Dopamine D2-family receptors in human postmortem brain: Comparison of normals and schizophrenics

P Poster Presentations

I P-15-131 Genetic-Epidemiology of Schizophrenia: A Pilot

173

I P-15-16I

I. Timotijevic, O. Marinkovic, Institute ofMental Health, Belgrade,

Changes of Platelet Serotonin-2 Receptors in Chronic Neuroleptic-Treated Schizophrenia WC. Liu, Y.H. Chou, WK. Chen, P.M. Chen, W.J. Tsai, J.F. Liao.

Yugoslavia

National Military Psychiatry Center, Taipei, Taiwan, R.O.C.

The hereditary component of schizophrenia still remain unclarified. In the effort to elucidate this complex problem, the genetic epidemiology approach was applied. The sample consisted of 169 schizophrenic patients. The selected patients group met ICD-9 and ICD-I 0 criteria. By the use of family screening method, with originally introduced genogram symbols for psychiatric illnesses, was identified 18 (10.6%) probands with unilineal or bilineal psychiatric morbidity affection. Among their 214 first degree relatives, the psychiatric morbidity was assessed in 26 (12.2%) individuals. The affective disorders, undiagnosed psychiatric features, schizophrenia and schizoaffective disorder prevalence for relatives at risk was 38.5%, 34.6%, 15.4% and 11.4% respectively. Despite the limitations regarding the small sample, this pilot study, suggests the psychiatric morbidity aggregation in the schizophrenic index patients families, therefore indicating elements for setting the impact and mode inheritance in the etiopathogenesis and comorbidity of psychiatric illnesses.

Human platelet serotonin-2 receptor binding and physiological responsiveness were determined in neuroleptic-treated schizophrenia and normal control. Binding indices were measured by a microassay employing 125 [ I]ILSD as radioligand and ketanserin to define specific binding. Functional responsiveness of the platelet 5-HT2 receptor complex was assessed by measurement of the extent to which serotonin (10 tIM) amplified platelet aggregation induced by threshold concentrations of adenosine diphosphate (ADP). The magnitude of serotonin amplified platelet aggregation was significant greater in clozapine-treated schizophrenia (10.4 ± 3.2, p < 0.05) than haloperidol-treated schizophrenia and normal control (1.1 ± 0.4). The maximum number of 5-HT2 binding sites (Bmax) was significantly higher in the clozapine-treated schizophrenia (447.3 ± 58.3 fmol/mg protein, p < O.OJ) and lower in the haloperidol-treated schizophrenia (238.5 ± 39.2f mol/mg protein, p < 0.05) than normal control (376.5 ± 46.0 fmol/mg protein). There was no significantdifference, however, between the Kd of neuroleptic-treated schizophrenia and normal control. Our results thus suggest that increase Bmax and physiological responsiveness of 5-HT2 receptor may play an important role in the mechanism of clozapine when treated schizophrenia, but not haloperidol. The opposite result of Bmax of 5-HT2 receptor in clozapine-treated and haloperidol-treated schizophrenia should be further evaluated.

Study

I P-15-141Intact 5·HT2AReceptor Genein Schizophrenia K. Ohara, T. Ishigaki, D.-W Xie, Y.Nakamura, K. Tani, K. Miyasato, K. Ohara. Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan

Genes that regulate serotonergic (5-HT) systems may underlie the etiology of schizophrenia. In this study, the gene encoding the 5-HT2A receptor in schizophrenics and healthy controls was examined. First, we sequenced all exons and the flanking introns of the 5-HT2A receptor gene in 10 schizophrenics and 10 controls. The substitution of C for T at position 102 inexon I, that had been reported by Warren et al. (1993), was confirmed. Restriction fragment length polymorphism analysis revealed no association between polymorphism and schizophrenia. There was no association between the polymorphism and subdiagnosis, family history, age of onset, amounts of antipsychotics, or positive and negative symptoms before or after medication. Other polymorphisms in the gene were screened in 100 schizophrenics by the single-strand conformation polymorphism method, but none was found. Our results suggest that an abnormality in the 5-HT2A receptor gene in schizophrenia is unlikely. [I] Ishigaki T, Xie D-W, Liu J-e. er al. Neuropsychophannacol, in press.

I P-15-15[lnositol-Lipid Signalling System in Blood Platelets of Schizophrenic Patients D. Rfpova, v. Nerncova, A. Strunecka 1, C. Hoschl, Prague Psychiatric Center, Prague, Czech Republic; I Dept. of Physiol. and Developmental Bioi., Fac. of Sci., Prague, Czech Republic

We studied levels of inositol 1,4,5-trisphosphate (I P3), cytosolic Ca2+ concentrations ([Ca2+] ;), and incorporation of [32P]-orthophosphate into inositol phospholipids and phosphatidic acid (PA) in platelets of drug-free and neuroleptic treated schizophrenics compared to controls. No difference was found in the turnover of phosphatidylinositol 4,5-bisphosphate between control subjects and drug-free or neuroleptic treated schizophrenics. However,we observed a decreasedcontent and an increased turnover of phosphatidylinositol in the platelets of drug-free schizophrenics. Neuroleptic treatment led to the increased turnover of PA.Significantly higher IP3 levels were found in platelets of drug-free and neuroleptic treated schizophrenics than in controls. The [Ca2+] ; in platelets of drug-free schizophrenics was higher (188 ± 12.5 nM) in comparison with controls (91 ± 6 nM). The study suggests that the phosphoinositide signalling system as well as calcium intracellular homeostasisare altered in platelets of schizophrenics. Supported by the Internal Grant Agency of the Ministry of Health of the Czech Republic (No. 0866-3).

I P-15-17!

Dopamine D2-Family Receptors in Human Postmortem Brain: Comparison of Normals and Schizophrenics

R.A. Lahti, R.C. Roberts, R.R. Conley, C.A. Tamminga. Maryland Psychiatric Research Center, Univ. ofMaryland School ofMed., Baltimore, MD, USA

The dopamine Dy-family receptors are the D2 , D3 and D4 receptors (Civelli er aI, 1991). The D2 receptor is primarily located in the caudateputamen-accumbens, D3 in the nuc. accumbens and the Isle of Caljia, D4 in the cortex and hippocampus. Most neuroleptics are D2 selective yet have high affinity for the D4 receptor; whereas clozapine is selective for the D4 receptor. Studies have found increases in the D4 density in caudate/putamen in schizophrenic vs normal postmortem tissue (Seeman, 1992; Meltzer, 1994; Murray, 1995). In this study the receptor distributions were determined in sections from normal humans using autoradiography. The ligands were [3Hl-raclopride for D2ID3 ; [3H]-YM-09l51-2 for D2ID3ID4 receptors. The difference between [3H]_YM-09151-2 and ['Hl-raclopride as the D4 distribution. D2 receptors are most dense in putamen, caudate and nuc. accumbens; D 3 in nuc. accumbens; D4 in cortical areas, hippocampus, with little evident in the caudate-putamen. Numerous brain structures were analyzed for receptor densities in normal controls (n = 8), and schizophrenic subjects off (n = 5) and on (n = 4) drug at the time of death. No statistically significant differences were found between normals and either group of schizophrenics with [3H]-YM09151-2, or eH]-raciopride, or the difference between the two ligands, the presumed D4 receptor. Substantial differences were found between the densities of [3H]-YM-09151-2 and ['H]-raclopride among all cases, in the following areas: insula, substantia nigra, hippocampus, entorhinal cortex and temporal cortex, suggesting these are D4 rich areas (Lahti et aI., 1995). No evidence was found for an increase in the dopamine D4 , or any other Ds-family receptor in schizophrenia.

IP-15-181

An Association StudyBetween Atypical Psychosis and Dopamine D2 Receptor Gene

I. Sakai, H. Yoneda, Y.Inayama, Y. Nonomura, Y. Kono, R. Takahata, 1. Koh, H. Toyoda,Y,Inada, A. Himei, T. Sakai. Dept. of Neuropsychiat., Osaka Medical College, Japan

Genetic contributions to the etiology of some psychoses have been generally well accepted. Atypical psychosis was defined as the fourth endogeneous psychosis in the areas where the three major psychoses overlap