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Antidepressants & 5-HT1A

Key message: 5-HT1A receptors exhibit complex signal transduction properties.
Targeting 5-HT1A receptor subpopulations with agonists displaying “biased agonism” may achieve improved therapeutic benefit.

  • 5-HT1A receptor agonists are potently active in models of anti-depressant-like activity.
  • 5-HT1A receptors exhibit brain region-dependent coupling to G-protein subtypes. Agonists exhibit distinct orders of potency ("biased agonism") for activation of signal transduction responses.
  • Sub-populations of 5-HT1A receptors can be targeted by agonists such as F15599: stimulation of frontal cortex electrical activity at doses that do not inhibit raphe neuron electrical activity.
  • Preferential activation of frontal cortex 5-HT1A receptors by F15599 translates to potent anti-depressant-like properties at doses that do not elicit 5-HT syndrome.
  • F15599 increases frontal cortex dopamine neurotransmision, attenuates PCP-induced cognitive deficits in rodent and shows a distinctive pattern of brain imaging in micro-PET studies.
# Article Title
1 A Postmortem Study to Compare Agonist and Antagonist 5-HT1A Receptor-binding Sites in Alzheimer's Disease.
2 Pinpointing brainstem mechanisms responsible for autonomic dysfunction in Rett syndrome: therapeutic perspectives for 5-HT1A agonists. (REVIEW) PDF
3 5-HT1A receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function. (REVIEW)
4 Radiosynthesis and Preclinical Evaluation of 18F-F13714 as a Fluorinated 5-HT1A Receptor Agonist Radioligand for PET Neuroimaging.
5 In vivo electrophysiological and neurochemical effects of the selective 5-HT1A receptor agonist, F13640, at pre- and post-synaptic 5-HT1A receptors in the rat.
6 Biased agonism at serotonin 5-HT1A receptors: preferential postsynaptic activity for improved therapy of CNS disorders. (REVIEW)
7 Differential ligand efficacy at h5 HT1A receptor-coupled G protein subtypes: a commentary. (REVIEW)
8 Preferential in vivo action of F15599, a novel 5-HT1A receptor agonist, at postsynaptic 5-HT1A receptors. PDF
9 F15599, a highly selective post-synaptic 5-HT1A receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity.
10 Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist. PDF
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