No D2 receptor increase in PET study of schizophrenia.
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Adult↗
Biomedical subjects
G Sedvall
Publications and source records attributed to G Sedvall.
Transplantation in Parkinson's disease: two cases of adrenal medullary grafts to the putamen.
Autologous adrenal medullary tissue was transplanted unilaterally to the putamen in two patients with severe Parkinson's disease. The first patient exhibited a transient, two-day improvement of motor performance in the limbs contralateral to the implantation site. He also had significantly longer episodes of normal function for about two months. The second patient reported a minor improvement of balance and gait, again lasting for two months. Electrophysiological studies of the motor readiness and auditory evoked potentials were consistent with increased catecholaminergic activity in the basal ganglia after transplantation in both patients. Positron emission tomography showed no postoperative alteration of receptor density in the putamen. No significant adverse effects of the transplantation were observed in the patients' performance on neurological and psychological tests or in their quantitative electroencephalogram and cerebral blood flow recordings. Immediately after the grafting, one patient showed transient signs of sympathetic hyperactivity, probably caused by release of catecholamines from the implanted tissue into the peripheral circulation. We conclude that catecholamine-rich cellular implants in the basal ganglia have transient beneficial effects in patients with severe Parkinson's disease.
Adrenal Medulla↗
PET analysis of human dopamine receptor subtypes using 11C-SCH 23390 and 11C-raclopride.
Tracer doses of 11C-SCH 23390 and 11C-raclopride, selective D1-dopamine and D2-dopamine receptor antagonists, respectively, were injected intravenously into three healthy male volunteers and two drug-treated schizophrenic patients. Regional radioactivity in brain and plasma was followed during 1 h by positron emission tomography (PET). After injection of both ligands a high accumulation of radioactivity was observed in the dopamine-rich caudate putamen. Experiments with 11C-SCH 23390, but not 11C-raclopride, showed a conspicuous accumulation of radioactivity also in the neocortex. None of the ligands accumulated in the dopamine-poor cerebellum. Specific binding of 11C-raclopride in the putamen was reduced by more than 80% in schizophrenic patients treated with antipsychotic doses of sulpiride or cis(Z)-flupentixol decanoate. 11C-SCH 23390 binding was slightly reduced in both the cortex and the putamen after treatment with cis(Z)-flupentixol decanoate but not after sulpiride. The results indicate that clinical antipsychotic drug treatment with sulpiride and cis(Z)-flupentixol decanoate causes a substantial blockade of D2-dopamine receptors in the basal ganglia but has only a minor effect on D1-dopamine receptors.
Adult↗
A quantitative cerebral and whole body autoradiographic study of a intravenously administered benzodiazepine antagonist 3H-Ro 15-1788 in mice.
3H-Ro 15-1788, a benzodiazepine receptor antagonist, was injected IV into male and pregnant mice. Autoradiograms were prepared from sagittal sections of animals killed after 30 s to 48 h. In the adult animal there was a rapid and high initial accumulation of radioactivity in the brain as compared to other organs and tissues. The highest accumulation was found in cortical brain areas, such as the olfactory bulb and the frontal cortex. Cerebellar cortex, globus pallidus, amygdala, substantia nigra, colliculus, hippocampus and pons followed in rank order. The rate of decline of radioactivity was highest in the pons and lowest in the olfactory bulb. The initial disappearance of radioactivity from the cerebellum was higher than from the other brain regions. Ro 15-1788 was rapidly eliminated; 4 h after drug administration there was an almost complete clearance of radioactivity from all tissues. After 24 h no trace of activity remained in the animal. The distribution of radioactivity at later time points indicates that metabolites of Ro 15-1788 are eliminated by fecal, urinary and nasal secretion. In the fetus also there was an early accumulation of radioactivity in the central nervous system. The radioactivity in fetal organs was lower than in the mother at all time intervals.
Animals↗
Perinatal origin of adult self-destructive behavior.
The study was undertaken to test whether obstetric procedures are of importance for eventual adult behavior of the newborn, as ecological data from the United States seem to indicate. Birth record data were gathered for 412 forensic victims comprising suicides, alcoholics and drug addicts born in Stockholm after 1940, and who died there in 1978-1984. The births of the victims were unevenly distributed among six hospitals. Comparison with 2,901 controls, and mutual comparison of categories, showed that suicides involving asphyxiation were closely associated with asphyxia at birth, suicides by violent mechanical means were associated with mechanical birth trauma and drug addiction was associated with opiate and/or barbiturate administration to mothers during labor. Irrespective of the mechanism transferring the birth trauma to adulthood--which might be analogous to imprinting--the results show that obstetric procedures should be carefully evaluated and possibly modified to prevent eventual self-destructive behavior.
Adult↗
Neurotransmitter receptor imaging in Alzheimer's disease.
Recent developments in positron emission tomography and ligand binding techniques have allowed the visualization of regional metabolism and neuroreceptor distributions in the living human brain. For dopamine-D 2 and benzodiazepine receptors it has also been possible to determine neuroreceptor characteristics such as Bmax and Kd by performing in vivo saturation analysis of ligand binding to the receptors. Using 11-C raclopride and 11-C-Ro 15-1788 as ligands for dopamine-D 2 and benzodiazepine receptors respectively we have determined Bmax and Kd-values in healthy volunteers and patients with various types of neuropsychiatric disorders. These ligands were also used in order to determine the degree of receptor occupancy in psychiatric patients treated with different types of drugs interfering with these neuroreceptors. We have administered 11-C-deoxy-glucose, 11-C-raclopride and 11-C-Ro 15-1788 to patients with Alzheimer's disease in order to examine possible alterations of glucose utilization and neuroreceptor distribution and quantities in these patients. The preliminary results indicate that this approach may be useful for the analysis of degenerative alterations of neuron populations and neuroreceptor systems in Alzheimer's disease.
Alzheimer Disease↗
Quantitative autoradiography of [3H]piquindone binding sites (dopamine D2 receptors) in rat brain.
(-)Piquindone is a new antipsychotic pyrroloisoquinoline derivative that binds to dopamine D2 receptors. We used in vitro quantitative autoradiography to determine the distribution of [3H](-)piquindone binding sites in rat forebrain. [3H](-)Piquindone binding to brain slices was sodium dependent, saturable and of high affinity (Kd = 5 nM at 0 degree C). In autoradiographic experiments, there was a good signal to noise ratio for [3H](-)piquindone binding with nonspecific binding representing only about 20% of total binding in caudate putamen. The D2 antagonists (-)sulpiride and raclopride were much more potent inhibitors of [3H](-)piquindone binding than the D1 antagonist SCH 23390. Dopamine inhibited binding with a potency similar to that previously found with standard membrane binding procedures. Autoradiography indicated that binding sites [3H](-)piquindone are localized to olfactory tubercle, accumbens nucleus, caudate putamen, cell bridges between caudate putamen and olfactory tubercle, and substantia nigra. Binding in these areas is stereoselective since we found no specific binding with [3H](+)piquindone, the biologically inactive enantiomer. Within caudate putamen, there was a lateral to medial gradient in the optical density of [3H](-)piquindone autoradiograms which might, in part, be attributable to white matter density rather than to D2 receptors.
Animals↗
Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET.
D2 dopamine receptors in the putamen of living human subjects were characterized by using the selective, high-affinity D2 dopamine receptor antagonist carbon-11-labeled raclopride and positron emission tomography. Experiments in four healthy men demonstrated saturability of [11C]raclopride binding to an apparently homogeneous population of sites with Hill coefficients close to unity. In the normal putamen, maximum binding ranged from 12 to 17 picomoles per cubic centimeter and dissociation constants from 3.4 to 4.7 nanomolar. Maximum binding for human putamen at autopsy was 15 picomoles per cubic centimeter. Studies of [11C]raclopride binding indicate that clinically effective doses of chemically distinct neuroleptic drugs result in 85 to 90 percent occupancy of D2 dopamine receptors in the putamen of schizophrenic patients.
Adult↗
Imaging of neurotransmitter receptors in the living human brain.
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Brain↗
Dopamine D1-receptor binding in the living human brain.
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Benzazepines↗
Radionuclide cisternography and computed tomography in 30 healthy volunteers.
Radiological assessments of patients with symptoms of impaired cerebrospinal fluid (CSF) circulation are usually based on observations of anatomical and functional alterations using computed tomography (CT) and radionuclide cisternography (RC). In order to define criteria of normality for these two techniques, 30 healthy volunteers have been studied. In the studies of CSF flow the radiopharmaceutical 99mTc-DTPA was used and single photon emission computed tomography (SPECT) was performed as a complement to planar scintigraphy. In 16 of the 30 volunteers the pattern of CSF flow was normal according to conventional criteria. In these subjects the radioactivity was symmetrically located over the parietal cortex 24 h after the injection and no intraventricular activity could be recorded. In 11 (41%) of the subjects, radioactivity could be observed in the lateral ventricles 6 h after injection. One of these subjects had a reflux of radioactivity into the lateral ventricles. The intraventricular radioactivity persisted for at least 24 h. This subject also had signs of obstruction of CSF flow over the convexities. Asymmetric distribution of radioactivity within the CSF spaces was observed in the images obtained after 6 but not 24 h in two cases. One of those also demonstrated transient intraventricular radioactivity. The results of the computed tomography were interpreted to be normal in 19 (63%) of the 30 volunteers. One subject had an asymmetric ventricular system. The CT scans of six subjects (20%) differed considerably from the others as they displayed wide cortical or vermian sulci at the borderline of normal variations. The case with the pathological RC belonged to the group of subjects who had wide sulci.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Concentrations of monoamine metabolites in the cerebrospinal fluid of twins and unrelated individuals--a genetic study.
The concentrations of the major monoamine metabolites, homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF), of platelet monoamine oxidase (MAO) and of dopamine beta-hydroxylase (DBH)-activity in serum and CSF were determined in pairs of healthy mono- and dizygotic twins, brothers and unrelated individuals. Intraclass correlations were calculated for each category of pairs. Of the monoamine metabolites, only MOPEG was found to be under any major genetic influence. Genetic heritability for MOPEG was 0.74 with no evidence of cultural heritability or environment common to twins. For HVA and 5-HIAA, a familial influence was found, where the cultural heritability was higher than the genetic. As in previous studies of MAO in blood platelets and of DBH activity in serum, there was strong evidence for a genetic component. The genetic heritability for MAO was 0.78. For DBH in serum the genetic component was 0.98, and for DBH in CSF, 0.83. The demonstration of a familial influence on 5-HIAA and HVA in CSF requires a more detailed analysis of the character of such environmental and genetic influences, using more direct techniques.
Adolescent↗
Urinary monoamine metabolites as indices of mental stress in healthy males and females.
Concentrations of the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA) and the noradrenaline metabolite 4-hydroxy-3-methoxyphenyl glycol (HMPG) were determined in urine samples from healthy male and female students by mass fragmentography. Urine samples were obtained after a demanding examination (mental stress) and a day of ordinary school work (control condition). Self-ratings were obtained of feelings induced by the examination, and of habitual psychosomatic symptoms. The results for both sexes showed that the examination stress induced a significant increase of HVA and HMPG excretion, but not of 5-HIAA. The males excreted significantly more of each of the metabolites than the females. The pattern of correlations between metabolite levels and psychological and psychosomatic variables were strikingly different for the two sexes.
Adolescent↗
Preparation of 11C-labelled SCH 23390 for the in vivo study of dopamine D-1 receptors using positron emission tomography.
The dopamine D-1 receptor antagonist, SCH 23390 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepin-7-ol), was labelled by alkylation of the desmethyl compound SCH 24518 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro-5-phenyl-1H-3-benzazepin-7- ol) with [11C]methyl iodide. A multivariate optimization method, Simplex, was employed to obtain the optimal radiochemical yield. Both straight-phase and reversed-phase preparative HPLC were investigated in the purification of [11C]SCH 23390. Reaction in acetone with subsequent straight-phase LC separation resulted in 80% radiochemical yield, based on [11C]methyl iodide, with a total synthesis time of 35-40 min and a radiochemical purity greater than 99%. The average specific activity was on the order of 11.1 GBq/mmol. The 11C-labelled SCH 23390 was used to visualize the dopamine D-1 receptor-rich areas of a monkey brain by positron emission tomography. The data obtained showed a rapid distribution of radioactivity into the brain and a conspicuous accumulation of [11C]SCH 23390 in the striatum.
Animals↗
Dexamethasone suppression test in schizophrenic patients before and during neuroleptic treatment.
The dexamethasone suppression test (DST) was performed in 21 drug-free schizophrenic patients. The patients satisfied DSM-III and Research Diagnostic Criteria for schizophrenia and were in an acute phase of the disease. In 15 of the patients the DST was repeated after about 5 weeks of treatment with neuroleptics. DST compliance was checked by analysis of dexamethasone concentrations in plasma. In the acute phase 71% (at 04 p.m.) of the patients were nonsuppressors. After neuroleptic treatment the frequency of abnormal responders had decreased to 20%. The decrease in nonsuppressors was not due to alteration of the dexamethasone concentration between the two test occasions. Prolactin levels were markedly increased at the second test occasion compared with the first. There were no significant relationships between cortisol levels, cortisol suppression and prolactin levels. The high frequency of nonsuppressors among schizophrenic patients in the acute phase of the disease indicates that acute stress may be a confounding factor in the outcome of DST.
Adult↗
Neuropharmacology and the human brain.
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Adrenergic alpha-Agonists↗
Clinical and biochemical effects of citalopram, a selective 5-HT reuptake inhibitor--a dose-response study in depressed patients.
Citalopram is a bicyclic phtalane derivative. In animal experiments, citalopram has been demonstrated to possess a potent and highly selective inhibitory effect on serotonin reuptake. Several studies in man have indicated that citalopram given in daily doses of 40-60 mg has antidepressant properties and few side effects. The present double-blind study investigated the effects of three doses of citalopram (5 mg, 25 mg, and 50 mg) on depressive symptoms and various biochemical variables in 26 depressive patients. A significant reduction of the clinical ratings of depressive symptoms occurred at all dose levels. In endogenously depressed patients, a dose of 25 or 50 mg daily seemed to have the most pronounced antidepressive effect. The side effects were few and not related to dose level. A highly significant decrease in 5-HIAA in the CSF was found. MO-PEG in the CSF was also significantly decreased, while HVA in the CSF was increased. In addition, a significant decrease in the plasma concentrations of valine, leucine, tyrosine, and histidine was found. None of the biochemical effects was dose-dependent. The complex pattern of biochemical effects indicate that the amelioration of depressive symptoms might be related to effects of citalopram on central monoaminergic mechanisms and peripheral amino acid concentrations.
Adjustment Disorders↗
Increased concentrations of the monoamine metabolites homovanillic acid and 5-hydroxyindoleacetic acid in lumbar and central CSF and of 3-methoxy-4-hydroxyphenylglycol in lumbar CSF after subarachnoid haemorrhage.
The concentrations of the dopamine metabolite homovanillic acid (HVA), the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MOPEG) were determined in cerebrospinal fluid (CSF) from patients with subarachnoid haemorrhage (SAH) using a mass fragmentographic method. In a first group of 24 patients lumbar CSF was collected during the first 10 days after SAH. The concentrations of HVA and 5-HIAA showed a several-fold increase in the majority of subjects while that for MOPEG was less pronounced in comparison to controls. In a second group of 12 SAH-patients, CSF was collected in 10 ml fractions during surgical clipping of aneurysms. The mean concentrations of HVA, 5-HIAA and MOPEG in lumbar CSF was 469,275 and 39 pmol/l, respectively, whereas central CSF concentrations were 1,212, 499 and 48 pmol/ml, respectively. Compared to healthy controls, both HVA and 5-HIAA showed increased levels (pl 0,01) but MOPEG was within the normal range. No correlation between the concentrations of the monoamine metabolites, the neurological condition or the cerebral vascular diameter was observed in neither of the two groups. It is suggested that the accumulation of HVA and 5-HIAA in SAH patients is explained by a disturbance of the active transport mechanism.
Adult↗