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Biomedical subjects

G Sedvall

Publications and source records attributed to G Sedvall.

At least 109 records · Page 6Linked to original sources
PubMed1989

Dopamine-regulated phosphorylation of synaptic vesicle-associated proteins in rat neostriatum and substantia nigra.

Dopamine, acting through dopamine D1 receptors and cyclic AMP-dependent protein kinase, has been found to increase the state of phosphorylation of the synaptic vesicle-associated phosphoproteins synapsin I and protein III in slices of rat neostriatum and substantia nigra. In the neostriatum, the effect of dopamine was mimicked by SKF 38393, a D2 receptor agonist, and was abolished by preincubation of the slices with fluphenazine or SCH 23390, antipsychotic drugs which are potent D1 receptor antagonists, but not by the D2 receptor antagonists l-sulpiride or spiroperidol. The maximal effect of dopamine in the neostriatum represented approximately 30-35% of the maximal effect induced by 8-bromo cyclic AMP, suggesting that a similar fraction of nerve terminals in the neostriatum may express the dopamine D1 receptor. Evidence for a small population of beta-adrenergic receptors regulating nerve terminal protein phosphorylation in the neostriatum, distinct from the D1 dopamine receptors, was also obtained. In the substantia nigra, the effect of dopamine also appeared to be mediated through a D1 dopamine receptor, since it was abolished by fluphenazine and SCH 23390. The maximal effect of dopamine in the substantia nigra represented approximately two-thirds of the effect induced by 8-bromo cyclic AMP, suggesting that a similar fraction of nerve terminals in the substantia nigra may express the dopamine D1 receptor. The ability of dopamine D1 receptor activation to stimulate both synapsin I and protein III phosphorylation and GABA release in both the neostriatum and substantia nigra may be causally linked.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

An analysis of postmortem brain samples from 32 alcoholic and nonalcoholic individuals for protein III, a neuronal phosphoprotein.

Protein phosphorylation is a primary mechanism of intracellular signal transduction, and abnormalities in protein phosphorylation have been implicated in the pathogenesis of several specific diseases. Protein III is a neuronal phosphoprotein that is associated with synaptic vesicles and is probably involved in the regulation of neurotransmitter release. Analysis of 32 postmortem brains has confirmed our previous report that variant forms of protein III with higher apparent molecular weights are found frequently in the brains of alcoholic individuals but rarely in the brains of nonalcoholic individuals who did not suffer from any other medical or neuropsychiatric disorders. Eight of 14 (57%) brain samples from alcoholic individuals and four of eight (50%) brain samples from suspected alcoholic individuals had variant forms, while none of 10 samples from nonalcoholic individuals had variant forms. Previous data indicate that variant forms of protein III are also associated with other neurodegenerative conditions, including various dementias, and, possibly, normal aging.

Alcoholic Intoxication↗
PubMed1989

Approaches for finding new types of antipsychotic compounds.

There is strong evidence that pharmacological interaction with central dopamine transmission at several levels may induce antipsychotic effects in psychiatric patients. All the pharmacological principles interacting with other systems have so far not been established with regard to antipsychotic potential. Besides the dopamine system pharmacological manipulation of central serotonergic, gabaergic and noradrenergic mechanisms may also be of therapeutic value in schizophrenia. The interaction of peptidergic mechanisms and central dopaminergic mechanisms is another avenue for further exploration regarding to pathophysiology of psychosis and its treatment. Elucidation of the heterogeneity and molecular structure of central dopamine receptors seems the most rational approach for creating new dimensions for further development of drug design for pharmacotherapy of psychosis. The detailed mapping of afferent and efferent systems coupled to central dopamine neurons is also an approach that may give guide-lines for finding new types of antipsychotic drugs.

Animals↗
PubMed1988

In-vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci.

Ten patients with partial epilepsy and five healthy controls had positron emission tomography (PET) of the brain after intravenous administration of the 11C-labelled benzodiazepine (BZ) receptor ligand 'Ro-15 1788'. In all ten patients BZ receptor binding was significantly lower in the epileptic focus than in the contralateral homotopic reference region and the remaining neocortex. No asymmetries in BZ receptor binding were observed between homotopic reference regions in the controls or the non-epileptic regions of patients. These results demonstrate the potential of the BZ receptor as a biochemical marker for display of epileptic foci by PET, and also strengthen the hypothesis that inhibitory mechanisms are disturbed in the epileptic focus.

Adult↗
PubMed1988

CSF creatinine in schizophrenia.

Concentrations of creatinine in cerebrospinal fluid (CSF) from schizophrenic patients and healthy control subjects were determined by a liquid chromatographic method. The concentration of creatinine in CSF from schizophrenic patients was lower (42.8 nmol/ml) than that of the controls (54.4 nmol/ml). The concentration of creatinine was correlated to the levels of homovanillic acid and 5-hydroxyindoleacetic acid. Treatment of the schizophrenic patients with sulpiride (800 mg daily), but not with chlorpromazine, elevated the concentration of creatinine in the CSF.

Adult↗
PubMed1988

Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs.

Using positron emission tomography and the carbon 11-labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11-raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy was found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline.

Adult↗
PubMed1988

PET scanning--a new tool in clinical psychopharmacology.

Quantitative methods were developed for the determination of dopamine and benzodiazepine receptor characteristics in the living human brain by positron emission tomography (PET). As ligands, the 11C-labelled analogues of the selective antagonists of dopamine receptor subtypes, SCH 23390 and raclopride, and the benzodiazepine antagonist, Ro 15-1788, were used. Tracer amounts of the ligands were injected intravenously into healthy volunteers and schizophrenic patients. The distribution of ligand indicated high densities of D1 as well as D2 dopamine receptors in the basal ganglia. Binding of [11C]-SCH 23390 was also significant in the neocortex where it was shown to represent binding to D1 as well as to 5-HT2 serotonin receptors. High densities of specific benzodiazepine receptor binding were obtained in most neocortical brain areas and in the cerebellum. Using saturation procedures, Bmax and Kd values could be obtained for D2 and benzodiazepine receptors. A comparison of D2 receptor densities in drug-naive schizophrenic patients and healthy volunteers demonstrated similar receptor characteristics in the major basal ganglia in these groups of subjects. Different chemical classes of conventional and unconventional antipsychotic drugs produced a 65%-85% occupancy of D2 receptors when given in clinical doses to schizophrenic patients. High does of diazepam produced a marked occupancy of benzodiazepine receptors during the first hours after oral administration to healthy volunteers. These in vivo methods should be valuable tools for the further analysis of the effects of drug on neuroreceptors in the living brain of neuropsychiatric patients.

Animals↗
PubMed1988

Remoxipride--a new potential antipsychotic drug. Pharmacological effects and pharmacokinetics following repeated oral administration in male volunteers.

Remoxipride, a new potential antipsychotic drug, was administered over 4 days at two dose levels, 70 and 140 mg t.i.d., to eight healthy male volunteers. Pharmacokinetics, safety, tolerability, and effect on plasma prolactin levels were evaluated. Remoxipride exhibited essentially linear pharmacokinetics. Only minor deviations in biochemical and physiological safety parameters were found. The drug was well tolerated by all subjects at the 70 mg dose level. At 140 mg akathisia appeared in seven subjects. The drug induced a rapid and transient increase in plasma prolactin concentrations at both dose levels after single doses. During steady state, a significant reduction in the prolactin response was observed as compared to after the first dose.

Administration, Oral↗
PubMed1988

An open label trial of raclopride in acute schizophrenia. Confirmation of D2-dopamine receptor occupancy by PET.

Raclopride, a highly selective D2-dopamine receptor antagonist, was administered in doses up to 4 mg b.i.d. to ten schizophrenic patients in an open label non-comparative study lasting 4 weeks. Safety, tolerability, potential antipsychotic effect, prolactin response and drug effect on plasma homovanillic acid were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography (PET). No major deviations were found in biochemical and physiological safety parameters. Raclopride was well tolerated. The mean BPRS score was reduced by 55% at endpoint. In the global evaluation seven patients were "very much" or "much" improved. Extrapyramidal side effects were recorded in four patients and disappeared after dose reduction or single doses of biperiden. An increase in plasma prolactin of short duration was observed in both sexes. A significant decrease of plasma HVA was obtained after 4 weeks of treatment. In two of the patients the central D2-dopamine receptors occupancy was measured using PET. The receptor occupancy was 68 and 72% which is the same as that found in patients treated with conventional neuroleptics.

Acute Disease↗
PubMed1988

Human dopamine receptor subtypes--in vitro binding analysis using 3H-SCH 23390 and 3H-raclopride.

Affinities and regional densities of the D1- and D2-dopamine receptor subtypes were studied in the human post-mortem brain in vitro using the two selective radioligands 3H-SCH 23390 and 3H-raclopride. 3H-Raclopride binding was confined to the caudate nucleus, the putamen and the substantia nigra, while 3H-SCH 23390 bound to cortical regions as well. The binding of 3H-SCH 23390 was reduced by a low concentration of ketanserin, indicating binding to 5-HT2 receptors in addition to the D1-dopamine receptors. The endogenous neurotransmitter dopamine interacted potently both with the D1-dopamine receptor and the D2-dopamine receptor, displaying two affinity states for each subtype. The distribution of the dopamine receptor subtypes obtained in the present in vitro investigation is in agreement with data obtained with 11C-SCH 23390 and 11C-raclopride in positron emission tomographic studies in human volunteers.

Adult↗
PubMed1988

A twin study of amino acid concentrations in cerebrospinal fluid.

The concentrations of amino acids in the cerebrospinal fluid (CSF) were measured in pairs of healthy mono- and dizygotic twins. Intraclass correlations were calculated. Genetic and cultural heritabilities were estimated using a path analytical model. CSF levels of glycine, tyrosine and arginine were shown to be influenced by genetic factors. Genetic variation was also shown for serine, alpha-aminobutyrate and leucine. The results were compared with results from a genetic analysis of the amino acids in serum.

Adolescent↗
PubMed1988

Characteristics of cerebrospinal fluid neuropeptides relevant to clinical research.

Studies of human cerebrospinal fluid (CSF) peptides were conducted in an attempt to broaden the utility of CSF peptide determinations in psychiatric research. Healthy volunteers had two lumbar punctures, at least 3 weeks apart, to assess reproducibility within subjects. CSF levels of eight peptides were reliably reproducible, indicating that longitudinal studies of these CSF neuropeptides are feasible. Levels of 10 peptides were determined in four sequential 8 ml aliquots of CSF. CSF rostrocaudal gradients were not found for any of these 10 peptides. Neuropeptide Y (NPY), growth hormone releasing factor (GHRF), and corticotropin releasing factor (CRF) were measured in CSF from twins and brothers. CSF NPY levels were heritable, while CRF and GHRF levels were influenced more by environment. CSF levels of CRF, beta-lipotropin, vasoactive intestinal peptide, adrenocorticotropic hormone, and somatostatin were highly correlated with one another, suggesting that a common factor is responsible for a significant proportion of the observed variance in their CSF levels. These results suggest that CSF peptide measurements may have a broad range of applicability to clinical psychiatric research.

Brain↗
PubMed1988

Raclopride, a new selective ligand for the dopamine-D2 receptors.

1. The use of raclopride, a new compound of the salicylamide series, as a ligand for the labelling of dopamine-D2 receptors in vitro and in vivo is described. 2. 3H-Raclopride has a high affinity for the dopamine-D2 receptors (Kd = 1 nM in rat striatum) with much less affinity for any other receptor. 3. 3H-Raclopride enters the brain easily and has therefore also been used in in vivo binding and autoradiography. The nonspecific binding is very low both in vitro and in vivo. 4. Raclopride has been labelled with 11C, and is used as a marker for dopamine-D2 receptors in the living human brain using positron emission tomography.

Animals↗
PubMed1988

11C-labelling of Ro 15-1788 in two different positions, and also 11C-labelling of its main metabolite Ro 15-3890, for PET studies of benzodiazepine receptors.

The benzodiazepine receptor antagonist Ro 15-1788 has been labelled with 11C in two different positions [( methyl-11C]Ro 15-1788 (I) and [ethyl-11C]Ro 15-1788 (II]. Product I was prepared by N-alkylation of the desmethyl compound (Ro 15-5528) with [11C]methyl iodide and product II was prepared by esterification of the desethyl compound (Ro 15-3890) with [11C]ethyl iodide. Ro 15-3890, the main metabolic product of Ro 15-1788, was labelled by two synthetic routes. In route A, [methyl-11C]Ro 15-3890 (III) was prepared by N-alkylation of the corresponding desmethyl compound (Ro 15-6877) with [11C]methyl iodide. In route B, III was prepared by a subsequent hydrolysis of I. The radiochemical yields were on the order of 15-60% (EOB) with an overall synthesis time of 40-50 min. Compounds I, II and III were isolated by semi-preparative HPLC and the radiochemical purity was in all cases greater than 99%.

Carbon Radioisotopes↗
PubMed1988

Workshop on schizophrenia, PET, and dopamine D2 receptors in the human neostriatum.

Recently, two research groups published numbers for D2 receptor sites in the neostriatum of drug-naive schizophrenic patients, obtained in vivo by positron emission tomography (PET). One study appeared to confirm the increase of D2 receptor numbers, while the other study did not. A workshop was convened in Montreal to examine the reasons for the discrepancy between the results obtained by the two groups. The workshop considered patient populations, PET instrumentation and scanning methods, pharmacology, and modeling. The workshop identified differences between the approaches of the two groups that could contribute to the divergent results, including age and chronicity of the patient samples, brain region selected for study, metabolism of the different radioligands in blood and brain, reversibility of binding, PET instrumentation, and complexity of data analysis. The workshop concluded that these initial efforts had made considerable progress in establishing the role of PET in the understanding of the biochemical processes underlying mental illness. In particular, the unique ability to quantify regional neuroreceptor density at different stages in the evolution of the disease has been implemented. At the same time, the work so far and this conference served to identify the main sources contributing to the different findings from the two centers. This information will be important in designing the next phase of the research which will build upon and reconcile these apparent discrepancies.

Adult↗
PubMed1988

PET determination of regional cerebral glucose metabolism in alcohol-dependent men and healthy controls using 11C-glucose.

Regional brain glucose metabolism was determined in 9 male alcohol-dependent inpatients and 12 male healthy controls. All the patients were socially impaired by the alcohol abuse. All the subjects had abstained from alcohol and drugs for more than four weeks before entering the study. Brain glucose metabolism was determined by positron emission tomography (PET) with 11C-glucose as the tracer. Regions of interest were drawn on displayed computed tomographic (CT) images of the brain. Regions were transferred to corresponding PET slices, allowing the determination of regional glucose metabolism. In the healthy volunteers there was a reduction in glucose metabolism with age. In 11 of the 19 brain regions examined, the alcoholics had a 20% to 30% lower glucose metabolism than the controls. This was true for both cortical and subcortical structures. The distribution of relative regional metabolic rates indicated that parietal cortical areas were most affected. Atrophic changes as shown by CT were not correlated to the reduced metabolism in the alcohol-dependent patients.

Adult↗