Preclinical and clinical characterization of the selective 5-HT <inf>1A</inf> receptor antagonist DU-125530 for antidepressant treatment

Mc Scorza, L. Lladó-Pelfort, S. Oller, R. Cortés, D. Puigdemont, M. J. Portella, R. Pérez-Egea, E. Alvarez, P. Celada, V. Pérez, F. Artigas

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39 Citations (Scopus)


Background and purpose: The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT1A autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT1A receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT 1A autoreceptors. However, it is unclear whether 5-HT1A receptor antagonists not discriminating between pre- and post-synaptic 5-HT 1A receptors would be clinically effective. Experimental approach: We characterized the pharmacological properties of the 5-HT1A receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression ( identifier NCT01119430). Key results: DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT1A receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT1A receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT1A receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. Conclusions and implications: DU-125530 is an excellent pre- and post-synaptic 5-HT1A receptor antagonist. However, blockade of post-synaptic 5- HT1A receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function. © 2011 The British Pharmacological Society.
Original languageEnglish
Pages (from-to)1021-1034
JournalBritish Journal of Pharmacology
Issue number5
Publication statusPublished - 1 Nov 2012


  • 5-HT receptors 1A
  • antidepressant drugs
  • major depression
  • prefrontal cortex
  • raphe nuclei
  • serotonin transporter


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