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D Lévesque

Publications and source records attributed to D Lévesque.

At least 19 recordsLinked to original sources
PubMed2003

Calcium-dependent, D2 receptor-independent induction of c-fos by haloperidol in dopamine neurons.

Antipsychotic drugs such as haloperidol act as dopamine D2 receptor antagonists to produce a number of cellular effects including the induction of immediate-early genes such as c-fos. It has been hypothesized that blockade of D2 receptors by antipsychotics is responsible for the induction of c-fos, but the mechanism has not been determined. Using cultured ventral tegmental area (VTA) dopaminergic neurons as a model, we report that nanomolar concentrations of haloperidol cause a time-dependent increase in Fos expression in dopaminergic neurons.Surprisingly, this induction was not mimicked by sulpiride, a selective D2 receptor antagonist, and was not blocked by Rp-cAMPS, an antagonist of protein kinase A (PKA), thus suggesting that D2 receptors and the cAMP cascade are not required. The induction of Fos expression was blocked by tetrodotoxin, BAPTA and KN-93, thus showing that it is activity- and calcium-dependent and requires the activation of a calmodulin-dependent kinase (CaMK). Together, these results suggest that haloperidol induces Fos expression in dopaminergic neurons through a D2 receptor-independent increase in intracellular calcium, leading to CaMK activation.

Animals↗
PubMed2002

Effects of cocaine on c-fos and NGFI-B mRNA expression in transgenic mice underexpressing glucocorticoid receptors.

Numerous evidences suggest that stress and stress-related hormones can modulate the activity of the brain reward pathway and thus may account for individual vulnerability towards the reinforcing effects of drugs of abuse. Transgenic (TG) mice expressing an antisense mRNA against the glucocorticoid receptor (GR), which partially blocks GR expression, were used to assess the role of GR dysfunction on cocaine (COC)-induced c-fos and Nerve-Growth Factor Inducible-B (NGFI-B, or Nur77) gene expression. These two genes belong to different families of transcription factors and have been shown to be modulated by various dopaminergic drugs. TG and wild-type (WT) mice were both acutely and repeatedly treated with COC (20 mg/kg, i.p.). In the chronic experiment, mice received a 5-day treatment of COC and were challenged 5 days later with COC or vehicle. Locomotor activity was assessed during the entire chronic experiment in the mouse home cages. Animals were sacrificed 1 h after the last injection and NGFI-B and c-fos mRNA levels in the prefrontal cortex, the nucleus accumbens and the striatum were measured by in situ hybridization. Acute COC administration led to significantly smaller c-fos increases in TG mice compared to WT, whereas repeated COC treatment potentiated c-fos induction both in TG and WT mice to equivalent levels. TG mice displayed higher basal NGFI-B expression in the nucleus accumbens and the level of NGFI-B mRNA was differently modulated by COC in TG mice compared to WT mice. In accordance with data on c-fos expression, behavioral data indicate a blunted locomotor effect on the first COC injection in TG mice, a phenomenon corrected by the repeated COC treatment. These results suggest that an alteration of the hypothalamus-pituitary-adrenal axis can modify COC-induced regulation of the transcription factors c-fos and NGFI-B, and that these changes parallel those seen at the behavioral level. It also demonstrates that the differences at the behavioral and molecular levels noted between TG and WT mice after acute COC injection disappear following repeated COC administration, suggesting that repeated COC has a greater impact in TG mice underexpressing GRs.

Animals↗
PubMed2002

On-line measurement of texture, thickness and plastic strain ratio using laser-ultrasound resonance spectroscopy.

Laser-ultrasound resonance spectroscopy, a non-contact ultrasonic technique, was used to determine reliably and rapidly the crystallographic texture, the average plastic strain ratio, and the thickness of sheet metal on the production line. As with laser-ultrasonics, a short laser pulse is used to generate a wide-band pulse of ultrasound and a laser interferometer is used for its detection. In this paper, a large number of echoes are collected and analyzed together using Fourier techniques to measure the natural resonance frequencies in the thickness of the sheet. One longitudinal and two shear resonance frequencies were measured together with their harmonics. From these frequencies, two crystallographic orientation distribution coefficients, W(400) and W(420), are obtained, as well as a highly accurate measurement of the sheet thickness that is corrected for changes in ultrasonic velocity caused by texture variations. Using these coefficients, the average and in-plane twofold and fourfold variations of the plastic strain ratio, respectively r delta(2)r, and delta(4)r, can be evaluated. These parameters are indications of the formability of metals sheets, which is of industrial interest. Measurements on 1 mm thick, low carbon steel sheets have shown the following measurement accuracies: r to within +/-0.08, delta(2)r, and delta(4)r to within +/-0.1, and thickness to better than +/-1 microm. On-line tests at LTV Steel Company showed that the sensitivity of the apparatus is sufficient to detect systematic variations in texture along the length of similar production coils and that the on-line repeatability for r was of order +/-0.02.

Journal Article↗
PubMed2002

Performance of laser-ultrasonic F-SAFT imaging.

The resolution and signal-to-noise ratio of laser-ultrasonics to detect small and buried defects can be greatly enhanced by using the synthetic aperture focusing technique (SAFT). Originally developed in the time domain, SAFT can also be implemented in the frequency domain (F-SAFT) using the angular spectrum approach for a significant reduction in processing time. In this paper, an F-SAFT based data processing method especially adapted to laser-ultrasonic data is presented. This method allows for further significant improvements towards laser-ultrasonic imaging of small defects. It includes temporal deconvolution of the waveform data, control for an optimal aperture and frequency bandwidth as well as spatial interpolation of the subsurface images. All the above operations are well adapted to the frequency domain calculations and embedded in the F-SAFT data processing. Also, the aperture control and spatial interpolation allow a reduction of sampling requirements to further decrease both inspection and processing times. The above improvements are illustrated using laser-ultrasonic data taken from an aluminum sample with flat-bottom holes.

Journal Article↗
PubMed2001

Autoreceptor preference of dopamine D2 receptor agonists correlates with preferential coupling to cyclic AMP.

Dopamine autoreceptors control the synaptic release and turnover of dopamine. Some dopamine agonists display a preference for modulation of autoreceptor functions rather than postsynaptic-driven behaviors. However, the nature of this apparent selectivity is still elusive. To investigate this property, we have used an heterologous expression system in which D2S receptors are coupled to both inhibition of cyclic AMP levels and stimulation of inositol triphosphate production. We show that D2-like receptor agonists display distinct potencies on these two second messenger pathways. Moreover, a strong correlation is observed between the potency of agonists to interact with adenylate cyclase and their potency to modulate autoreceptor functions. Such a correlation does not show up with the phospholipase C pathway. This suggests that autoreceptor preference of D2-like receptor agonists may be driven by a preferential interaction with a second messenger system.

Adenylate Cyclase Toxin↗
PubMed2001

Impact of antipsychotic drug administration on the expression of nuclear receptors in the neocortex and striatum of the rat brain.

We have recently shown that the expression of the nerve growth factor-inducible gene B (NGFI-B, or Nur77), a transcription factor belonging to the large ligand-activated nuclear receptor family, is modulated by antipsychotic drugs in the rat forebrain. In the present work, we have investigated the impact of antipsychotic drugs on a series of transcription factors also belonging to the nuclear receptor family. The receptors investigated include retinoid X receptor (RXR), thyroid hormone receptor (TR), retinoic acid receptor (RAR), RAR-related orphan receptor (RZR) and Rev-erb receptor isoforms in addition to the NGFI-B transcript. We have used in situ hybridization to monitor their mRNA levels after acute and chronic antipsychotic drug administration. RZRbeta and NGFI-B mRNA levels are down-regulated after chronic haloperidol or clozapine treatment in the primary somatosensory cortex. The TRbeta1 isoform mainly expressed in the cingulate cortex is modulated only after chronic clozapine treatment, whereas TRalpha isoform mRNAs are modulated by both antipsychotics in the cingulate cortex and nucleus accumbens shell; two brain areas associated with limbic functions. The RXRgamma1 isoform, mostly expressed in the dorsolateral portion of the striatum is modestly affected by antipsychotics. Modulation of the expression of transcription factors belonging to the ligand-activated nuclear receptor family by antipsychotics represents an additional molecular event in the mechanism of action of these drugs. We suggest that modification of the pattern of transcription factor expression may play a role in long-term cellular responses to these drugs.

Animals↗
PubMed2001

Natural 2',5'-phosphodiester bonds found at the ligation sites of peach latent mosaic viroid.

Peach latent mosaic viroid (PLMVd) is a circular RNA pathogen that replicates in a DNA-independent fashion via a rolling circle mechanism. PLMVd has been shown to self-ligate in vitro primarily via the formation of 2',5'-phosphodiester bonds; however, in vivo the occurrence and necessity of this nonenzymatic mechanism are not evident. Here, we unequivocally report the presence of 2', 5'-phosphodiester bonds at the ligation site of circular PLMVd strands isolated from infected peach leaves. These bonds serve to close the linear conformers (i.e., intermediates), yielding circular ones. Furthermore, these bonds are shown to stabilize the replicational circular templates, resulting in a significant advantage in terms of viroid viability. Although the mechanism responsible for the formation of these 2',5'-phosphodiester bonds remains to be elucidated, a hypothesis describing in vivo nonenzymatic self-ligation is proposed. Most significantly, our results clearly show that 2',5'-phosphodiester bonds are still present in nature and that they are of biological importance.

Mosaic Viruses↗
PubMed2000

Sequencing of peach latent mosaic viroid variants from nine North American peach cultivars shows that this RNA folds into a complex secondary structure.

We sequenced 34 new peach latent mosaic viroid (PLMVd) variants isolated from nine different peach cultivars. This study provides the widest view of PLMVd diversity reported to date and includes the original characterization of North American variants, which cannot be differentiated from European sequences. PLMVd appears as a species in which each isolate is a complex mixture of RNAs. Analysis of base-pair covariations supports the hypothesis that PLMVd folds into a complex branched structure with the potential of including three new pseudoknots. The resulting "globular-like" structure is in contrast to the rod-like one adopted by most other viroids.

Base Sequence↗
PubMed2000

Contrasting patterns and cellular specificity of transcriptional regulation of the nuclear receptor nerve growth factor-inducible B by haloperidol and clozapine in the rat forebrain.

This study was designed to investigate the possible involvement of members of the nuclear receptor family of transcription factors in the effects of antipsychotic drugs used in the treatment of schizophrenia. We have identified, using RT-PCR screening, an important modulation of nerve growth factor-inducible B (NGFI-B) mRNA levels by typical and atypical neuroleptics in the rat forebrain. NGFI-B, a member of the nuclear receptor family, can be observed in target structures of dopaminergic pathways. Using in situ hybridization, we also demonstrate that typical and atypical antipsychotics induced contrasting patterns of expression of NGFI-B after both acute and chronic administration. An acute treatment with clozapine or haloperidol induces high NGFI-B mRNA levels in the prefrontal and cingulate cortices and in the nucleus accumbens shell. However, haloperidol, but not clozapine, dramatically increases NGFI-B expression in the dorsolateral striatum. In contrast, chronic treatment with clozapine reduces NGFI-B expression below basal levels in the rat forebrain, whereas haloperidol still induces high NGFI-B mRNA levels in the dorsolateral striatum. Finally, using a double in situ hybridization technique, we show that acute administration of both neuroleptics increases NGFI-B expression in neurotensin-containing neurons in the nucleus accumbens shell, whereas the effects of haloperidol in the dorsolateral striatum are mainly observed in enkephalin-containing neurons. These results are the first demonstration that members of the nuclear receptor family of transcription factors could play an important role in the effects of antipsychotic drugs.

Animals↗
PubMed2000

Mapping in solution shows the peach latent mosaic viroid to possess a new pseudoknot in a complex, branched secondary structure.

We have investigated the secondary structure of peach latent mosaic viroid (PLMVd) in solution, and we present here the first description of the structure of a branched viroid in solution. Different PLMVd transcripts of plus polarity were produced by using the circularly permuted RNA method and the exploitation of RNA internal secondary structure to position the 5' and 3' termini and studied by nuclease mapping and binding shift assays using DNA and RNA oligonucleotides. We show that PLMVd folds into a complex, branched secondary structure. In general, this structure is similar to that reported previously, which was based on sequence comparison and computer modelling. The structural microheterogeneity is apparently limited to only some small domains. More importantly, this structure includes a novel pseudoknot that is conserved in all PLMVd isolates and seems to allow folding into a very compact form. This pseudoknot is also found in chrysanthemum chlorotic mottle viroid, suggesting that it is a unique feature of the viroid members of the PLMVd subgroup.

Base Sequence↗
PubMed1999

Effects of reciprocal chimeras between the C-terminal portion of third intracellular loops of the human dopamine D2 and D3 receptors.

The dopamine D3 receptor is a member of the G protein-coupled superfamily of receptors. However, its coupling with intracellular events is still not well understood. We have performed chimera constructions in which amino acid residues located in a region of the receptor involved in the coupling with second messengers (the C-terminal portion of the third intracellular loop) have been exchanged between dopamine D2 and D3 receptors. Chimera constructions did not modify substantially the pharmacological profiles, nor G protein coupling, as compared to their respective wild-type receptors. However, the D2 receptor chimera, containing the C-terminal portion of the third intracellular loop of the D3 receptor, has a lower potency to inhibit cyclic AMP production. The reciprocal construction generated a D3 receptor that is fully coupled to this second messenger pathway whereas, the native D3 receptor is uncoupled to this pathway in our transfected cells. These results suggest that the sequence selected is important for specific coupling characteristics shown by these two dopamine receptor homologues.

Amino Acid Sequence↗
PubMed1999

Dopamine D3 receptor antisense administration reduces basal c-fos and NGFI-B mRNA levels in the rat forebrain.

The physiological role of the dopamine D3 receptor is still unclear. The absence of selective pharmacological tools that can discriminate D3 over D2 receptor subtype activity is a major drawback in the elucidation of D3-mediated functions. In order to study D3 receptor actions in rat brain, we have developed an antisense strategy, using oligodeoxynucleotide (ODN) directed against the mRNA of the D3 receptor. Dopamine D2-like agents induce a cascade of events that affect numerous genes in the CNS. Transcription factors are among the most dramatically affected. Using the antisense strategy, we explored the involvement of the D3 receptor on the expression of two classes of transcription factors, the c-fos and NGFI-B. Intracerebroventricular injections of ODNs were made into the lateral ventricle (8 microg/hour, for 5 days). The effect of antisense administration on dopamine D1, D2, and D3 receptor binding was measured by means of receptor autoradiography, whereas transcription factor mRNA levels (c-fos and NGFI-B) were evaluated by in situ hybridization using specific complementary RNA probes. Dopamine D3 receptor levels were significantly decreased in the shell of nucleus accumbens of rats that received the D3 antisense ODN, whereas dopamine D1 and D2 receptor levels were not affected. Basal c-fos mRNA levels were concomitantly reduced in both cingulate and medial prefrontal cortices. Basal NGFI-B mRNA levels were also reduced in the cingulate cortex, shell of nucleus accumbens, and in the dorsomedial striatum, whereas the core of nucleus accumbens and the dorsolateral striatum were not affected after D3 antisense ODN treatments. Our results suggest that D3 receptors may tonically regulate transcription factor expression in rat forebrain. This supports the hypothesis of a constitutive activity of the D3 receptor in vivo.

Animals↗
PubMed1998

Architectural DNA-binding properties of the spermatidal transition proteins 1 and 2.

Mammalian spermiogenesis is characterized by replacement of somatic histones by a set of basic nuclear transition proteins thought to be actively involved in the chromatin remodeling process. The two major transition proteins of the elongating spermatids, namely TP1 and TP2, were expressed and purified using a bacterial expression system. Both topoisomerase and ligase-mediated supercoiling assays demonstrated that TP1, as well as TP2, did not produce detectable changes in the twist and/or writhe of DNA molecules upon binding. Ligase-mediated circularization assay further demonstrated that neither of the transition proteins under study produced bends in linear DNA but that they both have the capacity to stimulate oligomerization of linear DNA fragments. We further established that the transition proteins are in vitro substrates for the Ca+2-phospholipid-dependent protein kinase (PKC) as well as the cAMP-dependent protein kinase (PKA). PKC phosphorylation was found to strongly weaken the DNA-condensing ability of TP2. These results suggest that the major transition proteins represent architectural factors able to stabilize DNA in a nonsupercoiled state, thereby promoting DNA condensation.

Amino Acid Sequence↗
PubMed1998

Down-regulation of interleukin-1beta production and PGE2 accumulation by an indomethacin-phenylalanine derivative in human monocytes.

This study was initiated to investigate the mechanism of action of a new indomethacin derivative, indomethacin-phenylalanine (indo-Phe) in human monocytes. We determined the effect of indo-Phe on the induction by LPS of prostaglandin-E2 (PGE2) and interleukin-1beta (IL-1beta) production in human monocytes. Indomethacin and indo-Phe inhibited the PGE2 synthesis in treated and untreated IL-1beta or LPS-treated monocytes. Furthermore, in IL-1beta and LPS-treated monocytes, prostaglandin G/H synthase-1 (PGHS-1) protein expression was down-regulated with indomethacin or its indo-Phe analog whereas the level of the inducible protein (PGHS-2) was up-regulated. We analyzed the effect of indomethacin and indo-Phe on the expression of IL-1beta protein in LPS-treated monocytes and found that indo-Phe blocked the LPS-induction of IL-1beta synthesis while indomethacin did not. These differential effects of indomethacin and indo-Phe suggest that two independent ways are involved in the stimulation of monocytes by LPS: the PGHS-2 protein induction and the IL-1beta secretion.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

The antisense strategy applied to the study of dopamine D3 receptor functions in rat forebrain.

1. The authors have investigated the effects of a dopamine D3 receptor antisense oligodeoxynucleotide (ODN), on neuropeptides (neurotensin and dynorphin) and transcription factor (c-fos) mRNA levels in rat forebrain. 2. Intracerebroventricular injections of ODNs were made into the lateral ventricle (5 and 10 micrograms/h, for 5 days). Effect of antisense administration on dopamine D2 and D3 receptor binding were measured by means of receptor autoradiography. Neuropeptides and c-fos mRNA levels were evaluated by in situ hybridization using specific complementary RNA probes. 3. Dopamine D3 receptor densities were dose-dependently reduced in the shell of nucleus accumbens of rats that received the D3 antisense ODN. Sense and missense controls remained without effect. No significant effect was observed on D2 receptor binding in any of the ODN groups studied, as measured with [3H]raclopride binding. Concomitant reductions of dynorphin and neurotensin mRNA levels were observed in the shell of nucleus accumbens after D3 antisense ODN administration. Interestingly, the D3 antisense administration also reduced c-fos mRNA levels in the cingulate cortex of these animals. 4. The results show that D3 receptors may tonically regulate basal transcription factor, as well as neuropeptides, gene expression in the rat forebrain. These results clearly demonstrate that an antisense strategy could be useful to identify molecular targets under control of specific dopamine receptor subtypes.

Animals↗
PubMed1998

Associative and limbic regions of monkey striatum express high levels of dopamine D3 receptors: effects of MPTP and dopamine agonist replacement therapies.

The role of the dopamine D3 receptor subtype in the central nervous system is still not well understood. It has a distinct and restricted distribution, mostly associated with limbic territories of the striatum (olfactory tubercle and the shell of nucleus accumbens) in rat brain. Dopaminergic denervation induced by a 6-hydroxydopamine lesion of the nigrostriatal system in rat down-regulates the expression of the D3 receptor. In the present study, we investigated the functional neuroanatomy of the dopamine D3 receptor subtype in the monkey (Macaca fascicularis) basal ganglia. We also studied the effect of administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and chronic D1-like (SKF 82958) or D2-like (cabergoline) agonist treatments on dopamine D3 receptor levels using receptor autoradiography. Our results clearly show that the distribution of D3 receptors in the monkey is more closely related to associative and limbic components of the striatum (caudate-putamen), as compared with its sensorimotor counterpart. Hence, D3 receptors may be more specifically involved in cognitive and motivational aspects of striatal functions, which are elaborated in prefrontal, temporal, parietal, cingulate and limbic cortices. Moreover, MPTP administration significantly decreased levels of D3 receptors and this effect was reversed or compensated by a chronic treatment with a D1-like, but not a D2-like, receptor agonist. The D3 receptor may represent an important target for adjunct or direct therapy designed to improve cognitive deficits observed in patients with Parkinson's disease, schizophrenia and other illnesses with frontal lobe cognitive disturbances.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗