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Dopamine D2 receptor imaging of antipsychotic drug action
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Abstracts / Psychiatry Research: Neuroimaging 68 (1997) 155-184
~Department of Psychiatry, University of Magdeburg, Germany. blnstitute of Biometrics and Medical lnformatics. University of Magdeburg, Germany Forty-four schizophrenic patients fulfilling DSM-III-R and ICD 10 criteria were examined at the beginning of hospital treatment and after 6 weeks. Psychopathology was assessed with BPRS and CGI. CT scans were analyzed qualitatively and from the following structures the area was quantified: third ventricle, lateral ventricles (right/left) and frontal CSF space. The qEEG (10/20-system, eyes opened/closed) and the acoustic evoked potential (oddball-paradigm) with controlled influences of the neuroleptic plasma level were determined. Neuropsychological performance was assessed with a test battery. Specially developed stabilized correlation methods were used. We found significant correlations between the area of the third ventricle, performance on a word-memory-test and the absolute power of the delta band. The BPRS-subscore anergia correlated negatively with EEG-delta- and b e t a l / 2 power. Furthermore, there was a significant negative correlation between the alphal/2-power and the BPRS-subscore anxiety/depression. These preliminary results suggest that the intensity of psychopathological symptoms is associated with morphological, EEG and psychometric parameters. What is wrong with dopamine receptors in schizophrenia G. Sedvall
Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institute and Hospital. Stockholm. Sweden Perturbated dopamine regulated signaling in the brain has been implicated in the pathophysiology of schizophrenia for more than 30 years. Five distinct dopamine receptor subtypes with pre- and post-synaptic Iocalizations to a vast number of brain regions might represent components of altered dopamine signaling in schizophrenia. Where,ks D2 dopaminc receptors have prcviously been the focus of interest, current studies focus also on D3, D4 as well as D1 receptors. For the D2 dopamine receptor family (D2, D3, D4) the analysis is complicated due to the lack of highly selective ligands for any of these receptors. Thus, practically all suitable ligands with high affinity to D2 receptors also have high affinities for D3 receptors. Whereas most phenothiazinc and butyrophenones bind to D2, D3 as well as D4 receptors, the substituted benzamidcs (sulpiride, raclopridc, amisulpiride) bind with high affinities to D2 and D3 receptors but practically lack affinity for the D4 receptor. For the DI dopaminc receptor which is the most abundant of the receptor subtypes, previous postmortcm studies wcrc controversial. Our research group have now t,scd the PET tcchnique to examine DI dopamine receptor binding in drug naive schizophrenic patients using a relatively selective DI antagonist ([I IC]-SCH 23390). Using thc method of pcak pixel analysis, wc fotmd a significantly reduced DI rcccptor binding both in the basal ganglia and in neocortical regions (}[1 drug naive schizophrenic patients as compared to agc-matchcd control subiects. Thc DI rcccptor binding is particularly high in thc patch compartment of the
basal ganglia. Dl dopamine receptors in the neocortex have been implicated in the regulation of cognitive functions. Accordingly these results may reflect a selective alteration of DI dopamine regulated pathways that may involve the patch compartment of the basal ganglia and also the regulation of cognitive functions in neocortical brain regions. The communication will give a review concerning brain circuitries connecting frontal, limbic and striatal systems that may be important for the integration and coordination of brain activities relating to brain function in schizophrenia Dopamine D2 receptor imaging of antipsychotic drug action G. Sedvall
Department of Clinical Neuroscience, Psychiatn, Section, Karolinska Institute and Hospital, Stockholm, Sweden Among the brain imaging techniques developed during the past two decades positron imaging tomography has the highest sensitivity allowing the analysis of specific neurotransmitter mechanisms in the living human brain. By using a combination of selective ligands labeled with positron emitting isotopes, DI and D2 dopamine, serotonin, 5HT2 and benzodiazepine receptors have been examined in schizophrenic patients (DSM-II1-R) and in healthy control subjects. With this technique receptor populations could be visualized and quantified with regard to number and binding characteristics in several brain regions. In schizophrenic patients treated with chemically different types of antipsychotic drugs, major reductions of ligand binding were observed indicating specific induction of neuroreceptor occupancy. Thus, all the chemically different types of antipsychotic drugs examined induced a substantial occupancy of D2 dopamine receptors. Clozapine at high doses induced a significantly lower degree of D2 dopamine receptor occupancy than the conventional drugs. Some but not all antipsychotics also induced a significant DI dopamine receptor occupancy. In spite of the fact that the selective D1 antagonist SCH 39166 induced a substantial D1 occupancy, this drug did not exhibit an antipsychotic effect m schizophrenic patients. A very high degree of 5HT2 occupancy in neocortical regions was observed alter clinical treatment with antipsychotic drugs as clozapine, risperidone and thioridazine. Haloperidol did not affect 5HT2 occupancy. Quantitative relationships between D2 dopaminc receptor occupancy and extrapyramidal side-affects as well as antipsychotic effect could also be demonstrated in series of neuroleptic treated schizophrenic patients. Assessment of CNS involvement in lupus er~hematosus and the relationship to the detection of antiphospholipld antibodies R. Serlling ~', P. Schulzc b, E. Vohs a, 1. Gorynia ~', L. Niehaus ~, A. Bock c
~'l)epartment of Psychiatry. 671aritd Univer~'ity Ho.spital. Humholdt-Univer.sity Berlitz. Germany. bDepartment of Dermatology, Charity: UniversiO, Hospital, Humboldt-University Berlin. Germalty. CDepartment of Radiolqw. Char&; University Hospital. HmnboMt-{htivers'itv Berlitz. (~,ennanv.
Abstracts / Psychiatry Research: Neuroimaging 68 (1997) 155-184
~Department of Psychiatry, University of Magdeburg, Germany. blnstitute of Biometrics and Medical lnformatics. University of Magdeburg, Germany Forty-four schizophrenic patients fulfilling DSM-III-R and ICD 10 criteria were examined at the beginning of hospital treatment and after 6 weeks. Psychopathology was assessed with BPRS and CGI. CT scans were analyzed qualitatively and from the following structures the area was quantified: third ventricle, lateral ventricles (right/left) and frontal CSF space. The qEEG (10/20-system, eyes opened/closed) and the acoustic evoked potential (oddball-paradigm) with controlled influences of the neuroleptic plasma level were determined. Neuropsychological performance was assessed with a test battery. Specially developed stabilized correlation methods were used. We found significant correlations between the area of the third ventricle, performance on a word-memory-test and the absolute power of the delta band. The BPRS-subscore anergia correlated negatively with EEG-delta- and b e t a l / 2 power. Furthermore, there was a significant negative correlation between the alphal/2-power and the BPRS-subscore anxiety/depression. These preliminary results suggest that the intensity of psychopathological symptoms is associated with morphological, EEG and psychometric parameters. What is wrong with dopamine receptors in schizophrenia G. Sedvall
Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institute and Hospital. Stockholm. Sweden Perturbated dopamine regulated signaling in the brain has been implicated in the pathophysiology of schizophrenia for more than 30 years. Five distinct dopamine receptor subtypes with pre- and post-synaptic Iocalizations to a vast number of brain regions might represent components of altered dopamine signaling in schizophrenia. Where,ks D2 dopaminc receptors have prcviously been the focus of interest, current studies focus also on D3, D4 as well as D1 receptors. For the D2 dopamine receptor family (D2, D3, D4) the analysis is complicated due to the lack of highly selective ligands for any of these receptors. Thus, practically all suitable ligands with high affinity to D2 receptors also have high affinities for D3 receptors. Whereas most phenothiazinc and butyrophenones bind to D2, D3 as well as D4 receptors, the substituted benzamidcs (sulpiride, raclopridc, amisulpiride) bind with high affinities to D2 and D3 receptors but practically lack affinity for the D4 receptor. For the DI dopaminc receptor which is the most abundant of the receptor subtypes, previous postmortcm studies wcrc controversial. Our research group have now t,scd the PET tcchnique to examine DI dopamine receptor binding in drug naive schizophrenic patients using a relatively selective DI antagonist ([I IC]-SCH 23390). Using thc method of pcak pixel analysis, wc fotmd a significantly reduced DI rcccptor binding both in the basal ganglia and in neocortical regions (}[1 drug naive schizophrenic patients as compared to agc-matchcd control subiects. Thc DI rcccptor binding is particularly high in thc patch compartment of the
basal ganglia. Dl dopamine receptors in the neocortex have been implicated in the regulation of cognitive functions. Accordingly these results may reflect a selective alteration of DI dopamine regulated pathways that may involve the patch compartment of the basal ganglia and also the regulation of cognitive functions in neocortical brain regions. The communication will give a review concerning brain circuitries connecting frontal, limbic and striatal systems that may be important for the integration and coordination of brain activities relating to brain function in schizophrenia Dopamine D2 receptor imaging of antipsychotic drug action G. Sedvall
Department of Clinical Neuroscience, Psychiatn, Section, Karolinska Institute and Hospital, Stockholm, Sweden Among the brain imaging techniques developed during the past two decades positron imaging tomography has the highest sensitivity allowing the analysis of specific neurotransmitter mechanisms in the living human brain. By using a combination of selective ligands labeled with positron emitting isotopes, DI and D2 dopamine, serotonin, 5HT2 and benzodiazepine receptors have been examined in schizophrenic patients (DSM-II1-R) and in healthy control subjects. With this technique receptor populations could be visualized and quantified with regard to number and binding characteristics in several brain regions. In schizophrenic patients treated with chemically different types of antipsychotic drugs, major reductions of ligand binding were observed indicating specific induction of neuroreceptor occupancy. Thus, all the chemically different types of antipsychotic drugs examined induced a substantial occupancy of D2 dopamine receptors. Clozapine at high doses induced a significantly lower degree of D2 dopamine receptor occupancy than the conventional drugs. Some but not all antipsychotics also induced a significant DI dopamine receptor occupancy. In spite of the fact that the selective D1 antagonist SCH 39166 induced a substantial D1 occupancy, this drug did not exhibit an antipsychotic effect m schizophrenic patients. A very high degree of 5HT2 occupancy in neocortical regions was observed alter clinical treatment with antipsychotic drugs as clozapine, risperidone and thioridazine. Haloperidol did not affect 5HT2 occupancy. Quantitative relationships between D2 dopaminc receptor occupancy and extrapyramidal side-affects as well as antipsychotic effect could also be demonstrated in series of neuroleptic treated schizophrenic patients. Assessment of CNS involvement in lupus er~hematosus and the relationship to the detection of antiphospholipld antibodies R. Serlling ~', P. Schulzc b, E. Vohs a, 1. Gorynia ~', L. Niehaus ~, A. Bock c
~'l)epartment of Psychiatry. 671aritd Univer~'ity Ho.spital. Humholdt-Univer.sity Berlitz. Germany. bDepartment of Dermatology, Charity: UniversiO, Hospital, Humboldt-University Berlin. Germalty. CDepartment of Radiolqw. Char&; University Hospital. HmnboMt-{htivers'itv Berlitz. (~,ennanv.