title: alpha(1A)- and alpha(1B)-adrenergic receptors differentially modulate antidepressant-like behavior in the mouse.
abstract: Tricyclic antidepressant (TCA) drugs are used for the treatment of chronic depression, obsessive-compulsive disorder (OCD), and anxiety-related disorders. Chronic use of TCA drugs increases the expression of alpha(1)-adrenergic receptors (alpha(1)-ARs). Yet, it is unclear whether increased alpha(1)-AR expression contributes to the antidepressant effects of these drugs or if this effect is unrelated to their therapeutic benefit. In this study, mice expressing constitutively active mutant alpha(1A)-ARs (CAM alpha(1A)-AR) or CAM alpha(1B)-ARs were used to examine the effects of alpha(1A)- and alpha(1B)-AR signaling on rodent behavioral models of depression, OCD, and anxiety. CAM alpha(1A)-AR mice, but not CAM alpha(1B)-AR mice, exhibited antidepressant-like behavior in the tail suspension test and forced swim test. This behavior was reversed by prazosin, a selective alpha(1)-AR inverse agonist, and mimicked by chronically treating wild type mice with cirazoline, an alpha(1A)-AR agonist. Marble burying behavior, commonly used to model OCD in rodents, was significantly decreased in CAM alpha(1A)-AR mice but not in CAM alpha(1B)-AR mice. In contrast, no significant differences in anxiety-related behavior were observed between wild type, CAM alpha(1A)-AR, and CAM alpha(1B)-AR animals in the elevated plus maze and light/dark box. This is the first study to demonstrate that alpha(1A)- and alpha(1B)-ARs differentially modulate antidepressant-like behavior in the mouse. These data suggest that alpha(1A)-ARs may be a useful therapeutic target for the treatment of depression.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202, USA.
authors.forename: Van A
authors.initials: VA
authors.lastname: Doze
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: Handel
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Jensen
authors.forename: Belle
authors.initials: B
authors.lastname: Darsie
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Luger
authors.forename: James R
authors.initials: JR
authors.lastname: Haselton
authors.forename: Jeffery N
authors.initials: JN
authors.lastname: Talbot
authors.forename: Boyd R
authors.initials: BR
authors.lastname: Rorabaugh
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002395:Catecholamines / Q000378:metabolism*; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008808:Mice, Inbred CBA; D009483:Neuropsychological Tests; D011224:Prazosin / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism*; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism / Q000503:physiopathology
chemical_list: C547714:Adra1a protein, mouse; C547717:Adra1b protein, mouse; D000316:Adrenergic alpha-Agonists; D000928:Antidepressive Agents; D002395:Catecholamines; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; C014282:cirazoline; D011224:Prazosin