Antidepressant and anxiolytic effects of selective 5-HT6 receptor agonists in rats

Although selective serotonin reuptake inhibitors (SSRIs) produce clinical therapeutic effects on depression and anxiety through augmentation of serotonergic neurotransmission, there is little known about the potential contributions of the 5-HT6 receptor in the treatment of mood disorders. The aim of this study was to test the potential antidepressant-like and anxiolytic-like effects of the 5-HT6 receptor agonists WAY-208466 and WAY-181187 using established behavioral tests in rats. In order to determine if the 5-HT6 receptor agonists possess antidepressant-like activity, rats were treated with WAY-208466 or WAY-181187 and tested in the modified rat forced swim test (FST). Also, the potential anxiolytic-like effects of WAY-208466 and WAY-181187 were measured using the defensive burying (DB) test and novelty-induced hypophagia (NIH) test. WAY-208466 and WAY-181187 produced both antidepressant-like and anxiolytic-like effects. Both compounds decreased immobility and increased swimming behavior in the FST. The effects of the 5-HT6 receptor agonists were similar to those seen after treatment with the SSRI fluoxetine. Both 5-HT6 receptor agonists also decreased burying duration in the DB test, indicative of anxiolytic activity in the test. The anxiolytic effects of WAY-208466 were reproduced in the NIH test. Assessment of the anxiolytic effects of WAY-181187 in the NIH was confounded by alterations in home cage feeding behavior. These findings suggest that 5-HT6 receptor agonists may represent a new class of potential antidepressant and anxiolytic compounds and could possess a number of advantages over currently available treatments, including rapid onset of anxiolytic efficacy.