Serotonin1A receptors in the pathophysiology of schizophrenia: development of novel cognition-enhancing therapeutics.
Serotonin (5-HT) receptors have been suggested to play key roles in psychosis, cognition, and mood via influence on neurotransmitters, synaptic integrity, and neural plasticity. Specifically, genetic evidence indicates that 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor single-nucleotide polymorphisms (SNPs) are related to psychotic symptoms, cognitive disturbances, and treatment response in schizophrenia. Data from animal research suggest the role of 5-HT in cognition via its influence on dopaminergic, cholinergic, glutamatergic, and GABAergic function. This article provides up-to-date findings on the role of 5-HT receptors in endophenotypic variations in schizophrenia and the development of newer cognition-enhancing medications, based on basic science and clinical evidence. Imaging genetics studies on associations of polymorphisms of several 5-HT receptor subtypes with brain structure, function, and metabolism suggest a role for the prefrontal cortex and the parahippocampal gyrus in cognitive impairments of schizophrenia. Data from animal experiments to determine the effect of agonists/antagonists at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors on behavioral performance in animal models of schizophrenia based on the glutamatergic hypothesis provide useful information. For this purpose, standard as well as novel cognitive tasks provide a measure of memory/information processing and social interaction. In order to scrutinize mixed evidence for the ability of 5-HT(1A) agonists/antagonists to improve cognition, behavioral data in various paradigms from transgenic mice overexpressing 5-HT(1A) receptors provide valuable insights. Clinical trials reporting the advantage of 5-HT(1A) partial agonists add to efforts to shape pharmacologic perspectives concerning cognitive enhancement in schizophrenia by developing novel compounds acting on 5-HT receptors. Overall, these lines of evidence from translational research will facilitate the development of newer pharmacologic strategies for the treatment of cognitive disturbances of schizophrenia.
Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan. tomikisumiyoshi840@hotmail.com
Tomiki
T
Sumiyoshi
Vera
V
Bubenikova-Valesova
Jiri
J
Horacek
Bettina
B
Bert
D000818:Animals; D001519:Behavior / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002065:Buspirone / Q000494:pharmacology / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D054833:Isoindoles / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use
D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C055267:tandospirone; D002065:Buspirone