The procognitive effects of 5-HT6 receptor ligands in animal models of schizophrenia

In addition to positive and negative symptoms, cognitive deficits are increasingly being recognized as a core feature of schizophrenia. Neurocognitive impairments are strongly associated with functional outcomes; thus, the treatment of cognitive impairments is of central importance. A large body of evidence suggests that the serotonin 6 (5-HT6) receptors may be potential targets for cognitive improvement. Clinical and preclinical studies have supported the notion that using 5-HT6 receptor antagonists is a promising component in the treatment of cognitive dysfunctions associated with aging and Alzheimer's disease. However, less is known about the efficacy of this strategy in the treatment of schizophrenia-like cognitive disturbances. The purpose of this review is to summarize existing data on the effects of 5-HT6 receptor antagonists in animal experiments, utilizing tasks that assess cognitive domains that are relevant to the cognitive deficits characterizing schizophrenia. This review focuses primarily on animal models of schizophrenia that are based on the blockade of N-methyl-d-aspartate receptors; however, when relevant, data obtained in other models are also discussed. The putative procognitive actions of 5-HT6 agonists are also reviewed. Finally, the mechanisms that are putatively responsible for the procognitive effects of 5-HT6 receptor ligands are briefly discussed.