Jul 17, 2001

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

The Journal of Pharmacology and Experimental Therapeutics
John F CryanSteven A Thomas


Norepinephrine (NE) is thought to play an important role in the pathophysiology of depression, and in the mechanism of action of antidepressant compounds. Previously, we created mice that are unable to synthesize NE and epinephrine due to targeted disruption of the dopamine-beta-hydroxylase gene (Dbh). To specifically test the role of NE in mediating behavioral changes elicited 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(-/-) mice. However, the Dbh(-/-) mice failed to demonstrate antidepressant-like behavioral effects following the administration of several classes of antidepressants. These included the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion. In addition, desipramine significantly reduced immobility in the Dbh(-/-) mice following pretreatment with the synthetic NE precursor L-threo-3,4-dihydroxyphenylserine, but not saline. Biochemical studies showed that there was no significant difference in the regional brain levels of NE transporter immunoreactivity or monoamine ox...Continue Reading

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Mentioned in this Paper

Behavior, Animal
Monoamine Oxidase [PK]
Norepinephrine, (+, -)-Isomer
Monoamine Oxidase Inhibitors
Monoamine Oxidase

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