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Biomedical subjects

M Daoust

Publications and source records attributed to M Daoust.

At least 19 recordsLinked to original sources
PubMed2006

Early chronic ethanol exposure in rats disturbs respiratory network activity and increases sensitivity to ethanol.

Chronic ethanol exposure during the fetal period alters spontaneous neuronal discharge, excitatory and inhibitory amino acid neurotransmission and neuronal sensitivity to ethanol in the adult brain. However, nothing is known about the effects of such exposure on the central respiratory rhythmic network, which is highly dependent on ethanol-sensitive amino acid neurotransmission. In 3- to 4-week-old rats, we investigated (1) the effects of chronic ethanol exposure (10% v/v as only source of fluid) during gestation and lactation on phrenic (Phr) and hypoglossal (XII) nerve activity using an in situ preparation and on spontaneous breathing at rest in unanaesthetized animals using plethysmography; (2) the sensitivity of the respiratory system to ethanol re-exposure in situ; and (3) the phrenic nerve response to muscimol, a GABA(A) receptor agonist, applied systemically in an in situ preparation. In control rats, ethanol (10-80 mm) induced a concentration-dependent decrease in the amplitude of both XII and Phr motor outflows. At 80 mm ethanol, the amplitude of the activity of the two nerves displayed a difference in sensitivity to ethanol and respiratory frequency increased as a result of shortening of postinspiratory duration period. After chronic ethanol exposure, respiratory frequency was significantly reduced by 43% in situ and by 23% in unanaesthetized animals, as a result of a selective increase in expiratory duration. During Phr burst, the ramp was steeper, revealing modification of inspiratory patterning. Interestingly that re-exposure to ethanol in situ elicited a dramatic inhibitory effect. At 80 mm, ethanol abolished rhythmic XII nerve outflow in all cases and Phr nerve outflow in only 50% of cases. Furthermore, administration of 50 microm muscimol abolished Phr nerve activity in all control rats, but only in 50% of ethanol-exposed animals. Our results demonstrate that chronic ethanol exposure at an early stage of brain development depresses breathing in juvenile rats, and sensitizes the respiratory network to re-exposure to ethanol, which does not seem to involve GABAergic neurotransmission.

Animals↗
PubMed2001

Absence of the adenosine A(2A) receptor or its chronic blockade decrease ethanol withdrawal-induced seizures in mice.

Considering the existing interactions between ethanol and adenosine, the influence of the genetic impairment of the adenosine A(2A) receptor has been examined upon the seizures occurring at the cessation of chronic ethanol intake or 'ethanol withdrawal' in male mice. Acute clearance of ethanol did not differ between adenosine A(2A) receptor knockout and wild-type mice. Mice were exposed for 10 days to a diet consisting of a milky chocolate drink that contained increasing concentrations (1.8, 3.6 and 6.3% v/v) of ethanol. Adenosine A(2A) receptor knockout mice ingested similar amounts of the fluid, either containing alcohol or not, as did the controls. The severity of handling-induced convulsions during withdrawal was significantly reduced in the adenosine A(2A) receptor knockout mice as compared with their wild-type controls. The selective adenosine A(2A) receptor antagonist ZM 241385 (20 mg/kg) also significantly attenuated the intensity of withdrawal-induced seizures occurring in wild-type male mice when intraperitoneally administered twice daily during the last 5 days of the forced alcohol intake. These results suggest that selective adenosine A(2A) receptor antagonists may be useful in the treatment of alcohol withdrawal.

Administration, Oral↗
PubMed2000

Intracerebroventricular injection of antisense oligos to nNOS decreases rat ethanol intake.

Nitric oxide (NO) has been implicated in alcohol drinking behavior using NO synthase (NOS) inhibitors that are nonselective of the different isoforms of NOS. In the brain, there are two constitutive isoforms of NOS, neuronal NOS (nNOS) and endothelial NOS (eNOS). We used an antisense oligodeoxynucleotide directed against nNOS in ethanol dependent male Wistar rats to examine the specific contribution of nNOS in the control of ethanol intake. Rats were subjected to a free-choice situation water/ethanol (10% v/v) after chronic ethanol intoxication by inhalation of ethanol vapor. During the free-choice situation, rats were twice daily for 4 days intracerebroventricularly injected with either saline, or end-capped phosphorothioate-protected antisense or mismatch oligodeoxynucleotide (25 microg/4 microl per injection), or acamprosate (1 mg/kg body weight) as reference product for its anticraving properties. Our results showed that the antisense treatment, but not the mismatch treatment, reduced both ethanol intake and ethanol preference during treatment and posttreatment periods (by 25-30%) without alteration of the body weight gain. The antisense treatment, but not the mismatch treatment, also down-regulated nNOS mRNA levels (by 30%) and NOS activity in the hippocampus. The anticraving drug, acamprosate reduced both ethanol intake (by 58%) and ethanol preference. All these results suggest that nNOS is involved in the regulation of alcohol dependence.

Alcohol Drinking↗
PubMed2000

A novel indication for transvenous lead extraction: upgrading implantable cardioverter defibrillator systems.

UNLABELLED: Technological advances have resulted in the development of dual chamber pacemaker/defibrillator systems with smaller pectoral 'active cans'. Patients now have the option of upgrading from abdominal to pectoral or from single to dual chamber devices. In addition, due to the potential complications which may arise with abandoned ICD leads, extraction of preexisting leads may be preferable. METHODS AND RESULTS: Twenty consecutive patients (11 males), underwent lead extraction and upgrade, either from an abdominal to a pectoral, or from a single to a dual chamber device. The mean age was 62+/-18 years and mean implant duration was 50+/-14 months. Indications for extraction included lead fracture/malfunction (13), ERI/EOL (2), new SVT/VT (2), long charge times (2), and impending erosion (1). An initial attempt was made to remove the lead with gentle traction. If excessive scar tissue prohibited extraction, then a laser sheath was employed. Reimplantation proceeded following standard protocol. Clinical success was achieved in all patients. Eleven of thirty leads were removed with traction. The remaining 19 leads required removal with the laser sheath. All ICD reimplants were placed in the left pectoral position, of which 10 were dual chamber. The mean defibrillation threshold was 9.5+/-5.8 Joules. There were no procedure related perforations or deaths. At follow up (13+/-10 mos. ) there were no infections, lead malfunctions or venous thromboses. There were two deaths, both from intractable heart failure. CONCLUSIONS: This study demonstrates that, when indicated, ICD leads can be safely extracted and systems successfully upgraded to take advantage of new technology.

Abdomen↗
PubMed1999

Murine Pkd1 is a developmentally regulated gene from morula to adulthood: role in tissue condensation and patterning.

PKD1 is the most common genetically mutated gene involved in autosomal dominant polycystic kidney disease (ADPKD). Our previous studies have shown that the pathogenesis of human and murine polycystic kidney disease (PKD) involves failure to switch out of a renal developmental program, suggesting a role for PKD1 in development. To investigate this hypothesis, we have cloned a portion of the murine Pkd1 gene and characterized the fetal to adult tissue expression pattern of Pkd1. We chose to clone the transmembrane region of Pkd1, a region prone to mutations in ADPKD. The transmembrane coding region (2.6 kb) has 80.3% nucleotide homology with human PKD1 and 85.3% amino acid similarity. The cloned murine Pkd1 fragment closely resembles that of human PKD1 with respect to both genomic size and exon/intron position. We have demonstrated that this Pkd1 region is not conserved in lower organisms and is mammalian specific. A detailed expression analysis of Pkd1 revealed expression as early as the morula stage and in ES cells with differential expression levels in various tissues/organs throughout development. Highest expression levels were observed in the early condensing mesenchyme of primitive mesoderm and ectoderm. Pkd1 was also expressed at high levels in developing neural tube, neural crest derivatives, prechondrogenic tissue, metanephros, bladder, salivary glands, lung, and blood vessels with lower expression levels in other organs and tissues. Specific spatial and temporal patterns of Pkd1 expression were demonstrated in individual organs, such as lung, kidney, brain, indicating it is highly developmentally regulated. Particularly high levels persisted in mature derivatives of neural tube, neural crest, chondrogenic tissue, metanephros, and lung. In summary, our data suggest that Pkd1 has at least two cellular functions, one a basic function involved in early tissue condensation processes, and the other a mammalian-specific function, that evolved with tissue patterning and tubulogenesis in metanephric and pulmonary development.

Animals↗
PubMed1999

Does the short variant of the serotonin transporter linked polymorphic region constitute a marker of alcohol dependence?

The serotonin (5-hydroxytryptamine: 5-HT) system has been thought to play an important role in several steps of alcohol craving. A number of studies, including our own, have reported that alcohol dependence is associated with dysfunction of 5-HT transmission. Pharmacological and clinical studies have shown that the 5-HT transporter (5-HTT) and the 5-HT1A receptor appear to be candidate loci for the aetiology of alcohol dependence. We have analysed the presence of different 5-HTT and 5-HT1A variants in 104 alcohol-dependent patients and 38 controls for a possible association with alcohol dependence. In alcohol-dependent patients, we found a high frequency of the S allele of 5-HTTLPR (45.5% vs. 29%, chi2 = 6.33, p = 0.0081). No other significant differences were observed between the two populations for other polymorphisms. These results provide, for the first time, preliminary evidence that alcohol abuse disorders are associated with a genetic variant for 5-HT transmission. It might be possible to use this detection of the "S" allele as a clinical tool for pathology diagnosis and to advise recovering alcoholics and it could represent an aid to the prevention of relapse. Therapeutic actions could be envisaged to use this genotyping to help select the best therapeutic strategy.

Adult↗
PubMed1998

Pre-exposure to alcohol does not sensitize to the rewarding effects of cocaine.

The conditioned place preference (CPP) induced by cocaine 2.5 mg/kg was measured in rats pre-exposed to ethanol (14 days with only 10% v/v ethanol followed by a free choice between ethanol solution and water for 14 days). Rats were divided according to their alcohol intake during the free choice period into low-drinking (<3 g/kg per day), intermediate-drinking and high-drinking (> 4 g/kg per day) rats. Cocaine-induced CPP was not modified in high-drinking rats relative to controls. Low-drinking rats had a lower CPP than high-drinking rats and controls. We conclude that pre-exposure to alcohol did not sensitize to the cocaine rewarding effects, and that alcohol low-drinking rats showed the lowest preference for cocaine.

Alcohol Drinking↗
PubMed1998

Cyamemazine decreases ethanol intake in rats and convulsions during ethanol withdrawal syndrome in mice.

The effect of cyamemazine a dopamine D2 receptor antagonist on voluntary ethanol consumption in rats and on ethanol withdrawal in mice was examined. Male Sprague-Dawley rats were tested in a free choice (water and 10% ethanol) experiment and consumed 5 g/kg ethanol daily. Rats were treated daily IP with cyamemazine (0.5, 1, or 2 mg/kg) or acamprosate (100 mg/kg) during 2 weeks. Both acamprosate and 1 mg/kg cyamemazine significantly decreased ethanol intake by 45% without affecting either fluid or food intake. The lowest dose of cyamemazine had no effect on alcohol intake but increased food intake. The highest dose had no effect on any variables. During the post-treatment period, only 1 mg/kg cyamemazine decreased both ethanol and fluid intakes. Mice were made dependent on alcohol using a chocolate fluid diet containing increasing concentrations of alcohol and withdrawn after 9 days. Mice were treated with cyamemazine (1 or 0.5 mg/kg, respectively) or with the same doses of lorazepam acutely on the day of withdrawal or chronically (during alcohol treatment). Both chronic and acute cyamemazine and lorazepam treatments decreased convulsions during ethanol withdrawal. Both acute treatments decreased locomotor activity in control and alcohol dependent mice. Chronic treatment had no effect on locomotor activity. We suggest that cyamemazine could reduce alcohol consumption by antagonizing the activation of the dopaminergic pathways during the induction of alcohol dependence. The action of cyamemazine on 5-HT3 receptors could also explain its effect on alcohol convulsions during withdrawal convulsions.

Alcohol Deterrents↗
PubMed1998

Mechanism of action of acamprosate. Part I. Characterization of spermidine-sensitive acamprosate binding site in rat brain.

It has been suggested that the anticraving drug, acamprosate, acts via the glutamatergic system, but the exact mechanism of action is still unknown. The aim of this study was to characterize [3H]acamprosate binding and establish whether this showed any relation to sites on the NMDA receptor complex. We found saturable specific binding of [3H]acamprosate to rat brain membranes with a KD of 120 microM and a Bmax of 450 pmol/mg of protein. This acamprosate binding site was sensitive to inhibition by spermidine (IC50: 13.32 +/- 1.1 microM; Hill coefficient = 1.04), and arcaine and glutamate both potentiated the inhibitory effect of spermidine. Acamprosate binding to the acamprosate binding site was also sensitive to inhibition by divalent cations (Ca2+, Mg2+, and Sr2+). Conversely, acamprosate displaced [14C]spermidine binding from rat brain membranes with an IC50 of 645 microM and a Hill coefficient = 1.74. This inhibitory effect of acamprosate was not affected by arcaine, and was associated with a significant reduction in Bmax and binding affinity for spermidine, suggesting an allosteric interaction between acamprosate and a spermidine binding site. These data are consistent with an effect of acamprosate on the NMDA receptor protein complex, and acamprosate was also found to alter binding of [3H]dizocilpine to rat brain membranes. When no agonists were present in vitro (minimal NMDA receptor activation), acamprosate markedly potentiated [3H]dizocilpine binding at concentrations in the 5 to 200 microM range. However, under conditions of maximal receptor activation (100 microM glutamate, 30 microM glycine), acamprosate only inhibited [3H]dizocilpine binding (at concentrations concentrations >100 microM). When these binding studies were performed in the presence of 1 microM spermidine, the enhancing effects of acamprosate on [3H]dizocilpine binding were inhibited. The results show that acamprosate binds to a specific spermidine-sensitive site that modulates the NMDA receptor in a complex way. Together, with data from al Quatari et al. (see next paper), this work suggests that acamprosate acts as "partial co-agonist" at the NMDA receptor, so that low concentrations enhance activation when receptor activity is low, whereas higher concentrations are inhibitory to high levels of receptor activation. This may be relevant to the clinical effects of acamprosate in alcohol-dependent patients during abstinence.

Acamprosate↗
PubMed1997

An integrated genetic and physical map of the autosomal recessive polycystic kidney disease region.

Autosomal recessive polycystic kidney disease is one of the most common hereditary renal cystic diseases in children. Genetic studies have recently assigned the only known locus for this disorder, PKHD1, to chromosome 6p21-p12. We have generated a YAC contig that spans approximately 5 cM of this region, defined by the markers D6S1253-D6S295, and have mapped 43 sequence-tagged sites (STS) within this interval. This set includes 20 novel STSs, which define 12 unique positions in the region, and three ESTs. A minimal set of two YACs spans the segment D6S465-D6S466, which contains PKHD1, and estimates of their sizes based on information in public databases suggest that the size of the critical region is < 3.1 Mb. Twenty-eight STSs map to this interval, giving an average STS density of < 1/150 kb. These resources will be useful for establishing a complete transcription map of the PKHD1 region.

Base Sequence↗
PubMed1997

Experimental findings in the study of the reduction of alcohol intake.

Alcohol dependence represents a major problem in public health and different animal models of dependence have been developed in rodents with the aim of studying the mechanisms of alcohol abuse. Different ways of animal alcoholisation have been established. They permit a better understanding of which neurotransmitter system is involved in the regulation of alcohol dependence. Considerable attention has been given to the role of serotonin in the control of both alcohol craving and alcohol related pathologies, i.e. anxiety, aggression or memory loss. In conclusion, the use of animal models of alcohol abuse facilitates the understanding of alcohol behavior and permits the development of new therapeutic agents.

Alcohol Deterrents↗
PubMed1996

Ethanol potentiates lipopolysaccharide- or interleukin-1 beta-induced nitric oxide generation in RBE4 cells.

Our present study investigated the effects of ethanol treatment on inducible nitric oxide (NO) synthase pathway from lipopolysaccharide- or interleukin-1 beta-treated cultured rat blood-brain barrier cell line (rat brain endothelial 4 cells: RBE4 cells). Cells were lipopolysaccharide- or interleukin-1 beta-treated with or without ethanol (50, 100 or 200 mM) for 16 or 24 h. Inducible NO synthase activity and mRNA expression were measured using Griess reaction and reverse transcription-polymerase chain reaction (RT-PCR) respectively. In the absence of lipopolysaccharide or interleukin-1 beta, ethanol treatments failed to stimulate inducible NO synthase gene expression. Lipopolysaccharide or interleukin-1 beta increased nitrite production and inducible NO synthase mRNA levels, and ethanol potentiated this effect. We concluded that ethanol could aggravate the consequences of NO generation by RBE4 cells after inducible NO synthase induction following inflammation or sepsis. This ethanol action on NO generation could contribute to circulatory failure associated with shock due to sepsis or hemorrhage, and alter blood-brain barrier permeability.

Animals↗
PubMed1993

Platelets 3H 5-HT uptake in descendants from alcoholic patients: a potential risk factor for alcohol dependence?

We studied platelet 3H-serotonin uptake in 32 former alcoholics, withdrawn for from 1 month to 22 years, in their descendants (21.7 +/- 1.6 years old, n = 17; 10.9 +/- 0.7 years old; n = 19), and in respective control groups, paired in age and sex. All of the alcoholics presented high 3H-serotonin uptake (Vmax = 10.88 +/- 4.23 pmoles/10(8)pl/30 sec., vs. 0.93 +/- 0.15 pmole/10(8)pl/30 sec. Their descendants also showed high platelet serotonin uptake: 3.94 +/- 1.44 pmoles/10(8)pl/30 sec., vs. 0.93 +/- 0.15 pmoles/10(8)pl/30 sec. for adult descendants, and 5.99 +/- 2.23 vs. 0.84 +/- 0.15 pmole/10(8)pl/30 sec. for young descendants. All subjects were free of alcoholisation (biological parameters studied were blood ethanol concentration, gamma glutamyl transferase and mean corpuscular volume), and dependence of former alcoholics was evaluate by using, a posteriori, the CAGE test. In descendants, 28% of the subjects have Vmax values higher than the highest of the control group. Alcohol, in vitro, (54 mM) did not affect serotonin uptake in any group. These results indicate that in descendants of alcoholics, platelet serotonin uptake is altered, without modification of sensitivity to ethanol. The genetic basis of alcohol dependence could be linked with the platelet serotonin transport.

Adolescent↗
PubMed1993

Serotonin in animal models of alcoholism.

Ethanol naive alcohol preferring rodents have low serotonin transmission. Both pharmacological, biochemical and behavioral studies show that increased serotonin transmission influence reduces ethanol consumption in animals. This paper develops the role of serotonin in different lines of ethanol preferring rats and mice, and shows a regulation of 5-HT1A receptors in alcoholised dependent mice. Different sensitivities to ethanol observed between ethanol-preferring and non-preferring rats or mice seems to be at the root of the maintenance of alcohol intake.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Acamprosate modulates synaptosomal GABA transmission in chronically alcoholised rats.

Male Sprague-Dawley rats were pulmonary alcoholised for 30 days. Six were treated with acamprosate (400 mg/kg/day, PO) during alcoholisation. The control nonalcoholised group also received acamprosate (400 mg/kg/day, PO) during the 30 days. At the end of the experiment, brains areas (cortex, hippocampus, thalamus, striatum, and olfactory bulbs) were dissected for the study of synaptosomal 3H-GABA uptake. In another experiment, GABA levels were determined in the same areas using HPLC with electrochemical detection. Blood ethanol levels were also measured during alcoholisation. Acamprosate treatment did not modify blood ethanol levels. In cortex and olfactory bulbs, alcoholisation increased 3H-GABA uptake (Vmax) with an increase in the affinity (Km). 3H-GABA uptake was not affected by alcoholisation in other brain areas. In hippocampus and thalamus, acamprosate treatment enhanced 3H-GABA uptake (Vmax) only in alcoholised rats. Moreover, in thalamus, alcoholisation enhanced GABA levels. The effect of alcohol and acamprosate on GABA presynaptic events is discussed and it is concluded that the action of ethanol and acamprosate on GABA transport could be, in part, responsible for the modulation by acamprosate treatment of ethanol behaviour.

Acamprosate↗
PubMed1992

Triptosine, an L-5-hydroxytryptophan derivative, reduces alcohol consumption in alcohol-preferring rats.

Triptosine is a new L-5-hydroxytryptophan derivative whose effect has been studied in the Long-Evans alcohol-preferring rat. At an oral dose of 100 mg/kg once daily, triptosine reduced alcohol consumption by 42% in the second week of treatment and increased that of water by 80%. The results suggest that this precursor of serotonin might play an important role in diminishing preference for alcohol and reaccustoming the animal to water, without exerting an anorexic effect.

5-Hydroxytryptophan↗
PubMed1992

Tianeptine, a specific serotonin uptake enhancer, decreases ethanol intake in rats.

The effect on ethanol intake of the selective 5-HT uptake enhancer tianeptine was examined in rats and compared with that of fluoxetine, a specific 5-HT uptake inhibitor. Both treatments significantly decreased ethanol intake (54% by tianeptine and 57% by fluoxetine). Fluoxetine also decreased food intake whereas tianeptine did not. Body weight was decreased by 12.5% in fluoxetine-treated rats but was not modified by tianeptine. It is proposed that tianeptine has a specific action on ethanol intake, possibly related to its effect on serotonin function.

Alcohol Drinking↗