5-HT6 receptors: Contemporary views on their neurobiological and pharmacological relevance in neuropsychiatric disorders
Dialogues in Clinical Neuroscience. 2025-05-10; 27(1): 112-128
DOI: 10.1080/19585969.2025.2502028
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Chagraoui A(1)(2), Thibaut F(3)(4), De Deurwaerdère P(5).
Author information:
(1)Department of Medical Biochemistry, Rouen University Hospital, CHU de Rouen,
France.
(2)University of Rouen, Faculty of Medicine and Pharmacy, Inserm U1239,
Neuroendocrine, Endocrine, and Germinal Differentiation and Communication
(NorDiC), Mont-Saint-Aignan, France.
(3)Department of Psychiatry and Addictive Disorders, University Hospital Cochin
(site Tarnier) AP-HP, Paris, France.
(4)INSERM U1266, Institute of Psychiatry and Neurosciences, University of Paris,
Cité, Paris, France.
(5)Centre National de la Recherche Scientifique, Institut des Neurosciences
Intégratives et Cognitives d’Aquitaine, UMR 5287, Bordeaux, France.
Despite the relatively limited number of serotonergic neurons in humans,
serotonin plays a key role in neurophysiological functions, including sleep,
pain perception, learning, memory, cognition, emotion, reward, and mood
regulation. Altered serotonergic neurotransmission is linked to conditions such
as anxiety, depression, anorexia, migraine, insomnia, schizophrenia, Alzheimer’s
disease (AD), and cognitive impairments. The 5-HT6 receptor (5-HT6R), mainly
found in brain regions involved in cognition, is a promising therapeutic target
for cognitive deficits in neuropsychiatric disorders, particularly AD and
schizophrenia. Preclinical studies have shown that 5-HT6R antagonists improve
cognitive function. 5-HT6R interacts dynamically with an extensive intracellular
protein network, regulating the localisation, trafficking, and signalling of
these proteins. Proteomic and genetic studies have revealed interactions with
mTOR kinase and neurofibromin, both of which are crucial for synaptic
plasticity, learning, and memory. Fyn kinase is also associated with 5-HT6Rs,
reinforcing receptor expression and G-protein coupling. Notably, the G
protein-regulated inducer of neurite outgrowth 1 (GPRIN1) interacts with 5-HT6Rs
independently of agonists, enhancing receptor activity. This review highlights
the clinical testing of 5-HT6R ligands as regulators of these complex signalling
properties, underscoring their therapeutic potential in addressing cognitive
impairments associated with neuropsychiatric disorders.
DOI: 10.1080/19585969.2025.2502028
PMCID: PMC12068339
PMID: 40347153 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no interests or activities that
might influence the research (e.g., financial interests in a test or procedure
and funding by pharmaceutical companies for research). All authors approved the
final version of the manuscript.