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Article Dans Une Revue Scientific Reports Année : 2016

Selective serotonin 5-HT1A receptor biased agonists elicit distinct brain activation patterns: a pharmacoMRI study

Résumé

Serotonin 1A (5-HT 1A) receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target. The recent pharmacological concept of biased agonism asserts that highly selective agonists can preferentially direct receptor signaling to specific intracellular responses, opening the possibility of drugs targeting a receptor subtype in specific brain regions. The present study brings additional support to this concept thanks to functional magnetic resonance imaging (7 Tesla-fMRI) in anaesthetized rats. Three 5-HT 1A receptor agonists (8-OH-DPAT, F13714 and F15599) and one 5-HT 1A receptor antagonist (MPPF) were compared in terms of influence on the brain blood oxygen level-dependent (BOLD) signal. Our study revealed for the first time contrasting BOLD signal patterns of biased agonists in comparison to a classical agonist and a silent antagonist. By providing functional information on the influence of pharmacological activation of 5-HT 1A receptors in specific brain regions, this neuroimaging approach, translatable to the clinic, promises to be useful in exploring the new concept of biased agonism in neuropsychopharmacology. 5-HT 1A receptors belong to the family of serotonin receptors, composed of 13 receptor subtypes. 5-HT 1A receptors are known to play a key role in serotonin neurotransmission due to their localization both as pre-synaptic receptors located on serotonin cell bodies in the raphe nuclei (somatodendritic receptors) and as post-synaptic heteroreceptors in forebrain areas that receive serotonergic projections. In such areas, 5-HT 1A receptors are located on pyramidal and GABAergic neurons of the neocortex and limbic system 1,2. Because of their distribution pattern and of their central role in the modulation of the serotoninergic neurotransmission, 5-HT 1A receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target for psychiatric 3 and, more recently, for neurological disorders 4. Indeed, it is now well establish that 5-HT 1A receptors are one of the main targets for the treatment of mood disorders 5 , with different actions that depend strongly on their localization. For example, activation of soma-todendritic receptors by serotonin or 5-HT 1A receptor agonists decreases the firing of serotonin neurons in the raphe, and, consequently decreases its terminal release 6. This decrease is thought to be partially responsible for the delay in onset of the therapeutic action of selective serotonin reuptake inhibitors (SSRI) antidepressants 5. A recent study renewed this concept, showing that expression levels of 5-HT 1A somatodendritic receptors, are critically important for SSRI treatment response by controlling serotoninergic tone 7. On the other hand, the activation of postsynaptic 5-HT 1A receptors seems to be equally important for response to antidepressants 5,8. In a different therapeutic area, 5-HT 1A receptor agonism is also known as an important feature of some atypical antipsychotics including clozapine, aripiprazole, ziprasidone and quetiapine 9–12. Recently, 5-HT 1A receptors have attracted renewed interest as possible targets in neuropharmacology. For example, it was described that blockade of post-synaptic 5-HT 1A receptors, located on pyramidal cells, can improve cognition by enhancing glutamatergic transmission 13. This led to clinical trials using the 5-HT 1A antagonist lecozotan as a procognitive drug in Alzheimer's disease 14,15. Other 5-HT 1A receptor ligands such as sarizotan, buspirone and tandospirone were shown to alleviate dyskinesia in Parkinson's disease patients 16,17. More recently,
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Dates et versions

hal-01488190 , version 1 (13-03-2017)

Identifiants

Citer

G. Becker, R. Bolbos, N. Costes, J. Redouté, A. Newman-Tancredi, et al.. Selective serotonin 5-HT1A receptor biased agonists elicit distinct brain activation patterns: a pharmacoMRI study. Scientific Reports, 2016, 6 (1), pp.26633. ⟨10.1038/srep26633⟩. ⟨hal-01488190⟩
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