期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 167, 期 5, 页码 1021-1034出版社
WILEY
DOI: 10.1111/j.1476-5381.2011.01770.x
关键词
5-HT1A receptors; antidepressant drugs; serotonin transporter; major depression; prefrontal cortex; raphe nuclei
资金
- PN de I+D+I 2008-2011, ISCIII-Subdireccion General de Evaluacion y Fomento de la Investigacion [SAF 2007-62378, FIS PI09/1245]
- La Marato TV3
- Instituto de Salud Carlos III
- Centro de Investigacion Biomedica en Red de Salud Mental
- CIBERSAM
- Catalan Government [2009SGR220]
- Fundacion Carolina [DU-125530]
- CSIC
- Researcher Stabilization Program of the Health Department of the Generalitat de Catalunya
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.
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