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Biomedical subjects

G Sedvall

Publications and source records attributed to G Sedvall.

At least 73 records · Page 4Linked to original sources
PubMed1994

D1-, D2-, and 5-HT2-receptor occupancy in clozapine-treated patients.

Positron emission tomography (PET) and selective radioligands were used to determine central D1- and D2-dopamine- and 5-HT2-receptor occupancy in clozapine-treated patients with schizophrenia. In 16 patients, the mean D2-receptor occupancy was 47% (range, 20%-67%), which is lower than that previously demonstrated in patients treated with classical neuroleptics (range, 70%-89%). In 11 patients, the mean D1-receptor occupancy was 44% (range, 33%-59%), which is high when compared with that for classical neuroleptics. In a group of 5 patients, including some treated with low doses of clozapine, the mean 5-HT2-receptor occupancy was a high 89% (range, 84%-94%). By comparison to classical neuroleptics, clozapine is atypical with regard to central binding characteristics in the brain of treated patients.

Adult↗
PubMed1994

Expression of mRNAs encoding ARPP-16/19, ARPP-21, and DARPP-32 in human brain tissue.

In this study we have isolated and sequenced human cDNAs for the phosphoproteins DARPP-32, ARPP-21, and ARPP-16/19, and have compared these sequences to previously characterized bovine and rat cDNAs. In situ hybridization and Northern blot analysis with the human cDNA probes were used to study the expression of mRNAs encoding ARPP-16/19, ARPP-21, and DARPP-32 in human postmortem brain tissue. In situ hybridization was performed using horizontal whole hemisphere sections. Five representative levels of the brain ranging from 71 mm to 104 mm ventral to vertex were examined. All three probes showed distinct hybridization patterns in the caudate nucleus, putamen, nucleus accumbens, and the amygdaloid complex. For ARPP-16/19 mRNA, a hybridization signal comparable to the signal in caudate nucleus, putamen, and nucleus accumbens was also detected in the neocortex. ARPP-21 and DARPP-32 mRNA, on the other hand, were present in lower levels in neocortical regions. DARPP-32 mRNA was abundant in the cerebellar cortex at the level of the Purkinje cell layer. High levels of ARPP-16/19 and ARPP-21 mRNA were also found in the cerebellar cortex, where they were confined to deeper layers. The present result demonstrate that mRNAs for the three phosphoproteins are expressed in overlapping, but also distinct, areas of the human brain that in many cases coincide with previously described distribution of the dopamine D1 receptor.

Aged↗
PubMed1993

PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor.

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D1-dopamine receptor antagonists. Both compounds have been labeled with 11C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D1-dopamine receptors. This striatal uptake was displaced by high doses of the selective D1-antagonist SCH 23390 (2 mg/kg) but not by the 5HT2-antagonist ketanserin (1.5 mg/kg) or the selective D2-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [11C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [11C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24-28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [11C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [11C]NNC 756 the ratio was about 5. This ratio of 5 for [11C]NNC 756 is the highest obtained so far for PET radioligands for the D1-dopamine receptor.

Adult↗
PubMed1993

PET analysis of [11C]flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls.

Benzodiazepine (BZ) receptor binding in the brain was determined in five chronic alcohol-dependent men and in five healthy male control subjects using [11C]flumazenil (Ro 15-1788) and positron emission tomography (PET). Magnetic resonance imaging was used to evaluate brain anatomy and pathology, and to define regions of interest in the brain. [11C]Flumazenil binding was quantified by applying a saturation procedure with two PET experiments, the first with high (400-3400 Ci/mmol) and the second with low (approximately 1 Ci/mmol) specific radioactivity. Radioactivity in the pons was taken as an estimate of free and nonspecifically bound radioligand. Equilibrium was defined to prevail when the derivative of specific binding (dCb(t)/dt) was equal to zero. The values were used in a Scatchard analysis for determination of the maximum density of binding sites (Bmax) and the equilibrium binding constant (Kd). The mean values of Bmax and Kd were about the same in the two groups, but the Bmax variance for the alcoholics was significantly greater for all regions of interest as compared with the healthy volunteers. The results may indicate that chronic alcohol consumption has multiple effects on the BZ receptor complex.

Adult↗
PubMed1993

[11C]NNC 687 and [11C]NNC 756, dopamine D-1 receptor ligands. Preparation, autoradiography and PET investigation in monkey.

NNC 687 and NNC 756 [(+)-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl- 8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine and (+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine] are two new potent dopamine D-1 receptor antagonists. [11C]NNC 687 and [11C]NNC 756 were both prepared by N-methylation of the corresponding desmethyl compounds with [11C]methyl iodide. The reactions were performed in acetone with subsequent normal-phase semi-preparative HPLC and resulting in 50-60% radiochemical yield (from EOB and decay-corrected) with a total synthesis time of 30-35 min and a radiochemical purity higher than 99%. The specific radioactivity obtained at time of injection was about 1500 Ci/mmol (55 GBq/mumol). Autoradiographic examination of [11C]NNC 687 and [11C]NNC 756 binding in post-mortem human brain sections showed specific binding in the striatum, a region with high density of dopamine D-1 receptors. PET examination of the radioligands in a Cynomolgus monkey demonstrated accumulation of radioactivity predominantly in the striatum. The ratio between radioactivities in the striatum and the cerebellum was about 2 and 8 for [11C]NNC 687 and [11C]NNC 756 after 60 min. [11C]NNC 756 should have potential as PET ligand for examination of central dopamine D-1 receptors in man.

Alkylation↗
PubMed1993

Regional cerebral blood flow during experimental phobic fear.

Positron emission tomographic measurements of regional cerebral blood flow (rCBF) were used to investigate central nervous system correlates of fear and anxiety. Volunteers with symptomatic snake phobia were studied while exposed to visual phobogenic, aversive, and neutral stimuli. Anxiety ratings and the number of nonspecific electrodermal fluctuations increased as a function of phobic stimulation. Phobic, compared to neutral and aversive, stimulation elevated rCBF in the visual associative cortex. The basal ganglia were not activated more by phobic than aversive or neutral stimulation. However, cortical and thalamic rCBF were always correlated during phobic but not aversive or neutral stimulation. This indicates that the thalamus could be a relay station for phobic stimulus processing and affect.

Adult↗
PubMed1993

Lack of association between schizophrenia and alleles in the dopamine D3 receptor gene.

Dopamine receptor dysfunction has been implicated in the pathophysiology of schizophrenia. Schizophrenic patients (n = 76) and control subjects (n = 53) were examined for allele frequencies in a 2-allele BalI polymorphism, causing a serine-->glycine amino acid substitution in the coding sequence of the dopamine D3 receptor gene. No statistical significant differences of allele frequencies or genotype frequencies could be found between the two groups. Neither were there any significant relationships between allele frequencies and a number of clinical variables within the schizophrenic subsample. However, if not corrected for multiple testing, an association was found between homozygosity and positive response to neuroleptic drugs. The present study does not provide evidence that the BalI polymorphism in the dopamine D3 receptor gene is involved in the pathophysiology of schizophrenia. Further investigations with an increased number and variety of patients concerning response to neuroleptic drugs and expression of the receptor in human brain should be performed to definitively exclude this hypothesis.

Adult↗
PubMed1993

Binding of [3H]SCH 39166 to human post mortem brain tissue.

The dopamine D1 antagonist SCH 39166 was labelled with tritium and used for in vitro binding and autoradiography using human post mortem brain tissue. Competition studies on tissue from human nucleus caudatus showed that SCH 23390 inhibited the binding of [3H]SCH 39166 biphasically. The non-specific binding of [3H]SCH 39166 in both nucleus caudatus and cerebellum was lower after the addition of SCH 23390 or SCH 39166 than after flupentixol (10 microM). Autoradiography showed specific [3H]SCH 39166 binding in the caudate nucleus and putamen in the brain sections. The binding of [3H]SCH 39166 in the medial part of the caudate nucleus was very dense and similar to that obtained with [3H]SCH 23390, which was used as a reference ligand. Dense binding of [3H]SCH 39166 was also found in cortical regions, and binding was also obtained in the cerebellum and in the hippocampus. Addition of flupentixol (10 microM) abolished some but not all the binding of [3H]SCH 39166. The binding of [3H]SCH 39166 to caudate and putamen was not totally abolished by the addition of excess SCH 23390, while excess SCH 39166 diminished the binding of [3H]SCH 23390 in all regions. The present study indicates that [3H]SCH 39166, similar to [3H]SCH 23390, binds to dopamine D1 receptors in the human brain. It is concluded that [3H]SCH 39166 has a slightly different binding pattern than [3H]SCH 23390, which can be due to labelling of one or two additional binding site(s) pharmacologically unrelated to dopamine D1 receptors.

Autoradiography↗
PubMed1992

Gpp(NH)p stimulates [3H]raclopride binding to homogenates from human putamen and accumbens.

The effects of the stable GTP analogue Gpp(NH)p (5'-guanylyl imido diphosphate) were examined on in vitro [3H]raclopride binding to dopamine D2 receptors in preparations from post mortem human brains. The estimated number of receptors in the brain was 29% and 38% higher in putamen and accumbens, respectively, when determined in the presence of Gpp(NH)p as compared to its absence. The interaction of agonists was biphasic confirming the two affinity state model of the receptor--G-protein complex. The addition of Gpp(NH)p to the assay abolished the two site competition of apomorphine with [3H]raclopride binding in both regions studied. The non-specific binding at high concentrations of apomorphine was not significantly affected by the addition of Gpp(NH)p, indicating that only the specific binding of [3H]raclopride to the dopamine D2 receptor is increased.

Apomorphine↗
PubMed1992

Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects.

Positron emission tomography and selective radioligands were used to determine D1 and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neuroleptic-induced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D1 occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D1 occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.

Adolescent↗
PubMed1992

PET analysis of alcohol interaction with the brain disposition of [11C]flumazenil.

Acute alcohol administration to rats has in preliminary studies been reported to drastically increase the binding of the benzodiazepine (BZ) receptor antagonist [3H]flumazenil (Ro 15-1788) to central BZ receptors. In the present study the effect of acute alcohol ingestion on the disposition of [11C]flumazenil in the human brain and plasma was examined by positron emission tomography (PET) in four healthy volunteers. Neocortex, cerebellum and pons (reference region) were delineated using X-ray computerized tomography (CT). Alcohol did not increase either total radioactivity uptake or specific [11C]flumazenil binding in neocortex or cerebellum. However, alcohol had a small but significant effect on [11C]flumazenil in arterial blood. After alcohol the plasma radioactivity peak was higher, more narrow and occurred earlier than in the control experiments. The present experiments contradict the view that alcohol directly affects central BZ receptor binding in man. Thus the dramatic increase of flumazenil binding in rat brain reported previously could not be observed in the human brain.

Adult↗
PubMed1992

[11C]Ro 15-4513, a ligand for visualization of benzodiazepine receptor binding. Preparation, autoradiography and positron emission tomography.

Ro 15-4513, a partial inverse agonist at the benzodiazepine (BZ) receptor site was labelled with 11C and used for in vitro autoradiography on human post mortem brain sections and for positron emission tomography (PET) on Cynomolgus monkeys. The total radiochemical yield of [11C]Ro 15-4513 was 30-40% with an overall synthesis time of 40 min. The specific radioactivity was about 1000 Ci/mmol at end of synthesis. In vitro autoradiography showed that [11C]Ro 15-4513 bound specifically predominantly in the neocortex of the human brain. Specific binding was also demonstrated in the basal ganglia and the cerebellar cortex. Flumazenil (Ro 15-1788) and clonazepam inhibited the binding in cerebral regions, but a significant proportion in the cerebellum was not inhibited by these agents. This proportion may represent alpha 6-containing BZ receptors. PET examination of [11C]Ro 15-4513 binding in Cynomolgus monkeys demonstrated high uptake of radioactivity in neocortex. The uptake of radioactivity was markedly displaced by high doses of Ro 15-4513 or clonazepam. [11C]Ro 15-4513 should be a useful ligand to examine BZ receptor characteristics in the living human brain by PET.

Animals↗
PubMed1992

Effect of raclopride on dopamine D2 receptor mRNA expression in rat brain.

Prolonged treatment with dopamine D2 receptor antagonists is known to elevate the density of dopamine D2 receptor binding sites in caudate-putamen and nucleus accumbens in rat and human brain. In this study we used the dopamine D2 receptor antagonist raclopride (3 mumol/kg, s.c.) to determine if a single injection or daily administration of this drug for up to 18 days changed the expression of dopamine D2 receptor mRNA in rat caudate-putamen and accumbens as measured by in situ hybridization. A single injection of raclopride did not significantly change the numerical density of dopamine D2 receptor mRNA-expressing neurons in any of the regions examined. A daily administration of raclopride for 18 days resulted in a 31% increase in the number of cells expressing detectable amounts of dopamine D2 receptor mRNA in dorsolateral caudate-putamen and in a 20% increase in the area of silver grains over individual hybridization-positive neurons in this brain region measured on emulsion-dipped slides. The region-specific increase in the D2 receptor mRNA level in dorsolateral caudate-putamen was confirmed by measurement of the hybridization signal on X-ray film autoradiograms. The levels of D2 receptor mRNA remained unchanged in medial caudate-putamen and accumbens after 18 days' treatment. The region-selective increase in dopamine D2 receptor mRNA expression in dorsolateral caudate-putamen indicates a differential regulation of dopamine D2 receptor mRNA expression in a subpopulation of caudate-putamen neurons by this neuroleptic. We suggest that the increase in dopamine D2 receptor density in caudate-putamen known to follow prolonged dopamine D2 receptor blockade to some extent is regulated at the level of gene expression.

Analysis of Variance↗
PubMed1992

The current status of PET scanning with respect to schizophrenia.

PET scan studies of regional brain energy metabolism in schizophrenia have hitherto not been consistent in demonstrating any specific perturbation in heterogenous groups of patients. In some studies there was a tendency to reduced metabolic values in several regions in chronic patients. The variance of metabolic rates also tended to be greater in the group of schizophrenic subjects, but rates for most patients overlapped with those of the controls. Studies of regional brain energy metabolism also failed to disclose consistent effects of clinical antipsychotic drug treatment in schizophrenic patients. PET measurements of dopamine receptor functions in the major basal ganglia using different radioligands for D2 dopamine receptors also gave inconsistent results. One group reporting elevated densities of D2 dopamine receptors in the major basal ganglia of drug-naive schizophrenic patients could not be confirmed. PET measurements of dopamine receptor binding demonstrated profound and selective effects of clinical antipsychotic drug treatment on D2 and D1 dopamine receptor occupancy in schizophrenic patients. All chemically different categories of antipsychotic drugs induced a substantial occupancy of D2 dopamine receptors in relation to clinical treatment. This effect has been shown to be dose dependent and fully reversible. It appears much earlier than the antipsychotic effect and it is also present in neuroleptic-resistant patients. Accordingly, neuroleptic resistance is not related to individual pharmacodynamic or pharmacokinetic factors. Drug resistance is in all probability related to heterogeneity of biologic factors causing schizophrenia. Some, but not all, of the antipsychotic drugs also induce a significant D1 dopamine receptor occupancy. This effect was most marked for the unconventional drug clozapine, which showed about the same degree of D1 and D2 dopamine receptor blockade when given in conventional clinical doses. Further refinements of the resolution of PET scan instruments in the years to come and the development and application of new tracers will supply powerful tools for the further search for fundamental alterations of brain function in schizophrenia.

Brain↗
PubMed1991

11C-SCH 39166, a selective ligand for visualization of dopamine-D1 receptor binding in the monkey brain using PET.

The new selective D1-dopamine receptor antagonist SCH 39166 was labelled with the positron emitting isotope 11C and used as ligand for visualization of dopamine-D1 receptor binding in Cynomolgus monkeys by PET. After intravenous administration of the ligand a marked uptake of radioactivity was recorded in the D1-dopamine receptor-rich striatum and neocortex but not in the dopamine receptor-poor cerebellum. The uptake of radioactivity in striatum and neocortex was markedly displaced after the intravenous injection of a high dose of the D1-dopamine receptor antagonist SCH 23390 but not after the 5-HT2 receptor antagonist ketanserine. 11C-SCH 39166 should be a useful tool to explore D1-dopamine receptor characteristics in the living human brain by PET.

Animals↗