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

Abstract

BACKGROUND AND PURPOSEThe 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 b-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 APPROACHWe 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 RESULTSDU-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 IMPLICATIONSDU-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.

Molecular and Cellular Mechanisms of Antidepressant Action

“…Two recent meta-analyses of the pindolol trials report an increase in speed of onset of clinical effect (Portella et al 2011;Whale et al 2010). However, a recent study in depression administering an SSRI in combination with a selective 5-HT 1A receptor antagonist observed no benefit compared to SSRI treatment alone (Scorza et al 2012). Although the latter study was small and the findings await confirmation the data suggest that, contrary to predictions, 5-HT 1A receptor blockade may not be a useful for antidepressant augmentation strategy.…”

Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs

“…The interpretation was that simultaneous application of a 5-HT 1A buprenorphine samidorphan receptor antagonist with an SSRI would instantaneously inhibit the negative feedback mechanism and allow for an immediate and sufficient increase in 5-HT levels to produce a fast antidepressant response. However, since enhanced serotonergic neurotransmission through stimulation of postsynaptic 5-HT 1A receptors was hypothesized to be essential for the antidepressant effect of SSRIs, it was important to only block presynaptic 5-HT 1A receptors [21]. Encouraging results from clinical studies using combinations of SSRIs and pindolol, a 5-HT 1A receptor partial agonist and a badrenoceptor antagonist, showed a faster onset of antidepressant effect than SSRIs alone and further fueled the interest in this research area (e.g.…”

Targeting melanocyte and melanoma stem cells by 8-hydroxy-2-dipropylaminotetralin

“…8-DPAT has been studied previously as a serotonin receptor agonist and reuptake inhibitor, suggesting that there may be an interface of serotonergic and melanogenic pathways. In this respect it is important to mention that 8-DPAT preferentially binds to the serotonin reuptake receptor 5-HT1A (49). Signaling via this receptor can, in turn, affect the survival and proliferation of neural stem cells, which may explain the cytotoxic effects of 8-DPAT apparent from the current studies (50).…”