The noradrenergic system is involved in the regulation of many physiological and psychological processes, including the modulation of mood. The α2-adrenergic receptors (α2-ARs) modulate norepinephrine release, as well as the release of serotonin and other neurotransmitters, and are therefore potential targets for antidepressant and anxiolytic drug development. The current studies were undertaken to examine the role of the α2A subtype of α2-AR in mouse behavioral models of depression and anxiety. We have observed that the genetic knock-out of the α2A-AR makes mice less active in a modified version of Porsolt's forced swim test and insensitive to the antidepressant effects of the tricyclic drug imipramine in this paradigm. Furthermore, α2A-AR knock-out mice appear more anxious than wild-type C57 BI/6 mice in the rearing and light-dark models of anxiety after injection stress. These findings suggest that the α2A-AR may play a protective role in some forms of depression and anxiety and that the antidepressant effects of imipramine may be mediated by the α2A-AR.