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Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment.
Scorza, M C; Lladó-Pelfort, L; Oller, S; Cortés, R; Puigdemont, D; Portella, M J; Pérez-Egea, R; Alvarez, E; Celada, P; Pérez, V; Artigas, F.
Afiliação
  • Scorza MC; Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Cientificas (IIBB-CSIC), IDIBAPS, Barcelona, Spain.
Br J Pharmacol ; 167(5): 1021-34, 2012 Nov.
Article em En | MEDLINE | ID: mdl-22050051
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-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 ß-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. EXPERIMENTAL APPROACH: 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). KEY 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 AND IMPLICATIONS: 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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperazinas / Antagonistas da Serotonina / Tiazóis / Fluoxetina / Receptor 5-HT1A de Serotonina / Transtorno Depressivo Maior / Antidepressivos Tipo de estudo: Clinical_trials Limite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperazinas / Antagonistas da Serotonina / Tiazóis / Fluoxetina / Receptor 5-HT1A de Serotonina / Transtorno Depressivo Maior / Antidepressivos Tipo de estudo: Clinical_trials Limite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2012 Tipo de documento: Article