Signaling Pathways of 5-HT Receptors in Neuropsychiatric Disorders

Dear Colleagues,

Serotonin (5-HT) receptor signaling remains at the heart of neuropsychiatric research, bridging molecular pharmacology and clinical innovation. For this Special Issue, we invite contributions that will advance our understanding of biased, location-dependent, and network-integrated signaling at 5-HT receptors, particularly 5-HT_1A, 5-HT_2A/2B/2C, 5-HT₄, 5-HT₆, and 5-HT₇ subtypes, and their roles in mood, cognition, addiction, and stress-related disorders.

Among the serotonin receptor family, 5-HT_1A, 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors stand out as critical modulators of cortical excitability, mood regulation, and cognitive flexibility. The 5-HT1A receptor is still an important target in mood disorders, schizophrenia, and L-DOPA-induced dyskinesia. A better understanding of its cell interaction led to conceive biased agonists preferentially targeting autoreceptors or heteroreceptors.  At the 5-HT_2A receptor, biased agonism could delineate the boundary between psychedelic and therapeutic effects. Novel ligands are now being designed to favor the G-protein or β-arrestin pathway selectively, with the aim of retaining antidepressant or anti-addictive efficacy while minimizing hallucinogenic properties. In parallel, 5-HT_2C receptor biology exemplifies the complexity of RNA editing and isoform-specific coupling. The dynamic balance between edited and unedited receptor variants influences Gq/Gi signaling, dopaminergic output in the mesocorticolimbic system, and behavioral dimensions such as impulsivity and motivation. The 5-HT_2B receptor is still a very attractive target, and numerous data indicate that some of the effects attributed in the past to 5-HT_2A or 5-HT_2C receptors included 5-HT2B receptors. 5-HT₄, 5-HT₆, and 5-HT₇ receptors are described as receptors coupled with G proteins. However, it is now clear that they can couple with various partners, leading to distinct impacts on intracellular signaling pathways, depending on brain and cellular location.

Translational imaging and multi-omics approaches, including PET/MR hybrid platforms, radioligand mapping, and single-cell phosphoproteomics, are transforming these molecular observations into clinical readouts. They enable the correlation of biased signaling patterns with circuit-level biomarkers, opening up new avenues for mechanism-based patient stratification.

We welcome original studies, critical reviews, and methodological perspectives that address the following topics:

Functional and location bias in 5-HT receptor signaling;

Structural and allosteric mechanisms guiding ligand design;

Neuroimmune and glial modulation of 5-HT pathways;

Imaging and multi-omics approaches linking receptor signaling to clinical phenotypes;

Translational studies exploring biomarkers and early-phase interventions.

Our goal is to build a mechanistic map connecting receptor-level dynamics to therapeutic outcomes. Manuscripts employing state-of-the-art structural, cellular, or computational tools are particularly encouraged.

Illustrative Themes and Areas of Interest (Non-Exhaustive):

• 5-HT₂A functional selectivity separating therapeutic and hallucinogenic effects through biased signaling analysis;
• 5-HT₂C receptor diversity, including RNA editing, coupling shifts, and behavioral outcomes;
• Intracellular cascades (β-arrestin, Akt/GSK3, ERK/mTOR, PI3K) underlying antidepressant and antipsychotic efficacy;
• Subcellular and spatial dynamics of 5-HT receptors—trafficking, nanodomains, and primary cilia signaling;
• Neuro-glial and circuit interactions integrating serotonin into dopamine, glutamate, and immune pathways;
• Structural and computational pharmacology of GPCR active states, allostery, and in silico ligand design;
• Emerging targets: 5-HT₆/₇ receptors in cognition, circadian regulation, and sleep;
• Non-hallucinogenic 5-HT₂A agonists and their translational potential;
• Quantitative and multimodal tools (BRET/FRET, live-cell imaging, single-cell phosphoproteomics);
• Neuroimaging and biomarkers using PET/MR and multi-omics correlation;
• Receptor crosstalk and synaptic plasticity shaping network adaptation;
• AI-driven modeling for bias prediction, allostery mapping, and methodological standardization;
• The role of serotonin and serotonergic receptors in neurodevelopment and plasticity.

Dr. Abdeslam Chagraoui
Prof. Dr. Philippe De Deurwaerdère
Guest Editors

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• serotonin
• 5-HT Receptors
• allostery
• allosteric modulators
• synaptic plasticity
• psychedelics
• non-hallucinogenic agonists
• RNA editing
• Akt
• GSK3
• ERK
• PI3K
• mTOR
• microglia
• neuroinflammation
• dopamine
• glutamate
• prefrontal cortex
• hippocampus
• nucleus accumbens
• depression
• schizophrenia
• anxiety
• addictions
• cognition
• biosensors
• cryo-EM
• phospho-proteomics