title: The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice.
abstract: Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic neurons in the VTA project to the NAc, and these neurons play a pivotal role in the rewarding effects of drugs of abuse. Based on the anatomical distribution of GLP-1 receptors in the brain and the well-established effects of GLP-1 on food reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction.
authors.affiliation: Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark; Psychiatric Centre Copenhagen, University of Copenhagen, Denmark.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sørensen
authors.affiliation: Neuroscience Graduate Program, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA; Neuroscience Program in Substance Abuse, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: India A
authors.initials: IA
authors.lastname: Reddy
authors.affiliation: Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark; Psychiatric Centre Copenhagen, University of Copenhagen, Denmark.
authors.forename: Pia
authors.initials: P
authors.lastname: Weikop
authors.affiliation: Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee FL, USA.
authors.forename: Devon L
authors.initials: DL
authors.lastname: Graham
authors.affiliation: Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee FL, USA.
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Stanwood
authors.affiliation: Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark; Department of Public Health, University of Copenhagen, Denmark.
authors.forename: Gitta
authors.initials: G
authors.lastname: Wortwein
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA; Neuroscience Program in Substance Abuse, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
authors.affiliation: Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark; Psychiatric Centre Copenhagen, University of Copenhagen, Denmark. Electronic address: a.fink-jensen@dadlnet.dk.
authors.forename: Anders
authors.initials: A
authors.lastname: Fink-Jensen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000633:toxicity; D003042:Cocaine / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000633:toxicity; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D005106:Exploratory Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006948:Hyperkinesis / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012646:Self Administration; D013997:Time Factors; D014688:Venoms / Q000494:pharmacology*
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D007004:Hypoglycemic Agents; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; D014688:Venoms; C071262:SK&F 82958; D000077270:Exenatide; D003042:Cocaine; D004298:Dopamine
keywords: Addiction; Cocaine; Dopamine; Exendin-4; GLP-1; Self-administration; c-Fos