Neurotherapeutics

, Volume 5, Issue 3, pp 458–469

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

  • Neil Upton
  • Tsu Tshen Chuang
  • Ann J. Hunter
  • David J. Virley
Review Article

DOI: 10.1016/j.nurt.2008.05.008

Cite this article as:
Upton, N., Chuang, T.T., Hunter, A.J. et al. Neurotherapeutics (2008) 5: 458. doi:10.1016/j.nurt.2008.05.008

Summary

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.

Key Words

5-HT6 receptor antagonistsAlzheimer’s diseasecognitionlearningmemorybehavioral symptomsglutamatedopamineacetylcholinenorepinephrinesynaptic plasticitySB-742457neural cell adhesion molecule
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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2008

Authors and Affiliations

  • Neil Upton
    • 1
  • Tsu Tshen Chuang
    • 1
  • Ann J. Hunter
    • 1
  • David J. Virley
    • 1
  1. 1.GlaxoSmithKlineHarlowUK