Enhancing cognition in neurological disorders: Potential usefulness of 5-HT₆ antagonists

It is widely recognized that cognitive dysfunction is among the most debilitating symptoms of many neuropsychiatric disorders, including Alzheimer's disease and schizophrenia. Accordingly, there is a critical need for new drugs with procognitive activity. Recently, the role of the neurotransmitter serotonin (5-HT) and its receptor subtypes in cognition has emerged, and as a result, the focus on 5-HT receptor subtypes as targets for memory enhancement has increased. Among the 5-HT subtypes, the 5-HT₆ receptor may be a particularly attractive target given its almost exclusive localization in the brain and its expression in both limbic areas and other brain regions known to be critical to cognition. Novel ligands with selective affinity for 5-HT ₆ receptors would be predicted to have a low incidence of peripheral side effects and to potentially address both cognitive and noncognitive symptoms (e.g., anxiety, depression) of neuropsychiatric disorders. To date, several preclinical studies of 5-HT₆ antagonists in rodent models have indeed provided evidence of cognitive enhancement (especially in aged and pharmacologically impaired rats), as well as anxiolytic and antidepressant effects. Accordingly, several 5-HT₆ antagonists are currently in clinical trials for the treatment of neuropsychiatric disorders. The purpose of this review is to provide a brief overview of the 5-HT₆-related pharmacological approaches designed to enhance memory function.