Dysregulated 5-HT2A receptor binding in postmortem frontal cortex of schizophrenic subjects

• Published in: European neuropsychopharmacology Vol. 23; no. 8; pp. 852 - 864
• Main Authors: Muguruza, Carolina, Moreno, José L., Umali, Adrienne, Callado, Luis F., Meana, J. Javier, González-Maeso, Javier
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.08.2013
• Subjects: Aging; Internal Medicine; Postmortem human brain; Psychiatry; Radioligand binding; Schizophrenia; Serotonin; Serotonin 5-HT2A receptor; Suicide; Schizophrenia; Serotonin 5-HT2A receptor; Serotonin; Suicide; Radioligand binding; Postmortem human brain
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2012.10.006

Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT2A receptor (5-HT2AR) 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-HT2AR. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT2AR 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-HT2AR 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-HT2AR 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-HT2AR in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT2AR is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained.