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PMID: 18625457 Published · ppublish English Journal Article Review

5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics ·Vol. 5 ·No. 3 ·2008-07-00 ·Pages 458-69

Upton N, Chuang TT, Hunter AJ, Virley DJ

Abstract

Alzheimer's disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes, such as depression and psychosis. The neurochemical correlates of these clinical manifestations now appear to involve dysfunctions of multiple neurotransmitter pathways. Because of the extensive serotonergic denervation that has been observed in the AD brain and the important role played by serotonin (5-HT) in both cognition and behavioral control, this neurotransmitter system has become a focus of concerted research efforts to identify new treatments for AD. 5-HT exerts its diverse physiological and pharmacological effects through actions on multiple receptor subtypes. One of the newest members of this family is the 5-HT6 receptor, a subtype localized almost exclusively in the CNS, predominating in brain regions associated with cognition and behavior. With the subsequent development of selective 5-HT6 receptor antagonists, preclinical studies in rodents and primates have elucidated the function of this receptor subtype in more detail. It is increasingly clear that blockade of 5-HT6 receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms and also results in anxiolytic and antidepressant-like activity. These actions are largely underpinned by enhancements of cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission, together with learning-associated neuronal remodeling. A preliminary report that the cognitive enhancing properties of a 5-HT6 receptor antagonist (namely, SB-742457) extends into AD sufferers further highlights the therapeutic promise of this mechanistic approach.

MeSH Terms
Alzheimer Disease/complications,drug therapy Animals Cognition Disorders/drug therapy,etiology Humans Receptors, Serotonin/physiology Serotonin Antagonists/therapeutic use
Chemicals
Receptors, Serotonin Serotonin Antagonists serotonin 6 receptor
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Upton Neil
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, United Kingdom. Neil_Upton@gsk.com
Chuang Tsu Tshen
Hunter Ann J
Virley David J
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Article Info
Journal
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
Abbr.
Neurotherapeutics
ISSN
1933-7213
DOI
10.1016/j.nurt.2008.05.008
Email
neil_upton@gsk.com
Published
2008-07-00
Pages
458-69
Language
English
Region
United States
NLM ID
101290381
PMCID
PMC5084247
Subset
IM
External Links
PubMed source DOI: 10.1016/j.nurt.2008.05.008 PMC Full Text View journal details
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