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 α1-adrenergic receptors (α1-ARs). Yet, it is unclear whether increased α1-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 α1A-ARs (CAM α1A-AR) or CAM α1B-ARs were used to examine the effects of α1A- and α1B-AR signaling on rodent behavioral models of depression, OCD, and anxiety. CAM α1A-AR mice, but not CAM α1B-AR mice, exhibited antidepressant-like behavior in the tail suspension test and forced swim test. This behavior was reversed by prazosin, a selective α1-AR inverse agonist, and mimicked by chronically treating wild type mice with cirazoline, an α1A-AR agonist. Marble burying behavior, commonly used to model OCD in rodents, was significantly decreased in CAM α1A-AR mice but not in CAM α1B-AR mice. In contrast, no significant differences in anxiety-related behavior were observed between wild type, CAM α1A-AR, and CAM α1B-AR animals in the elevated plus maze and light/dark box. This is the first study to demonstrate that α1A- and α1B-ARs differentially modulate antidepressant-like behavior in the mouse. These data suggest that α1A-ARs may be a useful therapeutic target for the treatment of depression.

Norepinephrine (NE), an endogenous neurotransmitter, is involved in cognition as well as anxiety and depression. NE mediates its actions through the activation of adrenergic receptors (ARs). This study explored the effects of increased α1AAR activation on anxiety and depression in mice. Different sets of mice with varying degrees of α1AAR expression and activation were used in behavioral tests for anxiety and depression. The mice sets included transgenic mice with increased α1AAR expression, transgenic mice with a knockout of the α1AAR, mice treated with the α1AAR agonist cirazoline, and groups of normal control mice. The tail suspension and forced swim tests were used as models of depression and the light/dark, marble burying and elevated plus‐maze tests were used as measurements of anxiety. In addition, the open field test was used to determine the mobility of these animals. It was found that mice with increased α1AAR activation, in comparison to normal mice, demonstrated anxiolytic and antidepressant‐like behavior in several of these models. The mobility of these animals was similar. These results suggest that activation of the α1AAR reduces anxiety and depression in mice without affecting their mobility. This study was supported by NSF CAREER 0347259, NSF REU Site 0639227, NIH P20 RR016741, UND REFUNDU Program, American Physiological Society, and the Bower, Bennet & Bennet Endowed Research Award from ONU.