Use of dopamine-beta-hydroxylase-deficient mice to determine the role of norepinephrine in the mechanism of action of antidepressant drugs

Norepinephrine (NE) is thought to play an important role in the pathophysio logy of depression, and in the mechanism of action of antidepressant compou nds. Previously, we created mice that are unable to synthesize NE and epine phrine due to targeted disruption of the dopamine-beta -hydroxylase gene (D bh). To specifically test the role of NE in mediating behavioral changes el icited by antidepressants, these mice were examined in the forced swim test . There was no difference in baseline immobility scores in the forced swim test between Dbh(+/-) mice, which have normal levels of NE, and Dbh(-/-) mi ce. However, the Dbh(-/-) mice failed to demonstrate antidepressant-like be havioral effects following the administration of several classes of antidep ressants. These included the NE reuptake inhibitors desipramine and reboxet ine, the monoamine oxidase inhibitor pargyline, and the atypical antidepres sant bupropion. In addition, desipramine significantly reduced immobility i n the Dbh(-/-) mice following pretreatment with the synthetic NE precursor L-threo-3,4-dihydroxyphenylserine, but not saline. Biochemical studies show ed that there was no significant difference in the regional brain levels of NE transporter immunoreactivity or monoamine oxidase activity, the primary targets for most of the compounds examined. Taken together, these data sho w that the use of mice that lack endogenous NE may be an important strategy for unraveling the role of NE in tests sensitive to the effects of various psychotherapeutic agents.