Postsynaptic α-2 adrenergic receptors are critical for the antidepressant-like effects of desipramine on behavior

Han Ting Zhang, Lisa R. Whisler, Ying Huang, Yang Kevin Xiang, James M. O'Donnell

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

The antidepressant desipramine inhibits the reuptake of norepinephrine (NE), leading to activation of both pre- and postsynaptic adrenergic receptors, including α-1, α-2, β-1, and β-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 α-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 μg, 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 β-adrenergic antagonists propranolol and CGP-12177 or the α-1 adrenergic antagonist prazosin did not alter the antidepressant-like effect of desipramine on DRL behavior. The lack of involvement of β-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 β-1, β-2, or both β-1 and β-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 β-1 and β-2 adrenergic receptors. As antagonism of presynaptic α-2 adrenergic receptors facilitates NE release, which potentiates the effects of desipramine, the present results suggest that postsynaptic α-2 adrenergic receptors play an important role in its antidepressant effects.

Original languageEnglish (US)
Pages (from-to)1067-1077
Number of pages11
JournalNeuropsychopharmacology
Volume34
Issue number4
DOIs
StatePublished - Mar 2009
Externally publishedYes

Keywords

  • α-2 adrenergic receptors
  • β-adrenergic receptors
  • Antidepressant
  • Desipramine
  • DRL behavior
  • Forced-swim behavior

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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