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Preclinical and clinical characterization of the selective serotonin-1A receptor antagonist DU-125530 for antidepressant treatment.

Author(s): Scorza MC, Llado-Pelfort L, Oller S, Cortes R, Puigdemont D, Portella MJ, Perez-Egea R, Alvarez E, Celada P, Perez V, Artigas F

Affiliation(s): Department. of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomediques de Barcelona, Consejo Superior de Investigaciones Cientificas (IIBB-CSIC), IDIBAPS Department. of Psychiatry, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona (UAB), Barcelona Centro de Investigacion Biomedica en Red de Salud Mental, CIBERSAM, Spain Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED) Spain Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Publication date & source: 2011-11-03, Br J Pharmacol., [Epub ahead of print]

Background and purpose. The antidepressant efficacy of selective serotonin (5-HT) reuptake inhibitors (SSRI) and other 5-HT- enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) -autoreceptor (5-HT(1A) -AR) activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurons. 5-HT(1A) receptor (5-HT(1A) R) antagonists augment antidepressant-like effects in rodents by preventing this negative feed-back and the mixed ss-adrenoceptor/5-HT(1A) R antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) -AR. However, it is unclear whether 5-HT(1A) R antagonists not discriminating between pre- and postsynaptic 5-HT(1A) R would be clinically effective. Experimental approach. We characterized the pharmacological properties of the 5-HT(1A) R antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Likewise, we examined its capacity to accelerate/enhance the clinical effects of fluoxetine 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 postsynaptic 5-HT(1A) R in rat and human brain. It antagonized the suppression of serotonergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented the SSRI-induced increase in extracellular 5-HT to the extent obtained in mice lacking 5-HT(1A) R, indicating a silent, maximal occupancy of presynaptic 5-HT(1A) R at the dose used. Despite these properties, DU-125530 addition to fluoxetine treatment did not accelerate nor augment its antidepressant effects. Conclusions and implications. DU-125530 is an excellent pre- and postsynaptic 5-HT(1A) R antagonist. However, blockade of postsynaptic 5-HT(1A) R by DU-125530 cancels the benefits obtained by enhancing presynaptic serotonergic function. (c) 2011 The Authors. British Journal of Pharmacology (c) 2011 The British Pharmacological Society.

Page last updated: 2011-12-09

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