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G Sedvall

Publications and source records attributed to G Sedvall.

At least 91 records · Page 5Linked to original sources
PubMed1991

Autoradiography with saturation experiments of 11C-Ro 15-1788 binding to human brain sections.

In vitro autoradiography of a 11C-labelled ligand, Ro 15-1788, was used in saturation experiments in order to quantify benzodiazepine receptor binding in whole human brain hemisphere cryo-sections. A special incubation chamber was developed with the aim of performing standardized quantitative studies with short-lived positron emitting isotopes. 11C-labelled ligand binding was studied in temporal cortex, cerebellum, white manner and pons incubated in vitro. White manner, lacking benzodiazepine receptor binding, was used as an estimated of nonspecific binding, for calculation of Saturability of binding was demonstrated in the neocortical and cerebellar regions. Radioactivity counting of incubated adjacent tissue sections was done as a control. Computerized densitometry of the autoradiograms gave similar results as the tissue counting. A comparison with in vivo saturation experiments using the same 11C-labelled ligand and positron emission tomography in healthy human subjects also gave binding characteristics of the same magnitude. The 11C-autoradiograms showed a good spatial resolution (about 180 microns). 11C-autoradiography with suitable radioligands should be a valuable technique of screening the distribution and characteristics of neuroreceptors in the human brain. This quantitative method will provide the PET investigator with preliminary binding data, and may thus supply valuable information concerning positioning in PET and concerning significant regions of interest.

Autoradiography↗
PubMed1991

Distribution of cholecystokinin mRNA and peptides in the human brain.

Expression of preprocholecystokinin mRNA was studied in regions of post mortem human brain using RNA blot analysis (Northern blot) and in situ hybridization. Northern blot analysis using a cDNA probe showed high levels of an approximately 0.8 kb preprocholecystokinin mRNA in all regions of neocortex examined. Lower levels of preprocholecystokinin mRNA were detected in amygdaloid body and thalamus. In situ hybridization analysis using the same cDNA probe revealed numerous weakly labelled neurons in different areas of human neocortex and less numerous neurons in hippocampus and amygdaloid body. High-performance liquid-chromatography and gel-chromatography combined with radioimmunoassay of cholecystokinin-like immunoreactivity from human cerebral cortex and caudate nucleus revealed two major forms, one coeluting with sulphated cholecystokinin-8 and the other coeluting with sulphated cholecystokinin-58. Two minor components coeluting with cholecystokinin-4 and cholecystokinin-5 were also detected. The finding of cholecystokinin-like immunoreactivity corresponding to cholecystokinin-8 and cholecystokinin-58 in caudate nucleus where no preprocholecystokinin mRNA was found, indicates the presence of these peptides in afferent nerve terminals.

Blotting, Northern↗
PubMed1991

Synthesis of carbon-11 labelled SCH 39166, a new selective dopamine D-1 receptor ligand, and preliminary PET investigations.

SCH 39166 [(-)-trans-6,7,7a,8,9, 13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo(d)naphtho-(2,1- b)azepine] is a new more selective dopamine D-1 receptor antagonist than the widely used SCH 23390. [11C]SCH 39166 was prepared by N-methylation of the desmethyl compound SCH 40853 [(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-5H- benzo(d)naphtho-(2,1-b)azepine] with [11C]methyl iodide. Reaction in acetone with subsequent straight-phase semi-preparative HPLC resulted in 20-30% radiochemical yield (from EOB and decay-corrected) with a total synthesis time of 35-40 min and a radiochemical purity greater than 99%. The specific activity obtained at EOS was about 1500 Ci/mmol (55 GBq/mumols). [11C]SCH 39166 was injected into a Cynomolgus monkey. PET-analysis demonstrated accumulation in the striatum, a region known to have a high density of dopamine D-1 receptors. In a displacement experiment, radioactivity in the striatum was markedly reduced after injection of 6 mg unlabelled SCH 23390, thus demonstrating the specificity and reversibility of [11C]SCH 39166 binding to dopamine D-1 receptors.

Animals↗
PubMed1990

D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride.

Several groups have reported increased densities of D2 dopamine receptors in the basal ganglia of schizophrenic brains postmortem. The significance of this finding has been questioned, since an upregulation of receptor number may be a neuronal response to neuroleptic drug treatment. We have used positron emission tomography and [11C]raclopride to examine central D2 dopamine receptor binding in 20 healthy subjects and 18 newly admitted, young, neuroleptic-naive patients with schizophrenia. An in vivo saturation procedure was applied for quantitative determination of D2 dopamine receptor density (Bmax) and affinity (Kd). When the two groups were compared, no significant difference in Bmax or Kd values was found in the putamen or the caudate nucleus. The hypothesis of generally elevated central D2 dopamine receptor densities in schizophrenia was thus not supported by the present findings. In the patients but not in the healthy controls, significantly higher densities were found in the left than in the right putamen but not in the caudate nucleus.

Adult↗
PubMed1990

General assay for phosphoproteins in cerebrospinal fluid: a candidate marker for paraneoplastic cerebellar degeneration.

The components of protein phosphorylation systems (protein kinases, protein phosphatases, and their phosphoprotein substrates) are highly enriched in neuronal cells compared with other cell types. We exploited this relative neuronal enrichment of protein phosphorylation system components to develop a general assay technique for putative protein kinase substrates (phosphoproteins) in human cerebrospinal fluid. Using this cerebrospinal fluid phosphoprotein assay, we have detected a putative protein kinase C substrate protein of apparent Mr 60 kd in 6 of 14 patients with paraneoplastic cerebellar degeneration but not in any of 55 patients with a variety of other neurological diseases. Phosphoproteins in cerebrospinal fluid may provide novel and unique markers for the diagnosis or staging of neuronal diseases as well as offer potential insights into the biochemical characterization of affected neuronal populations.

Adult↗
PubMed1990

PET imaging of dopamine receptors in human basal ganglia: relevance to mental illness.

The development of PET and in vivo ligand-binding techniques over the past decade has allowed the analysis of dopamine receptor functions in the basal ganglia of human subjects. Using ligands selective for the different subtypes of dopamine receptors, their gross distribution, total number of binding sites and affinity have been determined in the caudate-putamen of the living human brain. Recent studies in young, drug-naive schizophrenic patients failed to demonstrate a consistent alteration in the densities or affinities of D2 dopamine receptors in the basal ganglia of these subjects, contradicting the view that elevated densities of D2 dopamine receptors are a major pathophysiological mechanism in this disorder. PET measurements of D2 dopamine receptor occupancy in relation to clinical antipsychotic drug treatment demonstrated that all chemically different categories of antipsychotic drugs induced a marked occupancy of D2 dopamine receptors. This effect was dose-dependent and fully reversible. It appeared earlier than the antipsychotic effect and was also present in neuroleptic-resistant patients. Resistance to neuroleptic drugs is in all probability related to heterogeneity of biological factors causing schizophrenia. Some, but not all, antipsychotic drugs also induced a significant D1 dopamine receptor occupancy. This effect was most marked for the unconventional drug clozapine, which showed about the same degree of D1 as D2 dopamine receptor blockade when given in clinical doses.

Basal Ganglia↗
PubMed1990

Central D1- and D2-receptor occupancy during antipsychotic drug treatment.

1. It has been unequivocally shown that antipsychotic compounds reduce dopaminergic transmission. A relationship in vitro between the potency for the antipsychotic effect and the blockade of D2-dopamine receptors has been shown. No such relationships have been demonstrated for any other central receptor population. 2. Positron emission tomography (PET) has made it possible to investigate interactions of psychotropic drugs with central receptors in the living human brain. Using the selective D2 receptor antagonist raclopride labelled with positron emitting isotope 11C, it has been shown that chemically distinct classical neuroleptics in conventional doses occupy a high degree (65-89%) of the D2-receptors in the human brain. The results substantiate the opinion that the antipsychotic effects is mediated by a blockade of D2-dopamine receptors. 3. The degree of binding to D1-receptors using the 11C-labelled D1-antagonist from Schering (SCH 23390) as the ligand was also determined. The D1-receptor occupancy seemed to be dependent on the type of the antipsychotic compound studied. 4. The atypical neuroleptic compound clozapine demonstrated a different binding profile than the classical neuroleptics. Thus, clozapine in conventional doses occupied D2-receptors to a smaller extent (40%, 40%, 65%) than classical neuroleptics. The occupation of D1-receptors was higher (40%, 42%) than that of classical compounds (0-36%). 5. The unique clinical profile of clozapine may be related to its potency on both D1- and D2-receptors. The distribution of D1-receptors varies from that of D2-receptors in the human brain which may be one reason for the importance of blocking both D1- and D2-receptors for a full antipsychotic response.

Adult↗
PubMed1990

Carbon-11 labelling of eticlopride in two different positions--a selective high-affinity ligand for the study of dopamine D-2 receptors using PET.

A new highly selective high-affinity dopamine D-2 receptor antagonist, eticlopride ((-)-(S)-5-chloro-3-ethyl-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxysalicylamide), was labelled with 11C in two different positions ([N-ethyl-11C]eticlopride (I)) and ([methyl-11C]eticlopride (II)). Product I was prepared by N-alkylation of the N-desethyl compound with [11C]ethyl iodide. II was prepared by O-alkylation of the diphenolic precursor with [11C]methyl iodide followed by separation of the two methylated products. The radiochemical yields were 15-20% (EOB) with an overall synthesis time of 45-60 min. Both compounds were isolated by semi-preparative HPLC and the radiochemical purity was in both cases greater than 99%. I was injected i.v. in a Cynomolgus monkey and brain radioactivity was measured by positron emission tomography (PET). The specific activity was 70 Ci/mmol at time of injection. There was a marked accumulation of radioactivity in the basal ganglia, regions known to have a high density of dopamine D-2 receptors.

Animals↗
PubMed1990

Temperature dependence of [3H]Ro 15-1788 binding to benzodiazepine receptors in human postmortem brain homogenates.

The temperature dependence of in vitro binding of [3H]Ro 15-1788 to benzodiazepine receptors in human postmortem neocortex and neocerebellum homogenates was studied. An increase of the equilibrium dissociation constants (KD) from 1.40 nmol/L and 1.04 nmol/L at 4 degrees C to 6.10 nmol/L and 8.91 nmol/L at 37 degrees C was found for neocortex and neocerebellum, respectively. In contrast, maximal binding (Bmax) remained in the range of 30-35 fmol/mg for neocortex and 24-27 fmol/mg of tissue (wet weight) for neocerebellum at all the temperatures. The KD of 6.10 nmol/L for neocortex at 37 degrees C in vitro is of the same order as the KD of 10 nmol/L obtained by positron emission tomography for [11C]Ro 15-1788 binding to benzodiazepine receptors in the human neocortex in vivo. The differences in KD between in vitro and in vivo benzodiazepine receptor binding to human neocortex and cerebellum seem to be due at least partially to temperature differences of in vitro and in vivo studies.

Brain↗
PubMed1990

Monoamines and schizophrenia.

The hypothesis that central biogenic amines may play a role in the pathophysiology of schizophrenia was originally based upon the fact that hallucinogenic and antipsychotic drugs have profound effects on central transmitter pathways where dopamine, noradrenaline and serotonin are involved. The structural similarities between hallucinogenic drugs such as amphetamine and mescaline, and catecholamines on the one hand and lysergic acid diethylamide (LSD) and indolamines such as serotonin on the other hand have by direct experimentation been shown to explain their important effects on the transmitter systems. The marked effect of several classes of chemically different antipsychotic drugs on central dopamine receptor function formed the basis for the dopamine hypothesis regarding the mechanisms of action of these drugs and also for the hypothesis that dopamine D2 receptor function played a significant role in the pathophysiology of schizophrenia. Direct experimental analysis of aminergic functions in the brain of schizophrenic patients, both during life and post mortem, has been and will for the foreseeable future continue to be a rational approach to the further elucidation of the validity of these hypotheses. Analysis of metabolite levels in the cerebrospinal fluid and plasma of schizophrenic patients has shown great variation in the results with reports of both elevated and reduced release of amines in the brains of schizophrenic patients. Analysis of the aminergic receptor structures in the postmortem human brain has relatively consistently revealed an increased density of D2 receptors in the major basal ganglia of schizophrenic patients. Whether these alterations represent a primary feature of brain structure in schizophrenia or a drug-induced effect still remains to be shown. Positron emission tomographic (PET) scan studies of D2 receptors in schizophrenia have demonstrated both increased densities and absence of change in the characteristics of D2 receptors in the patients as compared to matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Antipsychotic Agents↗
PubMed1990

Recent advances in psychiatric brain imaging.

The characterization of neuroreceptor functions in the living human brain has hitherto been hampered by the lack of techniques useful for the measurement of physiologic events within the human brain in vivo. Recent developments in positron emission tomography (PET) has allowed the quantitative tracing of intravenously administered molecules within tissue compartments of the brain. Using ligands binding with high affinity to cerebral neuroreceptors it has been possible to examine not only the distribution but also some quantitative aspects of brain neuroreceptors in living human subjects by the PET technique. By the selection of highly selective ligands for different receptor systems and by labeling them with positron emitting isotopes as 11C or 18F, methods have been developed for the characterization of receptor subtypes for the endogenous ligands dopamine, serotonin, opiates, acetylcholine, glutamate and GABA. The present communication describes the use of 11C-SCH 23390 and 11C-raclopride for the analysis of D1 and D2 dopamine receptors, the benzodiazepine (BZ) antagonist 11C-Ro 15-1788 for benzodiazepine receptors and 11C-nicotine for nicotine receptors. Specificity of binding was verified by using active and inactive stereoenantiomers of the ligands. After the intravenous administration of the ligands quantitative aspects of the receptor binding was calculated using models according to equilibrium or dynamic approaches. Bmax and Kd values for D2 dopamine and BZ receptors could be determined in the brain of healthy human subjects and patients with neuropsychiatric disorders. No alteration of D2 dopamine receptors in the major basal ganglia were found in drug naive schizophrenic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzazepines↗
PubMed1989

Distribution of galanin-binding sites in the monkey and human telencephalon: preliminary observations.

Using X-ray film autoradiography the distribution of 125I-galanin binding sites was studied in the forebrain of monkey and man. In the monkey a high density was found in all areas of the neocortex, especially layer 4, and in certain subfields in the hippocampal region. Also in the human brain high activity was seen in neocortex, mainly layer 6 and in hippocampal areas, as well as in amygdala, piriform cortex and hypothalamus. These results suggest that the 29-amino acid peptide galanin may be involved in the regulation of higher cortical functions in primates.

Amygdala↗
PubMed1989

D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics.

Using positron emission tomography and the selective ligands 11C-SCH23390 and 11C-raclopride, central D1- and D2-dopamine receptor occupancy was determined in schizophrenic patients treated with clinical doses of classical and atypical neuroleptics. Treatment with ten chemically distinct classical neuroleptics resulted in a 65-89% occupancy of D2-dopamine receptors. This finding represents strong support for the hypothesis that the mechanism of action of antipsychotic drugs is indeed related to a substantial degree of D2-dopamine receptor occupancy. In two patients treated with the atypical neuroleptic clozapine, 300 mg b.i.d. and 150 mg b.i.d., the D2-dopamine receptor occupancy was 65 and 40%, respectively. D1-dopamine receptor occupancy was determined in six antipsychotic drug-treated patients. No D1-dopamine receptor occupancy was found in patients treated with sulpiride and perphenazine, compounds known to be selective D2-dopamine receptor antagonists. The highest D1-dopamine receptor occupancy, 42%, was found in the patient treated with clozapine 150 mg b.i.d. The effects of the atypical neuroleptic clozapine may be related to a combined effect on both D1- and D2-dopamine receptors.

Antipsychotic Agents↗
PubMed1989

Remoxipride--a new potential antipsychotic compound. Tolerability and pharmacokinetics after single oral and intravenous administration in healthy male volunteers.

The tolerability and pharmacokinetics of remoxipride were studied in 18 healthy normal male volunteers. Increasing oral doses of 0.5-100 mg were given to eight male volunteers in one study (study I). In addition, an intravenous (IV) infusion of 20 mg remoxipride and a 20 mg oral dose were given in an open crossover study to ten males (study II). Remoxipride was well tolerated with respect to cardiovascular effects, clinical chemistry, body temperature and adverse effects in all subjects. Following IV administration, remoxipride plasma concentrations declined exponentially in five subjects and biexponentially in the remaining five. The mean apparent volume of distribution was 0.5 l/kg (SD = 0.10) and the mean half-life 4.1 h (range 2.6-6.6). The recovery of unchanged remoxipride in urine was 10-36%, and the mean renal clearance was 32 ml/min (SD = 13). Remoxipride was a low clearance drug with a total plasma clearance of about 120 ml/min (SD = 41). The mean oral bioavailability was 96%. There was a linear relationship between the peak plasma concentration as well as the area under the concentration versus time curve and the administered dose. A transient increase in plasma prolactin concentrations occurred but there were no effects on plasma growth hormone levels.

Administration, Oral↗
PubMed1989

Regional distribution of neuropeptide Y mRNA in postmortem human brain.

The distribution of messenger RNA encoding neuropeptide Y (NPY) was studied in 11 different postmortem human brain regions using in situ hybridization histochemistry, and RNA blot analysis. In situ hybridization data revealed that the highest numerical density of labeled cells corresponded to neurons in accumbens area, caudate nucleus, putamen, and substantia innominata. Significantly fewer NPY mRNA-containing neurons were found in frontal and parietal cortex, amygdaloid body and dentate gyrus. No NPY mRNA-containing cells were found in substantia nigra. NPY mRNA-positive neurons from all regions studied showed relatively similar labeling, as revealed by computerized image analysis. Blot analysis showed an approximately 0.8 kb NPY mRNA in all brain regions studied, except in substantia nigra and cerebellum. Densitometric scanning of the autoradiograms revealed levels of NPY mRNA in the following order: putamen greater than caudate nucleus greater than frontal cortex (Brodmann areas 4 and 6) greater than temporal cortex (Brodmann area 38) greater than parietal cortex (Brodmann areas 5 and 7) greater than frontal cortex (Brodmann area 11). Hence, although NPY mRNA is widely distributed in neurons of the human brain large regional variation exists, with the highest expression in accumbens area and parts of the basal ganglia.

Aged↗