, is secreted by the gastrointestinal tract [1], [2] and released from neurons in the nucleus of the solitary tract (NTS) [3], [4], [5]. Both GLP-1 and Exendin-4 (EX-4, a synthetic GLP-1 analog) administration attenuate the reinforcing properties of food, alcohol and psychostimulants [6], [7], [8], suggesting a role for GLP-1 that extends beyond regulation of energy homeostasis. The appetite suppressive effects of GLP-1 require both vagal afferent and central nervous system (CNS) signaling mechanisms [7]. Recent studies indicate that peripheral administration of GLP-1 attenuates psychostimulant-reinforced behaviors [9] and that GLP-1R stimulation within brain reward circuitry reduces alcohol consumption and food reinforcement [3], [8], [10]. However, it is unknown if activation of peripheral or CNS GLP-1R signaling regulates the reinforcing properties of psychostimulant drugs. It is also unclear what role peripheral GLP-1R signaling plays in the regulation of alcohol and palatable food intake. We hypothesized that peripheral GLP-1R signaling (i.e. vagal afferent signaling) regulates alcohol consumption and hedonic feeding behavior whereas central GLP-1R signaling controls psychostimulant reinforcement. To test this hypothesis, we evaluated amphetamine reward, alcohol consumption and hedonic food intake following peripheral administration of EX-4 in GLP-1R KDNestin mice in which GLP-1R was selectively ablated from the CNS.

Section snippets

Animals

GLP-1R KDNestin mice, where GLP-1R was selectively ablated from the CNS, along with their respective wild-type littermates were generated as reported previously [11]. Genetic ablation involved inserting loxP sites surrounding glp1r gene (FLOX) and crossbreeding with nestin-Cre mice, generating GLP-1R KDNestin mice. Study animals were derived from crosses between heterozygous animals back-crossed > 10 generations onto a C57BL6/J genetic background. Current studies were performed with male mice,

GLP-1R regulation of amphetamine CPP

A mixed model ANOVA revealed a main effect of exposure during conditioning suggesting that amphetamine induced a strong CPP in both FLOX and GLP-1R KDNestin (F1, 11 = 7.493, p = 0.019) mice. Following training, EX-4 pretreatment completely blocked the expression of Amp-CPP in the FLOX mice without affecting locomotion in either group. However, this treatment was ineffective at reducing Amp-CPP in the GLP-1R KDNestin mice (Fig. 1).

GLP-1R regulation of alcohol consumption

Baseline alcohol consumption did not differ among any of the groups

Discussion

The goal of the present study was to assess the necessity of central vs. peripheral GLP-1R signaling for the control of amphetamine reward, alcohol consumption and hedonic feeding behavior. Our results indicate that disruption of central GLP-1R signaling completely abolished the ability of EX-4 to reduce amphetamine-induced CPP and alcohol consumption. These effects were not due to non-specific motoric effects as EX-4 pretreatment was ineffective in altering locomotion in either group. In

Conclusion

Collectively, these data extend the current framework of understanding regarding how analogs of GLP-1 target peripheral and/or central signaling mechanisms to impact addictive behavior. A limitation in this area is the lack of studies that determine how and when the GLP-1 system becomes engaged in the context of addictive behavior. Therefore, future studies that evaluate activation of peripheral and/or central GLP-1 signaling mechanisms across the cycle of addiction (initiation, maintenance,

Acknowledgements

This project was supported, in part, by NIH grant DK093848 from National Institute of Diabetes and Digestive and Kidney Diseases awarded to RJS. SCB and RJS received research support from Ethicon Endo Surgery. RJS is a consultant and have received research support from Novo Nordisk, Endobetix, Novartis, Nestle, Takeda, Eisai, Boehringer-Ingelheim, Sanofi, Circuit Therapeutics and Givaudan.

Authors declare no conflict of interest.

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