title: Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive 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 KD(Nestin) (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 KD(Nestin) mice. Next, alcohol intake (10% v/v) was evaluated in FLOX and GLP-1R KD(Nestin) 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 KD(Nestin) 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 KD(Nestin) mice. Notably, hedonic feeding was partially blocked in the GLP-1R KD(Nestin) 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.
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA. Electronic address: sunil.sirohi@wsu.edu.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sirohi
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Schurdak
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Benoit
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA; Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, USA.
authors.forename: Jon F
authors.initials: JF
authors.lastname: Davis
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004032:Diet; D004195:Disease Models, Animal; D000077270:Exenatide; D005247:Feeding Behavior / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor / Q000172:deficiency / Q000235:genetics; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064231:Nestin / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014688:Venoms / Q000627:therapeutic use
chemical_list: D000697:Central Nervous System Stimulants; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D064231:Nestin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D000661:Amphetamine
keywords: Alcohol intake; Amphetamine reinforcement; GLP-1; GLP-1R; Hedonic feeding