Chemical brain anatomy in schizophrenia.
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Autoradiography↗
Biomedical subjects
G Sedvall
Publications and source records attributed to G Sedvall.
Schizophrenia and APP gene mutations.
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Amyloid beta-Protein Precursor↗
A set of male monozygotic triplets with schizophrenic psychoses: nature or nurture?
A set of schizophrenic male monozygotic triplets is described. At age 20 years, within 8 months the three men independently developed acute fulminant schizophrenic disorders (DSM-III-R) with auditory hallucinations, bizarre delusions, and thought disturbances. There were also great similarities between the triplets with regard to the chronic intermittent course of the disorder, impairment of social adjustment, and loss of working ability. The psychoses responded rapidly to conventional neuroleptic treatment. Neuropsychological assessment demonstrated similar marked reductions of attentional, mnestic, and executive functions. Magnetic resonance imaging (MRI) showed similar borderline ventricular enlargement and widened subarachnoid spaces over frontoparietal and basal regions as well as around the pituitary gland (empty sella). All the boys also had a right-sided hearing defect with a marked reduction of the ossicular bones on the right side. Possible clues as to etiological mechanisms were the lack of reported family history for the disorder and a possible influenza infection in the mother during the first trimester. It is suggested that a DNA aberration being present or occurring at conception initiated a precise time-programmed series of events that produced the very similar schizophrenic phenotypes. Such an aberration might have been induced by an external agent, occurred spontaneously, or been inherited by a recessive mechanism. It seems possible that the psychoses, the reductions of neuropsychological functions, the morphological MRI changes, and the right-sided ossicular reductions may all be related to such a DNA alteration.
Adult↗
Oral administration of NNC 756--a placebo controlled PET study of D1-dopamine receptor occupancy and pharmacodynamics in man.
NNC 756 is a new benzazepine with high affinity and selectivity for D1-dopamine receptors. In a double-blind, placebo controlled, cross-over study, positron emission tomography and the radioligand [11C]SCH 23390 were used to determine central D1-dopamine receptor occupancy after a single oral dose of 80 mg NNC 756 in three healthy men. NNC 756 induced 75, 66 and 47% occupancy of D1-dopamine receptors in the putamen of at 1.5 h after drug administration and 46, 36 and 24% after 7.5 h. There was a hyperbolic relationship between the occupancy values and the serum concentrations. The Ki value for the hyperbola was 6.4 ng/ml (+/- SD 1.4). The occupancy at 1.5 h is on the same level as that shown to induce effects in animal models for prediction of antipsychotic effect. Restlessness (akathisia) appeared in two subjects and nausea in one subject at time of peak drug concentration in serum. The oral dose level of 80 mg should be appropriate to investigate the potential antipsychotic effect of NNC 756.
Administration, Oral↗
Evaluation of SCH 39166 as PET ligand for central D1 dopamine receptor binding and occupancy in man.
SCH 39166 is the first selective D1-dopamine receptor antagonist developed for clinical trials in schizophrenia. SCH 39166 was evaluated as a radioligand for PET, labeled with 11C, and as a D1-dopamine receptor antagonist after single oral doses in healthy men. After intravenous injection of [11C]SCH 39166 distribution of radioactivity in brain grossly reflected D1-dopamine receptor density. The putamen to cerebellum ratio at equilibrium was low (1.54 +/- 0.18 SD), which makes [11C]SCH 39166 less suitable as a radioligand for applied PET studies. Saturability of specific binding was demonstrated after IV injection of [11C]SCH 39166 with low specific radioactivity. Stereospecificity of binding was examined using the stereoisomer [11C]SCH 39165. D1-Receptor occupancy was demonstrated with [11C]SCH 39166 2 h after administration of single oral doses of unlabeled SCH 39166 to each of three healthy subjects (25, 100 and 400 mg). There was a substantial reduction of specific [11C]SCH 39166 uptake in the putamen after all doses. Single oral doses of 100 mg induced approximately 70% D1-dopamine receptor occupancy in the basal ganglia, which should be sufficient to investigate the antipsychotic potential of D1-dopamine receptor antagonism in clinical studies.
Adult↗
Lack of apparent antipsychotic effect of the D1-dopamine receptor antagonist SCH39166 in acutely ill schizophrenic patients.
SCH 39166 is the first selective D1 dopamine receptor antagonist developed for the treatment of schizophrenic patients. To examine potential antipsychotic effect, tolerability and safety, SCH 39166 was given orally to 17 acutely ill drug free schizophrenic patients (DSMIIIR) in an open 4-week study. Doses were escalated from 10 to 100 mg b.i.d. according to a fixed schedule over 17 days and remained at 100 mg b.i.d. for another 11 days. The drug was withdrawn prematurely in ten patients because of deterioration or refusal to take SCH 39166. In the nine patients participating for more than 2 weeks, none had an apparent reduction of BPRS or CGI scores. Side effects were agitation, akathisia and emesis in single patients. After withdrawal of SCH 39166 of the patients improved when treated with classical neuroleptics or clozapine. The result of the study does not support the prediction that selective D1 dopamine receptor antagonism will produce antipsychotic effects in schizophrenia.
Adult↗
Distribution of messenger RNAs for D1 dopamine receptors and DARPP-32 in striatum and cerebral cortex of the cynomolgus monkey: relationship to D1 dopamine receptors.
Messenger RNAs for the D1 dopamine receptor and dopamine- and cyclic AMP-regulated phosphoprotein of relative mass 32,000 (DARPP-32) were examined by in situ hybridization in the cynomolgus monkey brain. The messenger RNA distribution was compared to the distribution of D1 dopamine receptors using [3H]SCH 23390 autoradiography. In the caudate nucleus and putamen, D1 dopamine receptor messenger RNA-positive cells were unevenly distributed. Clusters of cells with an approximately three-fold higher intensity of labeling, as compared to surrounding regions, were found. Some of these D1 dopamine receptor messenger RNA intensive cell clusters in the caudate nucleus appeared to some extent to be matched to regions of higher intensity of [3H]SCH 23390 binding. The distribution of cells expressing DARPP-32 messenger RNA in the caudate nucleus and putamen was found to be non-clustered. In neocortical regions, cells of different sizes expressing D1 dopamine receptor messenger RNA were present in layers II-VI. D1 dopamine receptor messenger RNA-positive cells were most abundant in layer V. Unexpectedly, no DARPP-32 messenger RNA signal was detected in neocortex. Chronic SCH 23390 administration did not change the relative levels of messenger RNAs for the D1 dopamine receptor and DARPP-32 or [3H]SCH 23390 binding as measured by quantitative image analysis. The clustered distribution of D1 dopamine receptor messenger RNA is in contrast to that of DARPP-32 messenger RNA. This suggests that D1 dopamine receptors may play a more significant role in regulating DARPP-32 function in patch regions as compared to matrix regions. D1 dopamine receptor messenger RNA-expressing cells could also be visualized in several layers of the primate neocortex, implying that dopamine acts through D1 dopamine receptors within functionally different neuronal circuits of the neocortex.
Animals↗
Effect of clozapine and risperidone on 5-HT2 and D2-dopamine receptor binding in the post-mortem human brain. An autoradiographic study.
Effects of the antipsychotics risperidone and clozapine on 5-HT2 and D2-dopamine receptor binding were examined using [3H]N-methylspiperone ([3H]NMSP) and in vitro receptor autoradiography on human whole hemisphere cryosections. The 5-HT2 receptor antagonist ketanserin and the D2-dopamine receptor antagonist raclopride were used as references. [3H]NMSP binding was observed in caudate nucleus, putamen, and cerebral cortex indicating binding to D2-dopamine and 5-HT2 receptors. Risperidone and clozapine counteracted the binding to both receptor types. This was in contrast to raclopride, which selectively blocked the D2-dopamine receptors in the basal ganglia, and ketanserin, which selectively blocked the 5-HT2 receptors in the cerebral cortex. Risperidone (100 nM and 10 microM) blocked up to 90% of [3H]NMSP binding to both receptor types, whereas the blocking capacity of clozapine (10 microM) was lower (approximately 60%). The lack of total blockade of D2-dopamine receptors is in line with results obtained in with [11C]raclopride and positron emission tomography studies of clozapine treated human subjects. However, autoradiographic studies of clozapine competition of [3H]raclopride binding show total displacement of the binding at high clozapine concentrations, thus contradicting the PET results with [11C]raclopride, as well as the autoradiographic results obtained with [3H]NMSP. In conclusion it can be stated that pharmacological concentrations of the two drugs clozapine and risperidone block a large proportion of D2-dopamine receptors and 5-HT2 receptors in the human brain. Moreover, the study shows the usefulness of human whole hemisphere autoradiography for the study of interaction of drugs with different central neurotransmitter receptors.
Adult↗
PET imaging of neuroreceptors in schizophrenia.
Among the brain imaging techniques developed during the past two decades positron emission tomography has the highest sensitivity, allowing the analysis of specific neurotransmitter mechanisms in the living human brain. By using a combination of selective ligands labelled with positron emitting isotopes, D1 and D2 dopamine, serotonin 5HT2 and benzodiazepine receptors were examined in schizophrenic patients (DSM-IIIR) and healthy control subjects. With this technique receptor populations could be excellently visualized and quantified with regard to number and binding characteristics in several brain regions. The characteristics of total D1 and D2 dopamine receptor populations in the caudate and putamen did not differ significantly in young drug naive schizophrenic patients and age matched control subjects. On the other hand, there was a highly significant reduction of the D1 signal in high intensity regions of the basal ganglia when [11C]SCH 23390, a selective D1 dopamine receptor antagonist, was used. These results suggest the possibility of a reduced D1 dopamine receptor density in the patch compartment of the basal ganglia in schizophrenia. For 5HT2 and benzodiazepine receptors no major alteration of receptor characteristics was observed in several neocortical and limbic brain regions.
Humans↗
Screening for CGG trinucleotide repeat expansion in the fragile X mental retardation 1 gene in schizophrenic patients.
Patients diagnosed using DSM-III-R criteria as having schizophrenia and other related disorders (n = 128) were assessed for CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR-1) gene. One subject, a woman with schizophreniform disorder, was found to have a premutation of the gene. Her case report is given. The present investigation supports the view that mutation or premutation of the FMR-1 gene is not of importance for the aetiology of the vast majority of schizophrenic patients.
Adult↗
D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients.
OBJECTIVE: Central D1, D2, and 5-HT2 receptor occupancy in schizophrenic patients treated with clozapine was determined and related to clozapine serum concentrations. METHOD: Seventeen patients treated with clozapine (125-600 mg/day) were examined with positron emission tomography (PET) and one to three of the following selective radioligands: [11C]SCH23390 (N = 11), [11C]raclopride (N = 16), and [11C]N-methylspiperone (N = 5). Clozapine concentration in serum was determined by gas chromatography/mass spectrometry. RESULTS: D2 receptor occupancy (20%-67%) was lower than that previously determined in patients treated with classical neuroleptics (70%-90%). D1 receptor occupancy (36%-59%) was higher than that induced by classical neuroleptics (0%-44%). 5-HT2 receptor occupancy was very high (84%-94%), even at low clozapine doses. Despite a 20-fold range in clozapine serum concentration (105-2121 ng/ml) at the time of PET examination, D2 receptor occupancy was low in all patients and was not described by the curvilinear relationship between serum drug concentration and receptor occupancy that has been demonstrated for classical antipsychotics. CONCLUSIONS: The results confirm in an extended series of patients that clozapine is atypical with regard to degree of D2 receptor occupancy, a finding that may explain the lack of extrapyramidal side effects. The combination of relatively high D1, low D2, and very high 5-HT2 receptor occupancy values is unique to clozapine. Clozapine serum concentrations have not been unequivocally shown to predict clinical effects. In this study, concentration did not predict degree of occupancy in brain. Thus, careful clinical titration cannot be replaced by monitoring of drug concentrations for optimization of clozapine treatment in individual patients.
Adult↗
Utilization of radioligands in schizophrenia research.
Interest in the role of monoaminergic mechanisms in schizophrenia has stimulated the development of specific radioligands that allow PET analysis of quantitative aspects of monoamine receptor subtypes in the living human brain. Clinical studies with such ligands have not consistently demonstrated specific alterations of the total populations of D1 and D2 dopamine receptors in the caudate putamen complex of drug-naive schizophrenic patients. However, recent studies using [11C]SCH 23390, a specific D1 dopamine receptor ligand, disclosed a highly significant reduction of ligand binding in pixel elements of the basal ganglia that normally contain high activity. This finding may be related to reduced D1 dopamine regulated transmission in subsets of neuronal pathways within the basal ganglia. D3, D4, and D5 receptor subtypes constitute minor fractions of the total number of dopamine receptors in the human brain. However, efforts to find selective ligands for D3 and D4 subtypes also show promise. Radioligands for monoamine receptors have also been used to follow drug effects on receptor subtypes in schizophrenic patients treated with different types of antipsychotic drugs. Such studies have allowed the analysis of relationships between occupancy of dopamine receptor subtypes and some clinical manifestations of drug treatment. Such studies with the selective D2 antagonist raclopride indicated quantitative relationships between the degree of D2 dopamine receptor occupancy in the basal ganglia and the extrapyramidal manifestations, as well as the antipsychotic action. Some of the currently available antipsychotic drugs also induced significant occupancy of D1 dopamine receptors. However, the selective D1 antagonist SCH 39166 in doses inducing a more than 70% occupancy of D1 dopamine receptors in the caudate putamen failed to induce an antipsychotic action. This indicates that, in contrast to D2 blockade, selective antagonism of D1-regulated pathways does not mediate antipsychotic action in schizophrenia. Some but not all antipsychotic drugs also induced high occupancy of neocortical 5HT2A receptors. Because selective 5HT2A antagonism does not appear to be an efficient treatment for schizophrenia, it seems most likely that 5HT2A receptors and, perhaps, D1 receptors act in concert to modify aspects of the mandatory D2 blockade to induce antipsychotic actions. Computer graphic methods for image analysis add new dimensions to brain imaging research, allowing three-dimensional visualization of receptor populations computed from molecular PET data. This will make possible further exploration of the detailed molecular compartmentalization of the human brain using radioligand binding.
Brain↗
Recent developments in PET scan imaging of neuroreceptors in schizophrenia.
Among the brain imaging techniques developed during the past two decades, positron emission tomography (PET) 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 D1- and D2 dopamine, serotonin 5HT2, and benzodiazepine receptors were examined in schizophrenic patients (DSM-III-R) and healthy control subjects. With this technique receptor populations could be excellently visualized and quantified with regard to number and binding characteristics in several brain regions. The characteristics of the total D1 and D2 dopamine receptor populations in the caudate and putamen did not differ in young drug-naive schizophrenic patients and age-matched control subjects. Also for 5HT2 and benzodiazepine receptors no major alteration of receptor characteristics was observed in several neocortical and limbic brain regions. However, in schizophrenic patients treated with chemically different types of antipsychotic drugs major reductions of ligand binding was observed indicating specific induction of neuroreceptor occupancy. Thus, all chemically different types of antipsychotic drugs examined induced a substantial occupancy of D2 dopamine receptors. Clozapine in 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 D1 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 in schizophrenic patients. A very high degree of 5HT2 occupancy in neocortical regions was observed after clinical treatment with antipsychotic drugs as clozapine, risperidone and thioridazine.(ABSTRACT TRUNCATED AT 250 WORDS)
Antipsychotic Agents↗
PET-determination of benzodiazepine receptor binding in studies on alcoholism.
Positron Emission Tomography (PET) and the radioligand [11C]flumazenil were used to examine benzodiazepine (BZ) receptor binding in the human brain. In a first study of healthy males acute ingestion of alcohol did not alter total radioactivity uptake or specific [11C]flumazenil binding in the neocortex or cerebellum. In a second study [11C]flumazenil binding was determined in 5 healthy male controls and 5 chronic alcohol dependent men using a saturation procedure with two PET experiments. Mean values for BZ-receptor density and affinity were similar in the two groups but the Bmax variance for the alcohol dependents was significantly larger (p < 0.05) for all regions. The present studies do not support the view that alcohol affects central BZ receptor binding in man.
Adult↗
Dopamine D1 receptor number--a sensitive PET marker for early brain degeneration in Huntington's disease.
D1-dopamine receptor binding in the brain was determined by positron emission tomography (PET) in five patients with Huntington's disease, in one asymptomatic gene carrier and in five control subjects. [11C] SCH 23390 was used as the radioligand. Brain morphology was recorded by MRI. The patients who all had a mild to moderate functional impairment showed an almost 50% reduction of putamen volume as well as D1-dopamine receptor density as compared to the controls. The total D1-dopamine receptor number in the putamen was reduced by 75% in the patient group. A similar reduction was found for the caudate nucleus. The asymptomatic gene carrier had volume and density values in the lower range of the control subjects. In the frontal neocortex there also tended to be a reduced D1-dopamine receptor binding in the symptomatic patients. The results indicate that [11C] SCH 23390 binding in combination with MRI can be used as a sensitive marker for early brain degeneration in Huntington's disease. This marker may be useful to monitor the pathophysiological effect of the disease gene and also to follow therapeutic interventions aiming at preventing the degenerative process.
Adult↗
Dopamine D2-receptor gene polymorphisms in Scandinavian chronic alcoholics.
Alterations in the dopamine system have been hypothesized as a predisposing factor in alcoholism. The presence of the TaqI A1 and B1 alleles adjacent to the dopamine D 2-receptor gene (DRD2) was studied in Scandinavian alcoholic inpatients (n = 74), alcoholics autopsied at a forensic clinic (n = 19) and controls (n = 81). There were no significant differences between controls and the alcoholics, but a tendency of increased DRD2 TaqI A1 or B1 allele frequencies in alcoholic groups selected for severity (i.e. severity according to DSM-III-R criteria, early onset or severe medical complications due to alcohol abuse) and decreased frequencies in the corresponding less severe alcoholic group. The present study does not yield evidence for the hypothesis of an association between the DRD2 TaqI A1 or B1 alleles and alcoholism.
Adult↗
Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain.
Densities and distribution of D1-dopamine and D2-dopamine receptors were investigated in vitro using [3H]SCH 23390 and [3H]raclopride in receptor binding assays and autoradiography on human post mortem whole hemisphere slices to serve as anatomical correlates to PET studies using [11C]SCH 23390 and [11C]raclopride. In addition, the levels of dopamine and its metabolites were determined by HPLC in various brain regions. Both dopamine receptor subtypes, as well as dopamine, HVA and DOPAC, were primarily found in the basal ganglia. Very high densities of D1-dopamine receptors were found particularly in the medial caudate nucleus, whereas D2-dopamine receptors were evenly distributed throughout the caudate. The densities of D1- and D2-dopamine receptors were similar in the caudate nucleus and the putamen, whereas there were 4 to 7 times higher densities of the D1- than of the D2-dopamine receptors in several limbic and neocortical regions. The receptor distribution in the autoradiographic study was consistent with that demonstrated in the living human brain using [11C]SCH 23390 and [11C]raclopride.
3,4-Dihydroxyphenylacetic Acid↗
[Image processing in psychiatry--a review].
The brain imaging technics computerized tomography (CT), positron emission tomography (PET) and nuclear magnetic resonance imaging (MRI) represent significant tools for a further categorization of psychiatric patients with regard to brain structure and function. Of these technics PET has the unique sensitivity to examine several aspects of brain function as blood flow, metabolic rates and neurotransmitter mechanisms. Since several decades monoaminergic transmitter mechanisms have been implicated in the pathophysiology of schizophrenia and affective disorders as well as in the action of several psychoactive drugs. With regard to schizophrenia and the mechanism of action of antipsychotic drugs Dopamine receptors are in the focus of interest. In order to analyze distribution and binding characteristics of dopamine receptor subtypes in the living brain in relation to neuropsychiatric disorders and antipsychotic drug treatment we developed 11C-Labelled selective ligands binding to dopamine receptor subtypes and used them in vivo PET experiments on human subjects.
Amino Acid Sequence↗