Serotonin1A receptors are increased in postmortem prefrontal cortex in schizophrenia

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10-27-4 1 cAMPSignal Cascade in Postmortem Brains of Depressives and Suicides H. Ozawa, E. Hashimoto I. L. Froelich 2, T. Saito, N. Takahata, P. Riederer I . Dept. of Neuropsychiatry, School of Medicine. Sapporo Medical University, Sapporo, Japan; I Dept. ofPsychiatry, Wiirzburg University. Wiirzburg, Germany; 2 Dept. of Psychiatry; Frankfurt University, Frankfurt am Main, Germany Previous our study suggest that an imbalance of G protein function may be involved in the pathophysiology of depression (Ozawaet al. 1993). The aim of the present study is to examine cAMP signal cascade in the levels of adenyalte cyclase activity and phosphodiesterase type 4 binding sites in membrane preparations from postmortem temporal, parietal cortex from monopolar depressives patients, suicides and aged-matched controls. Basal, GppNHp, forskolin and maganese stimulated adenylate cyclase activity were significant decreased in depressives and suicides compare to controls. However, the percentage of inhibition of adenylate cyclase activity by GppNHp(O.1 uM) was higher in depressives and suicides than controls. Moreover, the maximal binding numbers of phosphodiesterase type 4 labeled by [3H]-rolipram increased in depressives and suicides compared to controls in parietal cortex membranes without alterations of the affinity. These results suggest that disturbances of post-receptor transduction in depression may be related with decreased cAMP production via G protein and increased degradation systems.

10-27-5 1 Autoradiographic Localization of 5-HT1A-Receptors in the Human Brain H. Hall. C. Lundkvist, C. Halldin, v.w. Pike. J.A. McCarron, A. Fletcher, t A. Cliffe. L. Farde, G. Sedvall. Karolinska Institutet, Dept. Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden Detailed semiquantitative studies of the distribution of 5-HT 1A receptors were performed in the post-mortem human brain using whole hemisphere autoradiography and the selective 5-HTIA receptor antagonist [3HIWAY-l00635. The images obtained showed very dense binding to hippocampus, raphe nuclei and to superficial layers of the neocortex. Other regions such as the amygdala, septum, claustrum showed low density of 5-HT 1A receptors. There was no labelling of nucleus caudatus and putamen, in cerebellum or in other structures of the brain stem. The labelling of human 5-HTIA receptors with [3HJWAY-lOO635 was antagonized by the addition of the 5-HTIA agonists 5-HT, buspirone, pindolol or 8-0 H-DPAT, leaving a very low background of non-specific binding. WAY-lOO635 was also radiolabelled with the short-lived radionuclide carbon- Ll 10 compare the distribution of human 5-HTIA receptors visualized with eHJWAY-lOO635 and with (1 IC)WAY-l00635, a ligand for use in positron emission tomography (PET). [1'CjWAY-lOO635 gave similar images as eHJWAY-100635, although with a lower resolution, showing binding mainly in the hippocampal formation and neocortex. The selective labelling of 5-HT IA receptors with [3HIWAY-lOO635 and [IlClWAY-100635 clearly show that these ligands are useful for further studies of the human 5-HT 1A receptor subtype in vitro and in vivo, respectively.

10 -27-6 1 Serotonin 1A, 2A and 1D Receptor mRNAS in Human Brain Postmortem: A Comparative Study by Meansof In Situ Hybridization M. Pasqualetti I, 1.Nardi I, G.B. Cassano, D. Marazziti. Institute of Psychiatry. University ofPisa, Pisa, Italy; I Institute of Cellularand Developmental Biology, University of Pisa, Pisa, Italy The distribution of messenger RNAs (mRNAs) for serotonin (5-HT) receptors of lA, 2A and ID type (5HT 1A, 5HTzA, and 5HTiD) was examined and compared in autoptic human brain by means of in situ hybridization using cRNA probes, in those areas that have been reported to present the highest density of the receptors with binding techniques. The results showed that 5HT 1A receptor was abudantly expressed in the layers Il-VI of all cortical areas under examination. In the hippocampus,it was expressed in the granular cells of the dentate gyms and in the layer of the pyramidal cells of the Hammon's hom. The 5HTzA receptor, too, was present in all cortical areas in the layers III-V, while in the hippocampus

it was restricted to the CAl field of the Hammon's hom. No expression of both the 5HTJA and 5HTZA receptors was detected in the caudate nucleus. The 5HT1D receptor was found only in the CA3 field of the Hammon's hom and in the caudate nucleus. These findings confirm that 5-HT receptors are widely distributed in the brain, but that the different subtypes possess a selective localization in different neuronal populations which, in turn, may express one or more receptors.

I0-27-7 1 SerotoninlA Receptors are Increased in Postmortem Prefrontal Cortex in Schizophrenia T. Sumiyoshi 3, C. Stockrneier I , J. Overholser 2, G. Dilley I , H. Meltzer I. I Dept. ofPsychiatry. Case Western Reserve Univ., Cleveland. U.S.A.; 3 Dept. of Psychology, Case Western Reserve Univ., Cleveland. U.S.A.; Z Dept. of Neuropsychiatry, Saitama Med. Sch., lruma-gun, Saitama, Japan Accumulated evidence has suggested a role of the serotonergic system in the pathophysiology of schizophrenia. In this study, serotonin-5-HTIA receptors were measured with [3H]8-hydroxy-2-(di-n-propyl) aminotetralin ([3H]8-0 H-DPAT) in postmortem prefrontal cortex (area 10) of 12 pairs of subjects with schizophrenia and age-matched psychiatrically normal controls (mean ± S.E. age = 37.8 ± 2.9 and 37.1 ± 3.4 years, respectively). The saturation binding isotherms of [3H]8-0H-DPAT revealed high- and Jow-affinity binding sites. The density (Bm.. ) of the high-affin ity sites was significantly elevated by an average of 79 percent in subjects with schizophrenia (19.0 ± 2.8 vs, 10.6 ± 2.1 fmol/mg protein in controls). The dissociation constant (K.i) of the high-affinity sites in subjects with schizophrenia (0.71 ± 0.13 nM) was not significantly different from the control subjects (0.43 ± 0.14 nM). No significant difference was found in the density or the dissociation constant of the high-affinity sites between suicidal (n = 5) and non-suicidal (n = 7) subjects with schizophrenia. Increased 5-HTIA receptors in prefrontal cortex of patients with schizophrenia may be an adaptive attempt to normalize diminished 5-HT1A mediated neurotransmission. It may be clinically useful to target the 5-HT 1A receptor in future approaches to the treatment of schizophrenia.

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Cell Membrane Components in the Thalamus of Schizophrenic Brains e.G. Gottfries, K. Blennow,A. Lekman, P. Fredman. University of Goteborg, Institute of ClinicalNeuroscience, Dept of Psychiatryand Neurochemistry, Molndal, Sweden Magnetic resonance imaging has given evidence for thalamic degeneration in schizophrenia which dominates in the right thalamus [I]. In 19 schizophrenic brains and in 39 age-matched control subjects membrane components, gangliosides, phospholipids, cholesterol, cerebroside and sulfatide were determined in the right thalamus. No significant differences were recorded when schizophrenic brains were compared with controls. but somewhat lower concentrations of GMI and somewhat higher concentrations of GD3 were recorded in the schizophrenic brains. GMI is considered a marker for synapses, while GD3 is considered a marker for gliosis. Studies at our institute have shown that the synapse vesicle protein rab3A is clearly reduced in the left thalamus, while in the right thalamus the difference, although significant, is smaller. Obviously further investigations of the left thalamus have to be performed before valid conclusions can be drawn concerning the biological relevance of membrane component alteration in schizophrenia. [I] Andreas en, NC, et al, Science 266(1994) 294. (2J Blennow, K, et al, CINP abstract 1996.

10-27-91 Reduced D1-Dopamlne Receptor Binding in Schizophrenia - Relation to Psychopathology P. Karlsson. L. Farde, C. Halldin, G. Sedvall. Karolinska lnstitutet, Dept. of Clinical Neuroscience, Stockholm, Sweden Among the dopamine receptor subtypes the Dl receptor is the most abundant with high densities in the striatum, neocortical and limbic