Preclinical and clinical characterization of the selective 5-HT1A receptor antagonist DU-125530 for antidepressant treatment
Por:
Scorza, MC, Llado-Pelfort, L, Oller, S, Cortes, R, Puigdemont, D, Portella, MJ, Perez-Egea, R, Alvarez, E, Celada, P, Perez, V, Artigas, F
Publicada:
1 nov 2012
Resumen:
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 beta-adrenoceptor/5-HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT1A autoreceptors. However, it is unclear whether 5-HT1A receptor antagonists not discriminating between pre- and post-synaptic 5-HT1A 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 (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-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.
Filiaciones:
Scorza, MC:
IDIBAPS, Dept Neurochem & Neuropharmacol, CSIC, IIBB, Barcelona, Spain
Llado-Pelfort, L:
IDIBAPS, Dept Neurochem & Neuropharmacol, CSIC, IIBB, Barcelona, Spain
CIBERSAM, Ctr Invest Biomed Red Salud Mental, Madrid, Spain
Oller, S:
Univ Autonoma Barcelona, Dept Psychiat, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Cortes, R:
IDIBAPS, Dept Neurochem & Neuropharmacol, CSIC, IIBB, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain
Puigdemont, D:
CIBERSAM, Ctr Invest Biomed Red Salud Mental, Madrid, Spain
Univ Autonoma Barcelona, Dept Psychiat, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Portella, MJ:
CIBERSAM, Ctr Invest Biomed Red Salud Mental, Madrid, Spain
Univ Autonoma Barcelona, Dept Psychiat, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Perez-Egea, R:
CIBERSAM, Ctr Invest Biomed Red Salud Mental, Madrid, Spain
Univ Autonoma Barcelona, Dept Psychiat, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Alvarez, E:
CIBERSAM, Ctr Invest Biomed Red Salud Mental, Madrid, Spain
Univ Autonoma Barcelona, Dept Psychiat, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Celada, P:
IDIBAPS, Dept Neurochem & Neuropharmacol, CSIC, IIBB, Barcelona, Spain
CIBERSAM, Ctr Invest Biomed Red Salud Mental, Madrid, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain
Perez, V:
CIBERSAM, Ctr Invest Biomed Red Salud Mental, Madrid, Spain
Univ Autonoma Barcelona, Dept Psychiat, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Artigas, F:
IDIBAPS, Dept Neurochem & Neuropharmacol, CSIC, IIBB, Barcelona, Spain
CIBERSAM, Ctr Invest Biomed Red Salud Mental, Madrid, Spain
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain
Green Published
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