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