Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data

Mental disorders, such as depression and anxiety, pose both medical and social challenges. The clinical efficacy of current antidepressant/anxiolytic therapies is unsatisfactory; both antidepressant and anxiolytic drugs induce a variety of unwanted effects and have delayed onsets of action. Thus, a search for better and safer agents is continuously in progress. Preclinical results published so far have brought new insights into the possible role of recently discovered serotonin 5-HT6 receptors in these disorders. This review surveys the current state of knowledge regarding potential antidepressant and anxiolytic activities of selective 5-HT6 receptor ligands, namely, full agonists and antagonists, in animal models commonly used to predict such activity. Evidence indicates that both 5-HT6 agonists and antagonists may evoke identical responses in animal models of depression and anxiety; however, the possible mechanisms of these effects seem to be diverse and are not clearly understood. Especially interesting are the augmented effects achieved by combining antidepressants or diazepam with a selective 5-HT6 receptor antagonist.