Serotonin Receptor Modulation in Neurological and Central Nervous System Disorders

Serotonin receptor modulation underpins a wide spectrum of central nervous system functions and pathologies, from mood regulation to cognitive processing and motor control. Diverse receptor subtypes, including G protein-coupled 5-HT1A and ligand-gated 5-HT3A channels, exhibit distinct signalling and distribution patterns that can be selectively targeted by agonists, antagonists or biased ligands. Dysregulation of these systems contributes to depression, anxiety, schizophrenia, neurodegenerative disease and treatment-resistant syndromes. Recent advances in anatomical mapping, functional imaging and structural biology have converged to reveal how receptor subtype localisation, conformational states and intracellular coupling shape therapeutic outcomes. By linking receptor distribution atlases with in vivo activity profiles and high-resolution structures, researchers are devising next-generation compounds that engage precise signalling pathways, offering the prospect of rapid, efficacious treatments with reduced side effects.

Research from Nature Portfolio

A comprehensive immunofluorescence study has delineated the expression of 5-HT3A receptors across the mouse central nervous system, exposing dense populations in cortical and hippocampal interneurons and revealing previously unrecognised brainstem and spinal cord localisations. This receptor atlas clarifies the role of ionotropic 5-HT3A in fast excitatory transmission and cognitive–emotional integration, informing precise therapeutic targeting. In parallel, high-field functional MRI in rodents has compared the regional blood oxygen-level dependent responses elicited by chemically distinct 5-HT1A agonists. The contrasting activation patterns confirm that biased agonism can direct receptor signalling toward discrete intracellular cascades in vivo, validating the concept of designing ligands that preferentially evoke antidepressant or anxiolytic effects while limiting unwanted actions.

Serotonin Receptor Modulation in Neurological and Central Nervous System Disorders publication trend

The graph below shows the total number of articles in serotonin receptor modulation in neurological and central nervous system disorders across all publications each year (not limited to Nature Index journals).

Technical terms

G protein-coupled receptor (GPCR): A membrane receptor that activates intracellular signalling via G proteins.

5-HT1A receptor: A GPCR subtype widely expressed in brain areas governing mood, anxiety and cognition.

5-HT3A receptor: The sole ionotropic serotonin receptor, mediating rapid excitatory synaptic transmission.

Biased agonism: Functional selectivity of ligands that preferentially trigger specific signalling pathways downstream of the same receptor.

PET radiotracer: A positron-emitting ligand used in positron emission tomography to image and quantify receptor distribution and activity.

References

1. [18F]F13640: a selective agonist PET radiopharmaceutical for imaging functional 5-HT1A receptors in humans. European Journal of Nuclear Medicine and Molecular Imaging (2023).
2. Rapid reorganization of serotonin projections and antidepressant response to 5-HT1A-biased agonist NLX-101 in fluoxetine-resistant cF1ko mice. Neuropharmacology (2024).
3. Building a 5-HT3A Receptor Expression Map in the Mouse Brain. Scientific Reports (2017).
4. Selective serotonin 5-HT1A receptor biased agonists elicitdistinct brain activation patterns: a pharmacoMRI study. Scientific Reports (2016).