Preclinical and clinical characterization of the selective 5‐HT_1A receptor antagonist DU‐125530 for antidepressant treatment

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 β‐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.

DOI: 10.1111/j.1476-5381.2011.01770.x

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