title: GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality.
abstract: Glucagon-like peptide 1 (GLP-1), produced in the intestine and hindbrain, is known for its glucoregulatory and appetite suppressing effects. GLP-1 agonists are in clinical use for treatment of type 2 diabetes and obesity. GLP-1, however, may also affect brain areas associated with emotionality regulation. Here we aimed to characterize acute and chronic impact of GLP-1 on anxiety and depression-like behavior. Rats were subjected to anxiety and depression behavior tests following acute or chronic intracerebroventricular or intra-dorsal raphe (DR) application of GLP-1 receptor agonists. Serotonin or serotonin-related genes were also measured in the amygdala, DR and the hippocampus. We demonstrate that both GLP-1 and its long lasting analog, Exendin-4, induce anxiety-like behavior in three rodent tests of this behavior: black and white box, elevated plus maze and open field test when acutely administered intraperitoneally, into the lateral ventricle, or directly into the DR. Acute central GLP-1 receptor stimulation also altered serotonin signaling in the amygdala. In contrast, chronic central administration of Exendin-4 did not alter anxiety-like behavior but significantly reduced depression-like behavior in the forced swim test. Importantly, this positive effect of Exendin-4 was not due to significant body weight loss and reduced food intake, since rats pair-fed to Exendin-4 rats did not show altered mood. Collectively we show a striking impact of central GLP-1 on emotionality and the amygdala serotonin signaling that is divergent under acute versus chronic GLP-1 activation conditions. We also find a novel role for the DR GLP-1 receptors in regulation of behavior. These results may have direct relevance to the clinic, and indicate that Exendin-4 may be especially useful for obese patients manifesting with comorbid depression.
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
authors.forename: Rozita H
authors.initials: RH
authors.lastname: Anderberg
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Richard
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hansson
authors.affiliation: Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Nissbrandt
authors.affiliation: Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
authors.forename: Filip
authors.initials: F
authors.lastname: Bergquist
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden. Electronic address: Karolina.Skibicka@neuro.gu.se.
authors.forename: Karolina P
authors.initials: KP
authors.lastname: Skibicka
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000928:Antidepressive Agents / Q000494:pharmacology; D001007:Anxiety / Q000139:chemically induced*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004644:Emotions / Q000187:drug effects*; D000077270:Exenatide; D005247:Feeding Behavior / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000188:drug therapy; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D014688:Venoms; D012701:Serotonin; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: Anxiety; Depression; Exendin-4; Food intake; GLP-1; Obesity