title: Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.
abstract: Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA.
authors.affiliation: Neuroscience Program, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Reddy
authors.affiliation: Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.|Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Pino
authors.affiliation: Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.|Psychiatric Centre Copenhagen, University Hospital Copenhagen, Copenhagen, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Weikop
authors.affiliation: Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
authors.forename: N
authors.initials: N
authors.lastname: Osses
authors.affiliation: Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.|Psychiatric Centre Copenhagen, University Hospital Copenhagen, Copenhagen, Denmark.
authors.forename: G
authors.initials: G
authors.lastname: Sørensen
authors.affiliation: Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Bering
authors.affiliation: Departamento de Ciencias Básicas, Universidad de Viña del Mar, Viña del Mar, Chile.
authors.forename: C
authors.initials: C
authors.lastname: Valle
authors.affiliation: Neuroscience Program, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bluett
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Erreger
authors.affiliation: Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.|Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: G
authors.initials: G
authors.lastname: Wortwein
authors.affiliation: Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
authors.forename: J G
authors.initials: JG
authors.lastname: Reyes
authors.affiliation: Department of Biomedical Sciences and Center for Brain Repair, Florida State University, Tallahassee, FL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Graham
authors.affiliation: Department of Biomedical Sciences and Center for Brain Repair, Florida State University, Tallahassee, FL, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Stanwood
authors.affiliation: Neuroscience Program, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Hackett
authors.affiliation: Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.affiliation: Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.|Psychiatric Centre Copenhagen, University Hospital Copenhagen, Copenhagen, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Fink-Jensen
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: G E
authors.initials: GE
authors.lastname: Torres
authors.affiliation: Neuroscience Program, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Galli
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001095:Arachidonic Acids / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D063388:Endocannabinoids / Q000378:metabolism; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism; D006706:Homeostasis; D054795:Incretins / Q000494:pharmacology; D051379:Mice; D017551:Microdialysis; D010455:Peptides / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D001095:Arachidonic Acids; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D063388:Endocannabinoids; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D005989:Glycerides; D054795:Incretins; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; C493215:Slc6a3 protein, mouse; D014688:Venoms; D016718:Arachidonic Acid; C094503:glyceryl 2-arachidonate; D000077270:Exenatide; D003042:Cocaine; D004298:Dopamine; D000097789:Glucagon-Like Peptide-1 Receptor Agonists