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At least 703 records · Page 39Linked to original sources
PubMed1994

Dopamine D2 receptors mapped in rat brain with [3H](+)PHNO.

Previous work with membrane preparations had demonstrated that the agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) labels the high-affinity state of dopamine D2 receptors with 67-fold selectivity over D1 sites. In this study, quantitative autoradiography was used to examine the binding of [3H](+)PHNO to rat brain sections. Highest binding densities were found in caudate-putamen, accumbens, and olfactory tubercles, as expected, and also in specific layers of the olfactory bulb. In addition, a second group of brain regions, including lateral septum, entorhinal cortex, molecular layer of hippocampus, and several brainstem structures showed low but consistent levels of binding. In all brain regions [3H](+)PHNO binding (2 nM) was completely displaced by 10 microM sulpiride (> 99%). Addition of 150 microM guanilylimidodiphosphate, which normally converts D2 receptors from high to low affinity states, abolished [3H](+)PHNO binding in all brain regions (> 99%), except for the islands of Callejas. This is likely to reflect binding to D3 sites in this area. Omission of preincubation in binding assays decreased [3H](+)PHNO binding in a regionally dependent manner, with strongest effects (22%) seen in high-density areas. These preincubation results confirm that (+)PHNO may have limitations for in vivo imaging studies. On the other hand, [3H](+)PHNO's negligible levels of non-specific binding compared to other agonists and overall selectivity would make it an excellent tool for in vitro autoradiographic monitoring of the high affinity state of D2 receptors.

Animals↗
PubMed1995

Variability in D2-dopamine receptor density and affinity: a PET study with [11C]raclopride in man.

The variability of D2-dopamine receptor binding parameters in man was determined using Positron Emission Tomography (PET) and [11C]raclopride. A saturation analysis based on five PET-experiments was performed in each of ten men and ten women. The mean density of D2-dopamine receptors (Bmax) was 28 +/- 6.9 pmol/ml (mean +/- S.D.) and the apparent affinity (Kdapp) 9.1 +/- 1.9 pmol/ml. The Hill coefficient was in all subjects close to unity (nH: 0.999 +/- 0.020), thereby indicating binding to a homogeneous class of receptors. No significant differences between males and females were found in Bmax or Kdapp. The interindividual difference in Bmax was statistically significant (alpha = 0.01). The difference in Kdapp was not significant. Upregulation of the receptor density (Bmax) has been widely discussed as a mechanism for increased dopaminergic neurotransmission in schizophrenia. This study indicates that receptor density varies considerably in a group of healthy subjects.

Adult↗
PubMed1995

Repeated quinpirole treatment: locomotor activity, dopamine synthesis, and effects of selective dopamine antagonists.

Repeated treatment with the non-selective dopamine agonist apomorphine results in behavioral sensitization and enhanced dopamine synthesis in dopamine projection fields. To examine the role of D2-type dopamine receptors in modulating these effects, the present experiment assessed the effects of repeated treatment with the D2-type agonist quinpirole on locomotor activity and dopamine synthesis. In the first experiment, rats were treated with vehicle or one of two doses (0.3 or 3.0 mg/kg) of quinpirole for 8 days. Daily measures of locomotor activity revealed an initial suppression of activity produced by quinpirole which dissipated over the 8 days of treatment. A trend for an increase in activity for 3.0 mg/kg quinpirole compared to vehicle was obtained on day 8. Twenty-four hours after cessation of treatment, dopamine synthesis, measured as accumulation of 3,4-dihydroxyphenylalanine (DOPA) after treatment with the DOPA decarboxylase inhibitor NSD-1015, was enhanced in the striatum, but not nucleus accumbens-olfactory tubercle (NAOT) or ventral mesencephalon (VM). In Experiment 2, rats were treated for 8 days with vehicle, 3.0 mg/kg quinpirole or the D1 antagonist SCH 23390 (0.5 mg/kg) in a two (vehicle or quinpirole) x two (vehicle or SCH 23390) design. Quinpirole-alone treatment resulted in a reduction of the locomotor suppressant effects of the drug. SCH 23390-alone and quinpirole-SCH 23390 combined treatment resulted in decreased activity compared to the vehicle control group that did not change across days. DOPA accumulation was enhanced in the striatum and NAOT after quinpirole treatment; however, SCH 23390 had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effect of L-dopa and 6-hydroxydopamine lesioning on [11C]raclopride binding in rat striatum, quantified using PET.

A positron emission tomograph (PET) was used to image D2 dopamine receptor function in rat striata and to obtain regional time-radioactivity curves from individual rat brains following i.v. injection of carbon-11-labelled raclopride. Despite the limited resolution of the camera, together with associated spillover and partial volume effects, the kinetic data obtained from striata were such that specific binding of the radioligand could be quantified unilaterally, using a reference tissue compartmental model, with cerebellum data as an indirect input function. With the exception that the rat is anaesthetised, the experimental system is analogous to the acquisition and collection of clinical PET data and, by using animal models of disease, can be used to aid the interpretation of clinical studies. Using 6-hydroxydopamine (6-OHDA) lesioning of the substantia nigra pars compacta to produce a rat hemiparkinsonian model, the present results confirm that deafferentation causes a supersensitivity of post-synaptic D2 dopamine receptors. Saturation studies indicated that the measured 23% increase in [11C]raclopride binding potential reflected a change in receptor affinity. Modulation of extracellular dopamine concentration, monitored by in vivo microdialysis, demonstrated that the increased binding was unlikely to be due to a reduction in receptor occupancy by endogenous dopamine. Acute administration of L-3,4-dihydroxyphenylalanine (L-dopa) also caused an increase in [11C]raclopride binding potential, confirming the suggestion that L-dopa plays a more complex role than that of dopamine precursor in the nigrostriatal pathway.

Animals↗
PubMed2002

SHAM-sensitive alternative respiration in the xylose-metabolizing yeast Pichia stipitis.

SHAM-sensitive (STO) alternative respiration is present in the xylose-metabolizing, Crabtree-negative yeast, Pichia stipitis, but its pathway components and physiological roles during xylose metabolism are poorly understood. We cloned PsSTO1, which encodes the SHAM-sensitive terminal oxidase (PsSto1p), by genome walking from wild-type CBS 6054 and subsequently deleted PsSTO1 by targeted gene disruption. The resulting sto1-delta deletion mutant, FPL-Shi31, did not contain other isoforms of Sto protein that were detectable by Western blot analysis using an alternative oxidase monoclonal antibody raised against the Sto protein from Sauromatum guttatum. Levels of cytochromes b, c, c(1) and a.a(3) did not change in the sto1-delta mutant, which indicated that deleting PsSto1p did not alter the cytochrome pool. Interestingly, the sto1-delta deletion mutant stopped growing earlier than the parent and produced 20% more ethanol from xylose. Heterologous expression of PsSTO1 in Saccharomyces cerevisiae increased its total oxygen consumption rate and imparted cyanide-resistant oxygen uptake but did not enable growth on ethanol, indicating that PsSto1p is not coupled to ATP synthesis. We present evidence that the mitochondrial NADH dehydrogenase complex (Complex I) was present in wild-type CBS 6054 but was bypassed in the cells during xylose metabolism. Unexpectedly, deleting PsSto1p led to the use of Complex I in the mutant cells when xylose was the carbon source. We propose that the non-proton-translocating NAD(P)H dehydrogenases are linked to PsSto1p in xylose-metabolizing cells and that this non-ATP-generating route serves a regulatory function in the complex redox network of P. stipitis.

Amino Acid Sequence↗
PubMed1996

Synthesis of aryl azide derivatives of UDP-GlcNAc and UDP-GalNAc and their use for the affinity labeling of glycosyltransferases and the UDP-HexNAc pyrophosphorylase.

The chemical synthesis and utilization of two photoaffinity analogs, 125I-labeled 5-[3-(p-azidosalicylamido)-1-propenyl]-UDP-GlcNAc and -UDP-GalNAc, is described. Starting with either UDP-GlcNAc or UDP-GalNAc, the synthesis involved the preparation of the 5-mercuri-UDP-HexNAc and then attachment of an allylamine to the 5 position to give 5-(3-amino)allyl-UDP-HexNAc. This was followed by acylation with N-hydroxysuccinimide p-aminosalicylic acid to form the final product, i.e., 5-[3-(p-azidosalicylamido)-1-propenyl]-UDP-GlcNAc or UDP-GalNAc. These products could then be iodinated with chloramine T to give the 125I-derivatives. Both the UDP-GlcNAc and the UDP-GalNAc derivatives reacted in a concentration-dependent manner with a highly purified UDP-HexNAc pyrophosphorylase, and both specifically labeled the subunit(s) of this protein. The labeling of the protein by the UDP-GlcNAc derivative was inhibited in dose-dependent fashion by either unlabeled UDP-GlcNAc or unlabeled UDP-GalNAc. Likewise, labeling with the UDP-GalNAc probe was blocked by either UDP-GlcNAc or UDP-GalNAc. The UDP-GlcNAc probe also specifically labeled a partially purified preparation of GlcNAc transferase I.

Affinity Labels↗
PubMed1997

Antagonist binding characteristics of the Ser311-->Cys variant of human dopamine D2 receptor in vivo and in vitro.

We report in vivo and in vitro antagonist binding characteristics of the naturally occurring Ser311-->Cys variant of the human D2 dopamine receptor. Striatal receptor binding characteristics in vivo were measured with positron emission tomography and the D2 antagonist [11C]raclopride. The in vitro affinity of raclopride for the Ser311-->Cys variant and the wild type receptor was studied in membrane binding assays from stably transfected cell lines. One healthy male carrying the heterozygous Ser311-->Cys (TCC-->TGC) substitution was identified with denaturing gradient gel electrophoresis and DNA sequencing. The striatal D2 receptor binding characteristics in vivo in this subject were normal. This was supported by the in vitro data as the Ki values of raclopride for the Ser311-->Cys variant and the wild type receptor were identical. Our data suggest that the Ser311-->Cys variant of the human D2 receptor does not influence antagonist-receptor recognition in vivo or in vitro.

Adult↗
PubMed1997

Plasmodium falciparum: cyanide-resistant oxygen consumption.

It has been hypothesized that Plasmodium parasites utilize a branched chain respiratory pathway, consisting of a classical cyanide-sensitive branch and an alternative cyanide-resistant branch. To further explore this hypothesis, the effect of cyanide on Plasmodium falciparum was determined using a polarographic assay. The rate of oxygen consumption by saponin-freed parasites was approximately 5% that of control human white blood cells or of Toxoplasma gondii, consistent with an anabolic role for P. falciparum respiration. However, while all of the oxygen consumption of the control white blood cells and of T. gondii could be inhibited by cyanide, 25% of the oxygen consumption of the P. falciparum parasites was found to be insensitive to high concentrations of cyanide. The cyanide-resistant portion of the parasite oxygen consumption was completely inhibited by two inhibitors of alternative oxidase activities in other systems, propyl gallate and salicyclhydroxamic acid. These studies provide the first direct evidence for a branched chain respiratory pathway in P. falciparum. Furthermore, salicyclhydroxamic acid, propyl gallate, and related inhibitors of alternative oxidase activities were shown to inhibit the growth of P. falciparum in vitro. These results support the need for further investigation of alternative oxidase activity as an antimalarial chemotherapeutic target.

Animals↗
PubMed2001

Plasmodium falciparum: the effects of atovaquone resistance on respiration.

Atovaquone is an antimalarial agent that specifically inhibits the cytochrome bc(1) complex of the cytochrome pathway. High-level atovaquone resistance is associated with a point mutation in the cytochrome b gene. A pair of isogenic clinical isolates of Plasmodium falciparum derived from before and after the acquisition of atovaquone resistance was used to determine whether the change in the cytochrome b gene resulted in changes in respiration in response to atovaquone. Since P. falciparum appears to utilize a branched respiratory system comprising both the cytochrome and an alternative respiratory pathway, the proportion of each pathway utilized by the sensitive and resistant parasites was investigated. Atovaquone inhibited total parasite oxygen consumption by up to 66% in the sensitive isolate but only up to 28% in the resistant isolate. Both the atovaquone-sensitive and the atovaquone-resistant parasites were comparably sensitive to the alternative pathway inhibitor, salicylhydroxamic acid. Atovaquone appeared to partially inhibit the rate of oxygen consumed through the alternative pathway in only the atovaquone-sensitive isolate. Cross resistance was noted between atovaquone and a new antimalarial agent WR243251. However, the level of WR243251 resistance was very modest compared to the level of atovaquone resistance. WR243251 was shown to rapidly reduce the rate of parasite oxygen consumption by almost 80% in the atovaquone-sensitive isolate and by 57% in the atovaquone-resistant isolate. Drug interaction studies suggest that atovaquone and WR243251 may inhibit growth additively or with mild synergy. Together, these results suggest that while WR243251 may inhibit respiration, its target of action probably differs from that of atovaquone.

Acridines↗
PubMed1996

Dopaminergic control of prolactin secretion in the turkey.

The stimulatory and inhibitory effects of dopamine (DA) upon avian prolactin (PRL) secretion suggest that, in birds, these actions are mediated by multiple DA receptors. To test this hypothesis, combined intracranial infusions of DA and selective D1 or D2 DA receptor blockers, plus electrical stimulation (ES) of the brain and vasoactive intestinal peptide (VIP) immunoneutralization, were used to characterize the actions of DA on PRL secretion in the turkey. Blockade of D1 DA receptors prevented the increase in circulating PRL observed in response to infusion of stimulatory concentrations of DA or to ES. Stimulatory infusions of DA also failed to increase circulating PRL in birds immunized against VIP. Results from infusion of the D2 DA receptor antagonist were unclear. Low concentrations had no effect, while the highest concentration (100 nmol/min) produced an increase in plasma PRL. At the high concentration the drug may be affecting PRL secretion by (1) acting nonspecifically, (2) acting as a partial DA agonist on D1 DA receptors, or (3) diffusion to the pituitary and blockade of D2 receptors there. These data suggest that avian PRL secretion is mediated by D1 DA receptors within the brain and that the stimulatory effect of DA upon PRL secretion requires an intact VIPergic system.

Animals↗
PubMed1996

Simplified reference tissue model for PET receptor studies.

The reference tissue model allows for quantification of receptor kinetics without measuring the arterial input function, thus avoiding arterial cannulation and time-consuming metabolite measurements. The model contains four parameters, of which the binding potential (BP) is the parameter of interest. Although BP is robust, convergence rates are slow and the other parameters can have large standard errors. To overcome this problem, a simplified reference tissue containing only three parameters was developed. This new three-parameter model was compared with the previous four-parameter model using a variety of PET studies: [11C]SCH 23390 (D1 receptor) and [11C]raclopride (D2 receptor) in humans, and [11C]SCH 23390, [11C]raclopride and [11C]RTI-121 (dopamine transporter) in rats. The BP values obtained from both models were essentially the same for all cases. In addition, the three-parameter model was insensitive to starting values, produced stable results for the other parameters (small standard errors), and converged rapidly. In conclusion, for the ligands tested the three-parameter model is a better choice, combining increased convergence rate with increased stability.

Animals↗
PubMed1997

Parametric imaging of ligand-receptor binding in PET using a simplified reference region model.

A method is presented for the generation of parametric images of radioligand-receptor binding using PET. The method is based on a simplified reference region compartmental model, which requires no arterial blood sampling, and gives parametric images of both the binding potential of the radioligand and its local rate of delivery relative to the reference region. The technique presented for the estimation of parameters in the model employs a set of basis functions which enables the incorporation of parameter bounds. This basis function method (BFM) is compared with conventional nonlinear least squares estimation of parameters (NLM), using both simulated and real data. BFM is shown to be more stable than NLM at the voxel level and is computationally much faster. Application of the technique is illustrated for three radiotracers: [11C]raclopride (a marker of the D2 receptor), [11C]SCH 23390 (a marker of the D1 receptor) in human studies, and [11C]CFT (a marker of the dopamine transporter) in rats. The assumptions implicit in the model and its implementation using BFM are discussed.

Animals↗
PubMed1999

Mapping of central D2 dopamine receptors in man using [11C]raclopride: PET with anatomic standardization technique.

D2 dopamine receptors are of interest in the pathophysiology of schizophrenia. For group comparisons of neuroreceptor distribution measured by PET on a pixel-by-pixel basis, an anatomic standardization technique is required. The aim of the present study is to build a database of normal D2 dopamine receptor distribution using [11C]raclopride and an anatomic standardization technique. In each subject, two PET measurements were performed with rapid bolus injection and with continuous infusion of [11C]raclopride. The radioactivity of the PET images were integrated in the time interval. Integrated images were normalized by the radioactivity of the cerebellum, providing a measure of the binding potential (BP) in each pixel. Each PET image was transformed into a standard brain anatomy using a Computerized Brain Atlas system. From the standardized PET images, the sample mean and the SD of the BP were calculated in each pixel. On the anatomically standardized average images for the both rapid bolus injection and continuous infusion, high BP was observed in the putamen and the caudate nucleus, whereas low BP was observed in the cerebral cortices. The BP for the thalamus and the substantia nigra were slightly higher than those for the cerebral cortices. This regional distribution is in good agreement with the distribution of D2 dopamine receptors known from in vitro studies. The anatomic standardization technique permits to build a database of the normal D2 dopamine receptor distribution in the living human brain. This technique can be applied for group comparisons on a pixel-by-pixel basis.

Adult↗
PubMed1999

PET mapping of extrastriatal D2-like dopamine receptors in the human brain using an anatomic standardization technique and [11C]FLB 457.

The Computerized Brain Atlas (CBA) transforms PET images of individual subjects into a standard brain anatomy. We have previously applied this to PET images with [(11)C]raclopride and confirmed that the D2 dopamine receptors in the striatum can be evaluated accurately with a standard brain anatomy. There is growing evidence that extrastriatal D2 receptors, in spite of their low density, have pathophysiological significance for schizophrenia. We used the CBA to explore the extrastriatal distribution of D2 receptors in 13 healthy subjects using [11C]FLB 457, a substituted benzamide with very high affinity for D2 and D3 receptors. There was good agreement between the specific binding ratios from CBA quantification of standardized images and those from region-of-interest analyses of original images. The highest levels of binding were observed in the putamen and caudate nucleus, followed by the globus pallidus and nucleus accumbens. Besides the basal ganglia, the hypothalamus and nucleus ruber also showed high levels of binding. Intermediate levels were found in the substantia nigra, nucleus subthalami, amygdala, and thalamus. Interestingly, there was very heterogeneous binding among the thalamic nuclei. The anterior and mediodorsal nuclei showed relatively high binding. The cerebral cortices showed lower levels with significant regional differences. Binding was highest in the temporal cortex and hippocampus followed by the anterior cingulate gyrus, and the parietal and frontal cortices, but was lowest in the occipital cortex. The use of CBA for analysis of [11C]FLB 457 binding makes it possible to build a normal database for the extrastriatal D2 receptors in the living human brain. The heterogeneous distribution of D2 receptors provides an attractive opportunity for new research on the pathophysiology and drug treatment of schizophrenia.

Adult↗
PubMed2001

Error analysis for quantification of [(11)C]FLB 457 binding to extrastriatal D(2) dopamine receptors in the human brain.

To estimate receptor binding of ligand by positron emission tomography (PET) without an arterial input function, several quantitative approaches based on the use of a reference region have been proposed. We compared three approaches for quantifying extrastriatal D(2) dopamine receptors using [(11)C]FLB 457. The PET measurements were performed on seven healthy men. Binding potential (BP) of [(11)C]FLB 457 was calculated by the reference tissue model method, transient equilibrium method, and late time method. The reference tissue model describes the time-activity curve in a brain region in terms of that in the reference region, assuming that the levels of nondisplaceable radioligand binding in both regions are the same. The transient equilibrium theoretically occurs when the derivative for specific binding is zero. With the late time method, BP is calculated by integrating a late part of the time-activity curve. BP values obtained by all methods were in good agreement with those obtained by the kinetic approach, and the highest coefficient of correlation was observed in the reference tissue model method. In the simulation study, the error of BP calculated by the reference tissue model method was smallest. Moreover, the effect of the difference in the influx rate constant K(1) between the brain and the reference regions on BP was nearly avoided as theoretically predicted. We concluded that the reference tissue model method is most suitable for calculating BP of extrastriatal D(2) dopamine receptors with [(11)C]FLB 457.

Adult↗
PubMed2001

Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy--a simulation study based on experimental data.

The D2 dopamine receptor density ranges from 0.2 to 40 nM among human brain regions. For high density regions radioligands like [(11)C]raclopride provide accurate and reliable estimates of the receptor density. In research on neuropsychiatric disorders there is, however, a growing need for quantitative approaches that accurately measure D2 dopamine receptor occupancy induced by drugs or endogenous dopamine in regions with low receptor density. The new high affinity radioligands [(11)C]FLB 457 and [(123)I]epidepride have been shown to provide a signal for extrasriatal D2 dopamine receptor populations in the human brain in vivo. Initial observations indicate, however, that the time required to reach equilibrium is dependent on receptor density. Ratio analyses may thus not be readily used for comparisons among different brain regions. The aim of the present simulation study was to examine commonly used approaches for calculation of drug induced D2 dopamine receptor occupancy among regions with widely different receptor density. The input functions and the rate constants of [(11)C]FLB 457 and the reference ligand [(11)C]raclopride were first used in a simulation estimating the effect of receptor density on equilibrium time. In a second step we examined how errors produced by inaccurate determination of the binding potential parameter propagate to calculations of drug induced receptor occupancy. The simulations showed a marked effect of receptor density on equilibrium time for [(11)C]FLB 457, but not for [(11)C]raclopride. For [(11)C]FLB 457, a receptor density above about 7 nM caused the time of equilibrium to fall beyond time of data acquisition (1 h). The use of preequilibrium data caused the peak equilibrium and the end time ratio approaches but not the simplified reference tissue model (SRTM) approach to underestimate the binding potential and thus also the drug occupancy calculated for high-density regions. The study supports the use of ratio and SRTM analyses in extrastriatal low-density receptor regions for which the high affinity ligand [(11)C]FLB 457 was developed. However, in high-density regions such as the human striatum simple ratio approaches cannot be validly applied, whereas the SRTM approach has higher potential to provide valid estimates. Interestingly, the results suggest that published data on a proposed extrastriatal selectivity for the antipsychotic drugs clozapine and olanzapine may be due to erroneous estimations of the binding potential when using ratio approaches.

Benzamides↗
PubMed2002

Wavelet-aided parametric mapping of cerebral dopamine D2 receptors using the high affinity PET radioligand [11C]FLB 457.

The study of human neuroreceptor systems by means of positron emission tomography (PET) and suitable radioligands has proven to be of great importance in research on normal brain functions and the pathophysiology and treatment of neuropsychiatric disorders. A for long identified goal is to produce detailed parametric maps of showing neuroreceptor binding parameters for the entire human brain in vivo. The application of wavelet filters has recently been proposed as a solution to handle the inherently low signal-to-noise ratio of PET images. In the present study we applied the wavelet approach to data obtained from 10 healthy subjects who were examined with [11C]FLB 457. This high affinity dopamine D2-receptor antagonist provides a signal from a range of regions with a hundredfold difference in receptor density and should thus be suitable for evaluation of the wavelet approach. For cross-validation purposes the data were analysed with four methods: a traditional region-of-interest (ROI) based analysis, a pixel-based analysis and two variants of wavelet-aided analyses. In both variants the wavelet filter was spatially applied, but a two-dimensional filter was used in one case and a three-dimensional one in the other. The same linear-graphical binding potential (BP) estimation step was used for all methods and the results of the three parametric mapping techniques were compared to the reference ROI-based method by calculating the average BP of representative ROIs. The pixel-based and the two-dimensional-wavelet-based methods yielded highly correlated but systematically lower values when compared to the reference ROI-based method. The approach utilising three-dimensional wavelet filters yielded BP maps with regional averages closely matching the values of the ROI-based method. The results show that the combination of three-dimensional spatial wavelet filtering with established parameter estimation procedures provides detailed, accurate maps of radioligand binding parameters. Such maps can be used for in inter-individual or multi-condition comparisons of binding parameters at subregional levels.

Adult↗