Associate editor: B.L. Roth
5-HT6 receptors: a novel target for cognitive enhancement

https://doi.org/10.1016/j.pharmthera.2005.05.001Get rights and content

Abstract

Over the past decade, there has been increasing interest in the role of serotonin 6 (5-HT6) receptors in higher cognitive processes such as memory. Polymorphisms of the 5-HT6 receptor have been implicated in syndromes that affect cognition, such as schizophrenia and dementia. Manipulation of 5-HT6 receptor activity alters the transmission of several neurotransmitters important in memory: acetylcholine and glutamate, as well as dopamine, ã-aminobutyric acid (GABA), epinephrine (E), and norepinephrine (NE). Several 5-HT6 antagonists have been developed, advancing the understanding of the relationship between 5-HT6 blockade and memory consolidation in diverse learning paradigms. There is also evidence that 5-HT6 receptor activity affects anxiety behaviors and may be involved in the pathophysiology of schizophrenia. Several clinically useful atypical antipsychotics and antidepressants have 5-HT6 affinity, but recently developed selective 5-HT6 receptor antagonists may present attractive, new therapeutic options for several types of disease states.

Section snippets

Acetylcholine

Acetylcholine is directly involved in anxiety, arousal, attention, fatigue, and sleep, as well as several memory processes such as acquisition and consolidation (Wood et al., 1978, Perry et al., 1999). The first recognition of 5-HT6 influence on acetylcholine was the observation of yawning, chewing, and stretching, as well as a reduction in locomotion, immediately following administration of a 5-HT6 antagonist, Ro 04-6790 (Bourson et al., 1995, Sleight et al., 1996). Bentley and colleagues

Memory disorders/Alzheimer's disease

As described in previous sections, Bentley et al. (1999) demonstrated that atropine, a muscarinic antagonist, blocked yawning and stretching behavior induced by 5-HT6 inhibition via antisense oligonucleotides (AO). This finding implied that other processes involving acetylcholine may be influenced by 5-HT6 activity. Because acetylcholine transmission is crucial for long-term memory formation, several groups focused on characterizing the effect of 5-HT6 inhibition in diverse learning paradigms.

Conclusion

In this review, emphasis has been placed on understanding 5-HT6 receptor effects on several groups of neurotransmitters and how these effects may translate into improved cognition during treatment of neurological disorders. Although many enlightening discoveries have been made in 5-HT6 genetics, pharmacology, and physiology, there are still conspicuous holes in our knowledge, such as the role of 5-HT6 receptors in development. Many research groups are in accordance over the pronounced influence

Acknowledgments

This work was supported by a NARSAD Independent Investigator Grant (to J.F.N.) and a NIA Genetic Basis of Aging Training Grant (to E.S.M.).

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