TY - JOUR
T1 - Preclinical and clinical characterization of the selective 5-HT 1A receptor antagonist DU-125530 for antidepressant treatment
AU - Scorza, Mc
AU - Lladó-Pelfort, L.
AU - Oller, S.
AU - Cortés, R.
AU - Puigdemont, D.
AU - Portella, M. J.
AU - Pérez-Egea, R.
AU - Alvarez, E.
AU - Celada, P.
AU - Pérez, V.
AU - Artigas, F.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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 β-adrenoceptor/5-HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT 1A autoreceptors. However, it is unclear whether 5-HT1A 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-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. © 2011 The British Pharmacological Society.
AB - 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 β-adrenoceptor/5-HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT 1A autoreceptors. However, it is unclear whether 5-HT1A 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-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. © 2011 The British Pharmacological Society.
KW - 5-HT receptors 1A
KW - antidepressant drugs
KW - major depression
KW - prefrontal cortex
KW - raphe nuclei
KW - serotonin transporter
U2 - 10.1111/j.1476-5381.2011.01770.x
DO - 10.1111/j.1476-5381.2011.01770.x
M3 - Article
VL - 167
SP - 1021
EP - 1034
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 5
ER -