O:44 Changed kainate receptors in the Brodmann's area 9 from subjects with schizophenia
E. Scarr, M. Beneyto, J.H. Meador-Woodruff, G. Pavey, E.A. Thomas, B. Dean∗
The Centre for Neuroscience, The University of Melbourne and The Mental Health Research Institute, Victoria, Australia; The Department of Psychiatry, Mental Health Institute, University of Michigan, Ann Arbor, MI and the Department of Molecular Biology, Scripps Research Institute, CA, USA
Background Post-mortem studies have not produced consistent findings on cortical glutamatergic markers in schizophrenia. Therefore, to understand the role of changes in glutamate function in the pathology of the schizophrenia, we have measure markers of glutamatergic pathways in postmortem CNS from subjects with the disorder.
Methods The binding of radioligands to the ionotropic glutamate receptors (N-methyl D-aspartate ([3H]CGP39653, [3H]MK-801), amino-3-hydroxy-5-methyl-4-isoxazole ([3H]AMPA), kainate ([3H]kainate) and the high affinity glutamate uptake site ([3H]aspartate) was measured by in situ radioligand binding with autoradiography whilst mRNA for kainate receptor sub-units was measured using in situ hybridisation in Brodmann's area (BA) 9 from 20 subjects with schizophrenia and 20 controls matched for age and sex.
Results Levels of [3H]kainate binding were significantly decreased in cortical laminae I–II (p = 0.01), III–IV (p < 0.05) and V–VI, (p < 0.01) from subjects with schizophrenia. By contrast, levels of [3H]MK-801, [3H]AMPA, [3H]aspartate or [3H]CGP39653 binding did not differ between the diagnostic cohorts. Levels of mRNA for the GluR5 subunit were decreased overall (p < 0.05), with no changes in levels of mRNA for GluR6, GluR7, KA1 or KA2 in tissue from subjects with schizophrenia.
Conclusions These data suggest that the decrease in kainate receptors in BA9 from subjects with schizophrenia results, in part, from reduced expression of the GluR5 receptor sub-unit.
O:45 M1/M4 receptor expression in the hippocampus from subjects with schizophrenia
E. Scarr∗, S. Sundram, D. Keriakous, B. Dean
Rebecca L. Cooper Research Laboratories, The Mental Health Research Institute of Victoria and Centre for Neuroscience, The University of Melbourne, Parkville, Australia
Aims This study expands upon previous findings of decreased [3H]pirenzepine binding in the hippocampus from subjects with schizophrenia, to determine if there are changes in levels of mRNA of the muscarinic1 or muscarinic4 receptor in that CNS region from subjects with the disorder.
Methods [3H]pirenzepine binding and in situ hybridization, with oligonucleotides specific for the muscarinic M1 and M4 receptors, were completed using hippocampal tissue obtained from 20 controls and 20 subjects with schizophrenia.
Results [3H]pirenzepine binding was decreased in the dentate gyrus (p < 0.05), the CA3 (p < 0.01), CA2 (p < 0.05) and CA1 (p < 0.01) regions of the hippocampus from subjects with schizophrenia. Levels of muscarinic M1 mRNA were unchanged with schizophrenia whereas there was a global increase in the variance of M4 mRNA with schizophrenia (p = 0.01) that did not reach significance in any individual hippocampal region.
Conclusion This study confirms an earlier finding of decreased hippocampal [3H]pirenzepine binding in subjects with schizophrenia, which may involve changed expression of the M4 receptor.
O:46 Proteome analysis of the corpus callosum of schizophrenia
S. Sivagnanasundaram∗1,2, I. Dedova1,2, S. Cordwell3, I. Matsumoto1,2
1Neuroscience Institute of Schizophrenia and Allied Disorders, Sydney. 2Department of Pathology, University of Sydney. 3School of Molecular and Microbial Biosciences Facility, University of Sydney
Aim Abnormalities within the corpus callosum (CC) are thought to affect inter-hemispheric communication and this in-turn is postulated to underlie some schizophrenia (SCZ) symptoms. A significant reduction in the size of the CC, disruptions in the axonal density and integrity has been identified in SCZ post-mortem brains (PMB). In this study we employed 2D-gel electrophoresis (2DE) proteomics approach to identify proteins differentially expressed in the genu, body and splenium of the CC that may underlie white matter abnormalities.
Method Proteins were extracted from 10 SCZ and 10 control PMB provided by the NSW Tissue Resource Centre, matched for age, gender, hemisphere and post-mortem interval. Proteins were separated by 2DE on 11 cm pH 4–7 immobilized gradient strips and then on 6–15% 2D GelChips; samples run in duplicates. Protein/isoform spots were visualized using Coomassie stain. Protein profiles were analysed using Nonlinear Phoretix 2D Expression software and proteins identified using MALDI-TOF mass spectrometry (MS) on the basis of peptide mass fingerprinting.
Results We examined and compared the expression levels of approximately 800 protein spots varying in intensity in the genu, body and splenium. Differentially expressed protein/isoform spots involved in a number of cellular processes including myelination, microtubule formation and cytoskeleton regulation were identified. The results of these independent analysis and other comparisons will be presented.
Conclusion 2DE in combination with MS is an approach that can be successfully applied to identifying molecular factors that may underlie SCZ neuropathology.
O:47 Atypical antipsychotics associated with insulin resistance in New Zealand Maori
N.R. Poa∗, P.F. Edgar
Molecular Psychiatry Group, Department of Psychological Medicine. University of Otago, Christchurch, New Zealand
Aims/Background Atypical antipsychotics have been linked to new onset Type 2 diabetes. In New Zealand the prevalence of Type 2 diabetes in Maori is 21.1% compared to only 2.1–7.5% in non-Maori. The aim of this study was to determine whether antipsychotic treatment was associated with an increased prevalence of insulin resistance in New Zealand Maori as this ethnic group may be particularly vulnerable to antipsychotic induced impaired glucose metabolism.
Method We analysed fasting plasma glucose, insulin, HbA1c, triglycerides, total cholesterol, IGF-1 and cortisol in 30 Maori patients treated with atypical antipsychotics and 30 Maori controls. Data on weight, age, gender, personal and family history of diabetes was also recorded.
Results Antipsychotic-treated Maori demonstrated significantly higher insulin plasma levels, 148 pmol/L (SD = 138.96) compared with control Maori, 56.75 pmol/L (SD = 44.17) (p = 0.001). Antipsychotictreated Maori were significantly more insulin resistant than the controls (p = 0.003). Mean free cortisol levels were significantly higher in antipsychotic-treated Maori 58.53 nmol/L (SD = 24.12) than in the control group 35.46 nmol/L (SD = 21.35), (p = 0.000.5). There was no significant difference in body mass index (BMI), plasma glucose, HbA1c, triglycerides or cholesterol plasma levels between antipsy-chotic-treated Maori and control Maori.
Conclusion Maori treated with antipsychotic medication were significantly more insulin resistant than control subjects but had similar BMI to control Maori. Therefore, ethnicity is likely to be an important factor in susceptibility to antipsychotic induced impaired glucose metabolism and needs to be taken into account in prescribing practice and general care of this ethnic group.
Corresponding author: Nicola Poa, Department of Psychological Medicine, Molecular Psychiatry Research Group, Christchurch School of Medicine & Health Sciences, PO Box 4345, Christchurch, New Zealand, Ph/Fax +6433640569, Email: nicola.poa@chmeds.ac.nz
O:48 Antipsychotic drug effects on GABAA receptors
K.J Skilbeck, J.N. O'Reilly, G.A.R. Johnston, T. Hinton∗
Department of Pharmacology, School of Medical Sciences, The University of Sydney and Neuroscience Institute of Schizophrenia and Allied Disorders, New South Wales, Australia
GABAA receptor expression is altered in post-mortem schizophrenic brain, yet contention still rests over whether these changes are due to the disorder or to antipsychotic drug administration. Antipsychotic drugs such as haloperidol, clozapine and olanzapine are structurally similar to GABA or allosteric modulators of GABAA receptors. To investigate changes in GABAA receptor expression following chronic antipsychotic drug treatment, we administered vehicle, haloperidol (1.5 mg/kg) and olanzapine (7.5 mg/kg) in drinking water to male Sprague-Dawley rats for 7, 14 and 28 days. Quantitative receptor autoradiography using [3H]muscimol (binds to the total GABAA receptor population) and [3H]flunitrazepam (binds to the subset of benzodi-azepine-sensitive GABAA receptors) yielded changes in GABAA receptor density in the prefrontal cortex, hippocampus and thalamus over time. [3H]muscimol binding was significantly increased in the prefrontal cortex and hippocampus following 7 days treatment with haloperidol and olanzapine, and in the hippocampus and thalamus following 14 days olanzapine treatment. No changes in [3H]muscimol binding were observed in any region examined following 28 days treatment. [3H]Flunitrazepam binding was significantly decreased in the hippocampus following 14 days haloperidol and olanzapine administration, yet increased in the prefrontal cortex only after 28 days treatment. Further, in the thalamus, [3H]flunitrazepam binding was significantly increased after 7 and 14 days olanzapine administration, but decreased following 7 and 14 days haloperidol administration. In conclusion, effects of antipsychotic drug treatment on GABAA receptors vary according to period of drug administration and receptor subtype. Furthermore, chronic antipsychotic drug treatment appears unlikely to produce the changes in GABAA receptors observed in schizophrenic brain.
O:49 Neurochemical changes in frontal and temporal lobe of schizophrenic patients on conventional antipsychotic and clozapine treatment
P. Bhatia, B.M. Tripathi∗, N.R. Jagannathan, S.K. Khandelwal, M. Kumar
∗Professor of Psychiatry, All India Institute of Medical Sciences, New Delhi-110029, India
Background Antipsychotic drugs have been shown to lead to both structural and metabolic changes in the brain. In this study we compared clinical profile and brain neurochemistry in schizophrenic patients on clozapine and conventional antipsychotic treatment.
Methods Psychopathology and brain metabolites in the left frontal lobe and left temporal lobe were assessed in 20 schizophrenic patients (ICD-10 criteria) on clozapine treatment and were compared with 20 schizophrenic patients on conventional antipsychotic medication. All the subjects were right handed and in the age group 18–45 years. MRS data were acquired on a 1.5 T clinical MR scanner and NAA/Cr and Cho/Cr ratios were calculated by obtaining the peak area of the metabolite from each spectrum.
Results The metabolite ratios, NAA/Cr and Cho/Cr were similar in both the treatment groups. Temporal lobe NAA/Cr was related to positive and negative symptoms. Schizophrenic patients on clozapine treatment were more severely ill and had favourable clinical response.
Conclusions This cross-section study shows that the brain metabolite ratios not differ in schizophrenic patients on conventional antipsychotic treatment and clozapine treatment. It may suggest that different classes of antipsychotics do not produce differential effects on the neurochemistry in cross-sectional study design.
