alpha(1A)- and alpha(1B)-adrenergic receptors differentially modulate antidepressant-like behavior in the mouse

Brain Res. 2009 Aug 18;1285:148-57. doi: 10.1016/j.brainres.2009.06.035. Epub 2009 Jun 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adrenergic alpha-Agonists / pharmacology
  • Animals
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / physiopathology
  • Catecholamines / metabolism*
  • Depressive Disorder / drug therapy
  • Depressive Disorder / metabolism*
  • Depressive Disorder / physiopathology
  • Disease Models, Animal
  • Female
  • Imidazoles / pharmacology
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred CBA
  • Neuropsychological Tests
  • Prazosin / pharmacology
  • Receptors, Adrenergic, alpha-1 / drug effects
  • Receptors, Adrenergic, alpha-1 / metabolism*
  • Stress, Psychological / complications
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology

Substances

  • Adra1a protein, mouse
  • Adra1b protein, mouse
  • Adrenergic alpha-Agonists
  • Antidepressive Agents
  • Catecholamines
  • Imidazoles
  • Receptors, Adrenergic, alpha-1
  • cirazoline
  • Prazosin