Annual Report

37. Serotonin 5-HT2 Receptors in Schizophrenic Patients as Studied by Positron Emission Tomography

Yoshiro Okubo, Tetsuya Suhara, Kazutoshi Suzuki, Kaoru Kobayashi, Osamu Inoue, Omi Terasaki, Yasuhiro Someya, Takeshi Sassa, Yasuhiko Sudo, Eisuke Matsushima, Masaomi Iyo, Yukio Tateno and Michio Toru

Keywords: 5-HT2 receptors, positron emission tomography, [11C]N-methylspiperone, schizophrenia, prefrontal cortex

Using positron emission tomography (PET) and [11C]N-methylspiperone (NMSP), we examined 5-HT2 receptors in the cortex of schizophrenic patients in whom we had previously observed decreased prefrontal D1 receptor binding. The subjects were 10 neuroleptic-naive schizophrenic patients, 7 schizophrenic patients who were drug-free but had previously been treated with neuroleptics, and 12 normal controls. A non-significant trend towards decreased prefrontal [11C]NMSP binding was observed in the neuroleptic-treated patients, suggesting a possible effect of previous neuroleptic treatment on the alteration in cortical 5-HT2 function. However, the neuroleptic-naive patients showed no noticeable difference in cortical [11C]NMSP binding compared to the controls. Our results do not rule out the role of 5-HT2 function as a crucial site of therapeutic activity of schizophrenia, but they do suggest that cortical 5-HT2 receptors might not be primarily involved in the pathophysiology of schizophrenia.

The possible role of 5-HT dysfunction in the pathophysiology of schizophrenia has gained considerable attention over the last several years. This is partly due to the clinical efficacy of atypical antipsychotic drugs with relatively weak dopamine D2 antagonistic potency but high affinity for 5-HT2 receptors. Further, it has been hypothesized that dopamine receptor blockade would reduce positive symptoms in schizophrenia, while blockade of 5-HT2 receptors would reduce negative symptoms and decrease extrapyramidal side effects. In addition, postmortem studies have reported decrease 5-HT2 receptor densities in the prefrontal cortex of schizophrenic patients.

Several radioligands have been proposed for PET for the examination of 5-HT2 receptors in the living human brain. Recently, two PET studies used [18F]setoperone to investigate the cortical 5-HT2 receptors in schizophrenic patients and found no difference compared to controls. These findings are in contrast to those of the postmortem studies and need to be replicated with other PET radioligands for 5-HT2 receptors.

In our previous study on dopamine D1 and D2 receptors in schizophrenic patients, we used [11C]NMSP for striatal D2 receptors and [11C]SCH23390 for striatal and cortical D1 receptors. Although D1 and D2 receptors showed no changes in the striatum, D1 receptor binding in the prefrontal cortex of schizophrenic patients decreased compared to controls. We have evaluated only the striatal [11C]NMSP binding which represents dopamine D2 receptors. However, NMSP has a high affinity not only for D2 receptors, but also for 5-HT2 receptors. Since the cortical D2 receptor density is very low , the cortical binding of [11C]NMSP has been assumed to represent the binding to 5-HT2 receptors. Thus [11C]NMSP has been extensively used as a PET radioligand to investigate the cortical 5-HT2 receptors.

Okubo, Y., et al.: Life Sci., 66, 2455-2464, 2000.

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