1. ¹Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV, USA
2. ²Department of Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV, USA
3. ³Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
4. ⁴Department of Neurobiology and Anatomy, West Virginia University Health Sciences Center, Morgantown, WV, USA

Correspondence: Dr H-T Zhang, Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506-9137, USA. Tel: +1 304 293 1488, Fax: +1 304 293 1634, E-mail: hzhang@hsc.wvu.edu

Received 5 June 2008; Revised 26 August 2008; Accepted 16 September 2008; Published online 15 October 2008.

Abstract

The antidepressant desipramine inhibits the reuptake of norepinephrine (NE), leading to activation of both pre- and postsynaptic adrenergic receptors, including -1, -2, -1, and -2 subtypes. However, it is not clear which adrenergic receptors are involved in mediating its antidepressant effects. Treatment of mice with desipramine (20 mg/kg, i.p.) produced an antidepressant-like effect, as evidenced by decreased immobility in the forced-swim test; this was antagonized by pretreatment with the -2 adrenergic antagonist idazoxan (0.1–2.5 mg/kg, i.p.). Similarly, idazoxan, administered peripherally (0.5–2.5 mg/kg, i.p.) or centrally (1–10 g, i.c.v.), antagonized the antidepressant-like effect of desipramine in rats responding under a differential-reinforcement-of-low-rate (DRL) 72-s schedule, ie, decreased response rate and increased reinforcement rate. By contrast, pretreatment with the -adrenergic antagonists propranolol and CGP-12177 or the -1 adrenergic antagonist prazosin did not alter the antidepressant-like effect of desipramine on DRL behavior. The lack of involvement of -adrenergic receptors in mediating the behavioral effects of desipramine was confirmed using knockout lines. In the forced-swim test, the desipramine-induced decrease in immobility was not altered in mice deficient in -1, -2, or both -1 and -2 adrenergic receptors. In addition, desipramine (3–30 mg/kg) produced an antidepressant-like effect on behavior under a DRL 36-s schedule in mice deficient in both -1 and -2 adrenergic receptors. As antagonism of presynaptic -2 adrenergic receptors facilitates NE release, which potentiates the effects of desipramine, the present results suggest that postsynaptic -2 adrenergic receptors play an important role in its antidepressant effects.