Role of presynaptic α2-adrenoceptors in antidepressant action: Recent findings from microdialysis studies

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Abstract

The therapeutic effect of an antidepressant drug takes at least 2 to 3 weeks to develop and a significant proportion of patients have no or only partial benefit regardless of the class of antidepressant used. Research into the neurobiological basis of antidepressant action has suggested new strategies to improve the antidepressant effect. Recent microdialysis studies show that hypofunction of the presynaptic autoreceptors enhances the increase of extracellular serotonin (5-HT) induced by selective serotonin reuptake inhibitors (SSRIs) so it has been suggested that the antidepressant effect may be speeded up by blockade of the autoreceptors. The similarity between the synaptic mechanisms controlling serotonergic and noradrenergic transmission has stimulated preclinical research into the role of presynaptic α2-adrenoceptors in the effect of noradrenaline (NA) reuptake inhibitors (NRIs) on NA availability at central synapses. The microdialysis studies reviewed here indicate that NRIs including desipramine, reboxetine and atomoxetine, the mixed 5-HT/NA reuptake inhibitors sibutramine, duloxetine, venlafaxine or the NA/DA reuptake inhibitor amineptine, increased extracellular NA in various regions of the rat brain. The effect was enhanced by chronic treatment and even more by the co-administration of α2- adrenoceptor antagonists. The results support the theory that desensitization of the α2-adrenoceptor contributes to enhancing the effect of NRIs seen after chronic administration and may account for the slow onset of the antidepressant effect. Finally, they suggest that co-administration of an α2-adrenoceptor antagonist may improve the therapeutic effect of NRI.

Original languageEnglish
Pages (from-to)819-827
Number of pages9
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume28
Issue number5
DOIs
Publication statusPublished - Aug 2004

Keywords

  • α- adrenoceptor antagonists
  • α-adrenoceptors
  • 1-(2-pyrimidinyl)piperazine
  • 1-PP
  • 5-HT
  • A
  • Antidepressant drugs
  • atipamezole
  • CC
  • cingulate cortex
  • DA
  • Microdialysis
  • Noradrenaline
  • Noradrenaline reuptake inhibitors
  • serotonin

ASJC Scopus subject areas

  • Biological Psychiatry
  • Pharmacology

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