title: Dysregulated 5-HT(2A) receptor binding in postmortem frontal cortex of schizophrenic subjects.
abstract: Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT(2A) receptor (5-HT(2A)R) binding associated with the pathophysiology of schizophrenia. These studies were performed with ligands, such as ketanserin, altanserin and LSD, that may bind with high-affinity to different structural or functional conformations of the 5-HT(2A)R. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT(2A)R density by radioligand binding assays in postmortem prefrontal cortex of antipsychotic-free (n=29) and antipsychotic-treated (n=16) schizophrenics, suicide victims with other psychiatric diagnoses (n=13), and individually matched controls. [³H]Ketanserin binding, and its displacement by altanserin or the LSD-like agonist DOI, was assayed. Results indicate that the number of [³H]ketanserin binding sites to the 5-HT(2A)R was increased in antipsychotic-free (128 ± 11%), but not in antipsychotic-treated (92 ± 12%), schizophrenic subjects. In suicide victims, [³H]ketanserin binding did not differ as compared to controls. Aging correlated negatively with [³H]ketanserin binding in schizophrenia, suicide victims and controls. The fraction of high-affinity sites of DOI displacing [³H]ketanserin binding to the 5-HT(2A)R was increased in antipsychotic-free schizophrenic subjects. Functional uncoupling of heterotrimeric G proteins led to increased fraction of high-affinity sites of altanserin displacing [³H]ketanserin binding to the 5-HT(2A)R in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT(2A)R is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained.
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Muguruza
authors.forename: José L
authors.initials: JL
authors.lastname: Moreno
authors.forename: Adrienne
authors.initials: A
authors.lastname: Umali
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
mesh_terms: D000662:Amphetamines / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007650:Ketanserin / Q000031:analogs & derivatives / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000378:metabolism; D013405:Suicide; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000662:Amphetamines; D014150:Antipsychotic Agents; D009419:Nerve Tissue Proteins; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C071983:altanserin; D007650:Ketanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine