title: Preclinical and clinical characterization of the selective 5-HT(1A)  receptor antagonist DU-125530 for antidepressant treatment.
abstract: OBJECTIVE
  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-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective.
  
  
  METHODS
  We characterized the pharmacological properties of the 5-HT(1A) 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 (clinicaltrials.gov identifier NCT01119430).
  
  
  RESULTS
  DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) 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-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects.
  
  
  CONCLUSIONS
  DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.
authors: Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Cientificas (IIBB-CSIC), IDIBAPS, Barcelona, Spain.
authors: M C
authors: MC
authors: Scorza
authors: L
authors: L
authors: Lladó-Pelfort
authors: S
authors: S
authors: Oller
authors: R
authors: R
authors: Cortés
authors: D
authors: D
authors: Puigdemont
authors: M J
authors: MJ
authors: Portella
authors: R
authors: R
authors: Pérez-Egea
authors: E
authors: E
authors: Alvarez
authors: P
authors: P
authors: Celada
authors: V
authors: V
authors: Pérez
authors: F
authors: F
authors: Artigas
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000328:Adult; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D012702:Serotonin Antagonists / Q000008:administration & dosage*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage*
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C106973:1,2-benzisothiazol-3(2H)-one, 2-(4-(4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl)butyl)-, 1,1-dioxide