Paradoxical trafficking and regulation of 5-HT_2A receptors by agonists and antagonists

5-Hydroxytryptamine_2A (serotonin_2A, 5-HT_2A) receptors are important for many physiologic processes including platelet aggregation, smooth muscle contraction, and the modulation of mood and perception. A large number of pharmaceutical agents mediate their actions, at least in part, by modulating the number and/or activity of 5-HT_2A receptors. Drugs with action at 5-HT_2A receptors are used in the treatment of many disorders, including schizophrenia, depression, and anxiety disorders. This review summarizes over two decades of research on the regulation of 5-HT_2A receptors and provides a comprehensive review of numerous in vivo studies describing the paradoxical phenomenon of 5-HT_2A receptor down-regulation by chronic treatment with antidepressants and antipsychotics. In addition, studies reporting antagonist-induced internalization of 5-HT_2A receptors and other G protein-coupled receptors will be highlighted as a possible mechanism to explain this paradoxical down-regulation. Finally, a review of the cellular and molecular mechanisms that may be responsible for agonist-mediated desensitization and internalization of 5-HT_2A receptors will be presented.