Biomedical subjects

S Houle

Publications and source records attributed to S Houle.

At least 19 recordsLinked to original sources

PubMed2001

Functional neuroimaging of cerebellar activation during single word reading and verb generation in stuttering and nonstuttering adults.

Articulatory discoordinations typically observed in fluent and disfluent speech of stuttering adults suggest an underlying deficiency in the precise timing needed for speech production. Positron emission tomography scans of stuttering adults showed generally higher cerebellar activations pre-treatment compared to nonstuttering control subjects. Intensive fluency treatment resulted in increased cerebellar activation during reading immediately post-treatment and a decrease to near normal levels at the 1 year follow scan. In contrast, verb generation resulted in a gradual but consistent decrease over the three scans. The results suggest that automaticity in motor and cognitive processes during speech production may need to be considered as an important factor in future investigations of stuttering.

Adult↗

PubMed2001

Noradrenergic dysfunction in the prefrontal cortex in depression: an [15O] H2O PET study of the neuromodulatory effects of clonidine.

BACKGROUND: Noradrenergic dysfunction has been consistently implicated in depression. Much of the evidence, though, has been indirect, such as an attenuated growth hormone response to the alpha2-adrenoceptor agonist clonidine. To more directly examine central functioning of the noradrenergic system in depression, we have used [15O] H2O positron emission tomography (PET) to measure cerebral blood flow (rCBF) in combination with clonidine as a neuromodulatory probe. METHODS: Subjects were six depressed and six healthy women, medication free and matched for age and phase of menstrual cycle. Two PET scans were acquired at baseline and two scans at 20 and 35 min following an intravenous clonidine infusion of 1.4 microg/kg while subjects performed a sustained attention task. RESULTS: The growth hormone response did not show a significant difference between groups. However, PET results revealed a difference in the right superior prefrontal cortex that was resolved as an interaction from decreased rCBF in healthy control subjects but increased rCBF in the depressed group, which was not accounted for by differences in task performance. CONCLUSIONS: This differential effect of clonidine in the right prefrontal cortex provides in vivo evidence of noradrenergic dysfunction in depression, which we postulate arises from functionally impaired presynaptic alpha2-adrenoceptors as well as regionally "supersensitive" postsynaptic cortical alpha2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed2001

Carbon-11 labelled cholecystokininB antagonists: radiosynthesis and evaluation in rats.

Three cholecystokinin type B (CCKB) receptor antagonists were labelled with 11C and evaluated ex vivo in rat biodistribution studies. The CCKB antagonists were YF 476 and two other compounds of the basic 3-ureido-1,4-benzodiazepine class. Following tail-vein administration of [11C]-YF 476 exceedingly low levels of radioactivity were found in all brain regions from 5 to 60 min post-injection. Similar results were obtained using the other two 11C-labelled CCKB antagonists. In light of the very poor brain penetration of these compounds, reports on the central nervous system activity of this class of CCKB antagonists should be viewed with caution.

Animals↗

PubMed2001

An admonition when measuring the lipophilicity of radiotracers using counting techniques.

Log P measurements are a fundamental physico-chemical parameter and one of the cornerstones of structure activity relationships in medicinal chemistry. Despite the attractiveness of the method, the use of counting techniques to measure the log P of lipophilic radiotracers is fraught with pitfalls due to the amplifying effects of small quantities of radioactive impurities. For example, a radiotracer with a log P of 4 containing only 0.1% of a radioactive impurity with a log P of -1 will have an apparent log P of 3 if measured using conventional shake-flask partition techniques, counting the radioactivity in each phase. However, pre-washing the radiotracer-containing organic phase with aqueous phase can, in many cases, allay doubts about the validity of such measurements.

1-Octanol↗

PubMed2001

Effects of radiation therapy on vascular responsiveness.

The use of radiation therapy to inhibit vascular proliferative diseases has produced encouraging results in several clinical trials. However, little is known about the possible side effects of radiation on vascular responsiveness. Our goal was to study the in vitro vascular responses of the rabbit aorta to various agonists immediately after several regimens of radiation therapy administered at doses prescribed in clinical protocols and at two different dose rates. High-dose-rate radiation was administered either by brachytherapy, using a gamma source, iridium 192, or an external electron beam producing beta radiation. Low-dose-rate radiation was administered by brachytherapy using a liquid-filled balloon with the beta emitter 32P. Vascular reactivity after the various regimens of irradiation was determined using the organ bath pharmacology assay. Various agonists were applied to the rabbit aorta to produce full cumulative concentration-response curves. Radiation, administered using an external electron beam, did not alter endothelium-dependent relaxation of the aorta induced by acetylcholine. However, the use of a catheter-based system to deliver radiation disrupted the endothelial cell lining of the vessel, causing a lack of relaxation by acetylcholine. Therefore, to compare all modalities of radiation therapy on vascular responsiveness, the agonists used in this study are known to act directly on the smooth muscle. Radiation therapy had no effect on the contractile responses induced by the following agonists: phenylephrine and potassium chloride. Vascular dilatation induced by nitroglycerin, a nitric oxide donor, was unaffected by radiation therapy. The contractile response induced by des-Arg9-bradykinin, a kinin B1 receptor agonist, was significantly increased twofold to threefold by all types of irradiation under study. This enhanced response is attributable to an increase of mRNA levels coding for this receptor. In all cases, radiation therapy did not alter the effective concentration producing 50% of maximal responsiveness (EC50) and did not reduce the vascular responsiveness induced by agonists. Taken together, we conclude that radiation therapy does not hinder endothelium-independent vascular responsiveness and increases the kinin B1 receptor-mediated vasoconstriction.

Acetylcholine↗

PubMed2001

The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study.

OBJECTIVE: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. METHOD: After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. RESULTS: 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. CONCLUSIONS: 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.

Adolescent↗

PubMed2001

Ligand-mediated regulation of kinin receptors in the rabbit.

The kinin B1 receptors (B1Rs), stimulated by des-Arg9-kinins, are completely inducible, notably following treatment of animals with bacterial lipopolysaccharide. Several studies based on cultured cells have suggested a form of autoregulation of kinin receptors, because B2 receptor (B2R) or B1R stimulation could transcriptionally upregulate B1R expression. The B2R may rather be downregulated in inflammatory conditions. A rabbit B2R-green fluorescent protein (GFP) conjugate stably expressed in HEK 293 cells was rapidly internalized in response to the agonist bradykinin. Ligand-induced receptor cycling was documented applying confocal microscopy. The results confirm agonist-induced B2R endocytosis, but extensive recycling to the cell membrane does not support agonist-induced downregulation.

Animals↗

PubMed2001

Bradykinin B(2) receptor endocytosis, recycling, and down-regulation assessed using green fluorescent protein conjugates.

Agonist-induced endocytosis and/or down-regulation have been evaluated using green fluorescent protein (GFP) conjugates of the rabbit bradykinin (BK) B2 receptor (B2R). COS-1 cells transiently transfected with vectors coding for either of two rabbit B2R fluorescent variants, B2R-GFP and B2R-GFP DeltaS/T (with previously identified Ser/Thr phosphorylation sites in the C-terminal tail mutated to Ala), exhibited specific and saturable binding (K(D) in the lower nM range). The acute addition of BK (10-100 nM) to HEK 293 cells stably expressing B2R-GFP in the presence of cycloheximide was rapidly followed by translocation of the surface receptors into the cells, with essentially complete recycling of the surface receptors in 1 to 3 h (confocal microscopy, cell fractionation). Adding captopril to inhibit angiotensin I-converting enzyme activity increased the half-life of BK in the culture medium (enzyme immunoassay) and, accordingly, promoted B2R-GFP internalization for at least 3 h. However, agonist-induced down-regulation was not observed under conditions optimal for endocytosis (microscopy, immunoblot using anti-GFP antibodies). In contrast, B2R-GFP was partially degraded following a short treatment of cells with trypsin. B2R-GFP internalized following agonist treatment was colocalized with fluorescent transferrin, supporting translocation of the receptor to recycling endosomes. B2R-GFP DeltaS/T failed to translocate into the cells following treatment with BK, but exhibited at baseline an altered subcellular distribution relative to B2R-GFP. The agonist BK promotes B(2)R receptor endocytosis followed by recycling to the cell surface, but does not promote receptor down-regulation in the heterologous system that we used here. Digestion initiated by extracellular proteases may be involved in pathological B2R down-regulation, as suggested by the simulation involving trypsin.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2000

Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of (11)C-labeled 2-(phenylthio)araalkylamines.

A series of four 2-(phenylthio)araalkylamines have been radiolabeled with (11)C and evaluated as potential radiotracers for imaging the serotonin transporter (SERT) by positron emission tomography (PET). All four candidates display high affinity for SERT and low affinity for the dopamine or norepinephrine transporters using in vitro binding assays. Biodistribution studies in rats demonstrated that tail-vein injection of the (11)C-labeled radiotracers resulted in high brain uptake of radioactivity with a preferential distribution in brain regions known to be rich in SERT such as hypothalamus and thalamus. The most promising candidate, 16, had hypothalamus-to-cerebellum ratios of 9:1, 1 h postinjection, an indication of high specific to nonspecific binding. Ex vivo pharmacological studies demonstrated that uptake in SERT-rich brain regions was both saturable and selective for SERT. Two of the tested radiotracers, 15 and 16, have highly favorable properties for imaging SERT and will be used in pilot human PET imaging studies.

Aniline Compounds↗

PubMed2000

Increased left posterior parietal-temporal cortex activation after D-fenfluramine in women with panic disorder.

It is unclear whether the functional changes found in panic disorder reflect disturbed physiology of particular neurotransmitters. One method of investigating altered neurotransmission is to assess regional brain activations in response to agonist challenges. D-Fenfluramine is a medication that induces neuronal release of serotonin. Using ¿15OH(2)O and positron emission tomography (PET), measurements of regional cerebral blood flow (rCBF) were done at t=-20, -5, +20 and +35 relative to the IV D-fenfluramine injection (t=0) in nine panic-disordered and 18 healthy subjects. Subjects were otherwise healthy, right-handed, non-smoking and not taking psychotropic medication. ¿15OH(2)O PET scans were assessed with Statistical Parametric Mapping using individual global cerebral blood flow as a covariate. Comparisons of the (baseline) first two scans between healthy and panic-disordered subjects showed a decreased rCBF in the left posterior parietal-superior temporal cortex in the patient group. Fenfluramine-induced increases as defined by the last two scans minus the first two scans were compared between groups and a significantly greater increase in the same left posterior parietal-superior temporal region was found in panic-disordered subjects. Consistent with this finding, differences between the last two scans (post-fenfluramine) of the healthy and panic-disordered subjects showed an increased rCBF in the left superior temporal cortex in panic-disordered subjects. Functional pathology in the left parietal-superior temporal cortex in panic disorder may be related to abnormal modulation by serotonin.

Adolescent↗

PubMed2000

Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study.

RATIONALE: Dopamine D2 receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D2 receptor upregulation has long been postulated as central to tardive dyskinesia (TD). OBJECTIVE: Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D2 receptor up-regulation also occurs in humans. METHODS: The long-term effects of traditional and novel antipsychotics on dopamine D2 receptors were investigated in nine subjects meeting DSM-IV criteria for schizophrenia who were deemed eligible for temporary treatment washout. Subjects had been treated with traditional antipsychotics (haloperidol n=3, perphenazine n=1) and novel antipsychotics (risperidone n=3, olanzapine n=2) in the moderate to high dosage range. Fourteen days after treatment withdrawal, the binding potentials (BPs) of dopamine D2 receptors were measured using 11[C] raclopride. The obtained BPs were compared to the BPs from antipsychotic-naive control subjects with schizophrenia. RESULTS: There was a significant increase in the D2 BP in both groups combined that reached 34%. The increases in the D2 BPs in the groups treated with conventional and novel antipsychotics were 37% and 31%, respectively. Significantly, the patients showing the highest degree of D2 receptor upregulation (98%) developed severe and persistent TD shortly after being started on a new antipsychotic with low affinity for D2 receptors. CONCLUSION: This study demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D2 receptor binding is increased after long-term treatment with antipsychotics in humans. The data suggest that both traditional and novel antipsychotics with high affinity for dopamine D2 receptors are associated with a substantial increase in D2 receptor binding. The present data in humans agree well with animal data that implicate D2 receptor-mediated mechanisms in motor hyperactivity.

Adult↗

PubMed2000

Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB.

Two novel radioligands, N,N-dimethyl-2-(2-amino-4-methoxyphenylthio) b enzylamine (DAPP) and (N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (D ASB), were radiolabeled with carbon-11 and evaluated as in vivo probes of the serotonin transporter (SERT) using positron emission tomography (PET). Both compounds are highly selective, with nanomolar affinity for the serotonin transporter and micromolar affinity for the dopamine and norepinephrine transporters. Six volunteers were imaged twice, once with each of the two radioligands. Both ligands displayed very good brain penetration and selective retention in regions rich in serotonin reuptake sites. Both had similar brain uptake and kinetics, but the cyano analogue, [11C]DASB, had a slightly higher brain penetration in all subjects. Plasma analysis revealed that both radiotracers were rapidly metabolized to give mainly hydrophilic species as determined by reverse-phase high-performance liquid chromatography. Inhibition of specific binding to the SERT was demonstrated in three additional subjects imaged with [11C]DASB following an oral dose of the selective serotonin reuptake blocker citalopram. These preliminary studies indicate that both these substituted phenylthiobenzylamines have highly suitable characteristics for probing the serotonin reuptake system with PET in humans.

Adult↗

PubMed2000

Neural correlates of semantic associative encoding in episodic memory.

Associations between individual items are the basic building blocks of learning and memory. Functional neuroimaging has now made it possible to study neural correlates of such associations. The present PET study examined three associative encoding conditions differing in the number of words (0, 1, or 2) semantically related to a third word representing the name of a semantic category. A recall task consisting in the presentation of the category names as cues for retrieving the other two members of the triads followed each encoding condition. As expected, retrieval performance increased as the number of semantic exemplars at encoding increased (10%, 43%, 70% items recalled, respectively). A first analysis (partial least squares, PLS) of the PET data identified task-related patterns of activity for associative encoding and cued-recall tasks. A second analysis identified brain regions whose activity was modulated by the number of semantic exemplars at encoding. Some of the task-related brain regions also showed modulated activity by semantic relatedness and consisted in the left inferior prefrontal cortex, right medial temporal lobe, fusiform gyrus and inferior temporal gyrus bilaterally. Some of these regions showed greater activity when words in a triad were unrelated, whereas others did so when the three words were semantically related. These regions have been consistently reported in previous functional neuroimaging studies of associative encoding and may constitute key structures in association formation.

Adult↗

PubMed2000

Imaging the 5-HT(1A) receptors with PET: WAY-100635 and analogues.

This paper summarizes our work on WAY-100635 and analogues, labeled either with carbon-11 or fluorine-18, as potential radioligands for the 5-hydroxytryptamine(1A) (5-HT(1A)) neuroreceptors. Other facets of our work include: (1) human studies with [O-methyl-(11)C]WAY-100634, the major radioactive metabolite of [O-methyl-(11)C]WAY-100635, and with [(11)C]CPC 222; (2) use of a human liver metabolism model to screen in vitro potential metabolic problems in humans; (3) modification of the "dry method" to prepare [carbonyl-(11)C]WAY-100635; and (4) validation studies in humans with [carbonyl-(11)C]WAY-100635.

Animals↗

PubMed2000

Radiotracer synthesis from [(11)C]-iodomethane: a remarkably simple captive solvent method.

A new method of [(11)C]-methylation is described, which attains the goals of simplicity, high radiochemical yields, speed, versatility, and automation. A standard high performance liquid chromatography (HPLC) injection loop on a standard HPLC injection valve is loaded with a solution (80 microL) of precursor (0.3-1.0 mg) in dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) (+ base if required). At ambient temperature [(11)C]-iodomethane is passed through the loop for 3-4 min with >90% trapping of activity. After a further 1-5 min, the contents of the loop are quantitatively injected onto the HPLC column for purification. Radiochemical yields are equal to or superior to conventional solution methods in all cases, even though no heat is applied. [(11)C]-labeled radiotracers that have been prepared by this method for human or animal studies include Raclopride, N-methylspiperone, Ro 15-1788, FLB 457, RTI-32, Rolipram, SCH 23390, and SKF 82957. Since no vials, transfer lines, cooling, heating, or sealing valves are required, no transfer losses occur, yields are high, and cleanup is minimal, this "loop method" is ideal for most radiopharmaceuticals prepared from [(11)C]-iodomethane.

Antipsychotic Agents↗

PubMed2000

Non-competitive pharmacological antagonism at the rabbit B(1) receptor.

The B(1) receptor for kinins, stimulated by kinin metabolites without the C-terminal Arg residue (e.g., des-Arg(9)-bradykinin (BK) and Lys-des-Arg(9)-BK), is an increasingly recognized molecular target for the development of analgesic and anti-inflammatory drugs. Recently developed antagonists of this receptor were compared to a conventional antagonist, Ac-Lys-[Leu(8)]-des-Arg(9)-BK, in pharmacological assays based on the rabbit B(1) receptor. B-9858 (Lys-Lys-[Hyp(3), Igl(5), D-Igl(7), Oic(8)]des-Arg(9)-BK) and three other analogues possessing the alpha-2-indanylglycine(5) (Igl(5)) residue (order of potency B-9858 approximately B-10146>B-10148>B-10050) were partially insurmountable antagonists of des-Arg(9)-BK in the contractility assay based on rabbit aortic rings. B-9858-induced depression of the maximal effect was more pronounced in tissues treated with the protein synthesis inhibitor cycloheximide to block the spontaneous increase of response attributed to the post-isolation formation of B(1) receptors, and only partly reversible on washing. By comparison, Ac-Lys-[Leu(8)]des-Arg(9)-BK was a surmountable antagonist (pA(2) 7. 5), even in cycloheximide-treated tissues. B-9958 (Lys-[Hyp(3), CpG(5), D-Tic(7), CpG(8)]des-Arg(9)-BK) was also surmountable (pA(2) 8.5). The binding of [(3)H]-Lys-des-Arg(9)-BK to recombinant rabbit B(1) receptors expressed in COS-1 cells was influenced by two of the antagonists: while Ac-Lys-[Leu(8)]des-Arg(9)-BK competed for the radioligand binding without affecting the B(max), B-9858 decreased the B(max) in a time-dependent and washout-resistant manner. B-9858 and analogues possessing Igl(5) are the first reported non-competitive, non-equilibrium antagonists of the kinin B(1) receptor.

Animals↗

PubMed2000

Antagonist-induced intracellular sequestration of rabbit bradykinin B(2) receptor.

In a contractility assay based on the rabbit jugular vein, the structurally related drugs NPC 17731 or icatibant (1 to 3 nmol/L) were insurmountable antagonists of bradykinin (BK) B(2) receptors (B(2)Rs). After ample washing (3 hours), the antagonism exerted by these peptides was not reversible. By contrast, the antagonist LF 16. 0687 (30 to 100 nmol/L) was competitive and reversible. A rabbit B(2)R-green fluorescent protein (B(2)R-GFP) conjugate was expressed in mammalian cells. In COS-1 cells, it exhibited an affinity for [3H]BK (K(D)=1.61 nmol/L) similar to that of the wild-type rabbit B(2)R. The stably expressed construction in HEK-293 cells was functionally active (phospholipase A(2) assay), and the antagonists mentioned above retained their respective surmountable or insurmountable behavior. Competition of [(3)H]BK binding to B(2)R-GFP by the antagonists or BK was largely reversible after a 3-hour washout period at 0 degrees C; at 37 degrees C, icatibant or NPC 17731 effects were not reversible. B(2)R-GFP was visualized in the plasma membranes of HEK-293 cells and rapidly internalized in response to BK. NPC 17731 or icatibant slowly translocated B(2)R-GFP into cells over 24 hours, whereas LF 16.0687 had no effect on the subcellular distribution of B(2)R-GFP. Cell extract immunoblotting with anti-GFP antibodies revealed a 101- to 105-kDa protein that was not significantly degraded on 24 hours of cell treatment with any of the ligands but was translocated in part to the 15 000-g pellet of the extract on treatment with BK or the noncompetitive antagonists. NPC 17731 and icatibant are noncompetitive, nonequilibrium antagonists that promote the cellular sequestration of rabbit B(2)R expressed in an heterologous system.

Animals↗

PubMed2000

Large scale neurocognitive networks underlying episodic memory.

Large-scale networks of brain regions are believed to mediate cognitive processes, including episodic memory. Analyses of regional differences in brain activity, measured by functional neuroimaging, have begun to identify putative components of these networks. To more fully characterize neurocognitive networks, however, it is necessary to use analytical methods that quantify neural network interactions. Here, we used positron emission tomography (PET) to measure brain activity during initial encoding and subsequent recognition of sentences and pictures. For each type of material, three recognition conditions were included which varied with respect to target density (0%, 50%, 100%). Analysis of large-scale activity patterns identified a collection of foci whose activity distinguished the processing of sentences vs. pictures. A second pattern, which showed strong prefrontal cortex involvement, distinguished the type of cognitive process (encoding or retrieval). For both pictures and sentences, the manipulation of target density was associated with minor activation changes. Instead, it was found to relate to systematic changes of functional connections between material-specific regions and several other brain regions, including medial temporal, right prefrontal and parietal regions. These findings provide evidence for large-scale neural interactions between material-specific and process-specific neural substrates of episodic encoding and retrieval.

Adult↗