New insight into the therapeutic role of 5-HT1A receptors in central nervous system disorders.
The serotonergic system plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among 5-HT receptor subtypes, 5-HT(1A) receptors have long been implicated in the pathogenesis and treatment of anxiety and depressive disorders. 5-HT(1A) receptors function as both presynaptic (autoreceptor) and postsynaptic receptors in specific brain regions such as the limbic areas, septum and raphe nuclei. 5-HT(1A) receptors negatively regulate cAMP-dependent signal transduction and inhibit neuronal activity by opening G-protein-gated inwardly rectifying potassium channels. The therapeutic action of 5-HT(1A) agonists and their mechanism in alleviating anxiety and depressive disorders have been well documented. In addition, recent studies have revealed new insights into the therapeutic role of 5-HT(1A) receptors in treating various CNS disorders, including not only depressive disorders (e.g., delayed onset of action and refractory symptoms), but also schizophrenia (e.g., cognitive impairment and antipsychotic-induced extrapyramidal side effects) and Parkinson's disease (e.g., extrapyramidal motor symptoms and L-DOPA-induced dyskinesia). These lines of evidences encourage us to design new generation 5-HT(1A) ligands such as 5-HT(1A) agonists with greater potency, higher selectivity and improved pharmacokinetic properties, and 5-HT(1A) ligands which combine multiple pharmacological actions (e.g., inhibition of serotonin transporter, dopamine D(2) receptors and other 5-HT receptor subtypes). Such new 5-HT(1A) ligands may overcome clinical efficacy limitations and/or improve adverse reactions in current CNS therapies.
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. yohno@gly.oups.ac.jp
Yukihiro
Y
Ohno
D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D015394:Molecular Structure; D010300:Parkinson Disease / Q000188:drug therapy*; D044282:Receptor, Serotonin, 5-HT1A / Q000627:therapeutic use*; D012559:Schizophrenia / Q000188:drug therapy*; D012701:Serotonin / Q000737:chemistry / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000627:therapeutic use; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors