Biomedical subjects

M Daoust

Publications and source records attributed to M Daoust.

At least 19 recordsLinked to original sources

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↗

PubMed1991

Ethanol intake and 3H-serotonin uptake I: A study in Fawn-Hooded rats.

Ethanol intake and synaptosomal 3H-serotonin uptake were studied in male Fawn-Hooded and Sprague-Dawley rats. Fawn-Hooded rats consumed more alcohol and more water than Sprague-Dawley rats. Plasma alcohol levels of Sprague-Dawley rats were not detectable but were about 5 mg/dl in Fawn-Hooded rats. Ethanol intake increased the Vmax of serotonin uptake in Fawn-Hooded rats in hippocampus and cortex, but not in thalamus. In Fawn-Hooded rats, serotonin uptake (Vmax) was higher than in Sprague-Dawley rats cortex. Ethanol intake reduced the Vmax of serotonin uptake in Fawn-Hooded rats in hippocampus and cortex. In cortex, the carrier affinity for serotonin was increased in alcoholized Fawn-Hooded rats. These results indicate that synaptosomal 3H-serotonin uptake is affected by ethanol intake. In Fawn-Hooded rats, high ethanol consumption is associated with high serotonin uptake. In rats presenting high serotonin uptake, alcoholisation reduces 3H-serotonin internalisation in synaptosomes, indicating a specific sensitivity to alcohol intake of serotonin uptake system.

Analysis of Variance↗

PubMed1991

Ethanol intake and 3H-serotonin uptake. II: A study in alcoholic patients using platelets 3H-paroxetine binding.

The kinetic parameters of 3H-paroxetine binding and 3H-serotonin uptake were studied in platelets of alcoholic patients. There was no difference between alcoholic and non alcoholic subjects in 3H-paroxetine binding. When binding and 3H-serotonin uptake were studied, in the same plasma of the same subjects, the Vmax of serotonin uptake was increased in alcoholics. The data confirm the involvement of serotonin uptake system in alcohol dependence and suggest that serotonin uptake and paroxetine binding sites may be regulated independently in this pathology.

Adult↗

PubMed1991

[Benzodiazepine receptors during various treatments of alcohol withdrawal].

Drugs most commonly used in the treatment of alcoholic withdrawal are antianxiety agents, namely benzodiazepines. Some similarities may be found between the mechanism of action of such active principles and that of alcohol at the GABAergic transmission level. In mice with physical dependence, in vivo binding of [3H]-RO 15-1788 to central benzodiazepine receptors increases during the initial period, but then tends to taper down to its basal value in the course of withdrawal. Neurochemical treatment with alpha-adrenergic drugs or with agents than can stimulate serotonergic transmission, as opposed to meprobamate therapy, promotes faster recovery of basal levels. In man, these data may be referred to decreased benzodiazepine consumption in the course of alcohol withdrawal. The results suggest that both noradrenergic and serotonergic treatments may be associated with significantly lower risks for newly induced benzodiazepine dependence.

Animals↗

PubMed1991

Comparison of oral bioavailability of two dosage-forms of progesterone in women.

For poorly water soluble drugs, the dissolution process in biological fluids the rate limiting step in absorption. However, the utilization of some galenic processes such as solid dispersions (SD) leads to an improvement in quality and intensity of the drug gastro-intestinal absorption. In a previous work, the in vitro studies of the dissolution curves of both the pure micronized progesterone (MP) and the progesterone-PEG 6000 SD revealed marked increases in the progesterone dissolution rates for all the SD investigated compared to the pure MP. The aim of this work was to investigate the in vitro results after oral administration of the two pharmaceutical forms to menopaused volunteer women.

Administration, Oral↗

PubMed1990

Noradrenergic system: effect of DSP4 and FLA-57 on ethanol intake in ethanol preferring rats.

Ethanol preferring rats (male Long-Evans; n = 6) were selected as drinking rats (DR) and treated with DSP4 (50 mg.kg-1 IP) at the end of the preference selection. Two more groups received DSP4 (50 mg.kg-1 IP) + the inhibitor of dopamine beta-hydroxylase FLA-57 (1 mg.kg-1.d-1 during two weeks), IP (n = 5) or FLA-57 alone (1 mg.kg-1.d-1 during two weeks IP) (n = 5). The control DR group (n = 6) received NaCl 0.9%. 3H-Noradrenaline uptake was studied at the 17th day of treatment in DR, treated or not with DSP4, and in ethanol naive rats treated (n = 6) or not (n = 6) with DSP4 (50 mg.kg-1, IP) DSP4 does not modify ethanol intake in DR, and both treated groups (DR or ethanol naive rats). 3H-Noradrenaline uptake was decreased (about 60%), both in cortex and hippocampus. But the association of FLA-57 and DSP4 decreases both ethanol and fluid intakes. It was suggested 1) that the 40% of intact neurons was able to compensate the DSP4-induced noradrenergic neurons destruction, 2) that the destruction of noradrenergic pathways (FLA-57 + DSP4) is associated with a decrease in ethanol intake but also in fluid intakes, suggesting finally 3) that the modulation of ethanol intake by the noradrenergic system was partial or indirect.

Alcohol Drinking↗

PubMed1990

Acamprosate appears to decrease alcohol intake in weaned alcoholics.

Five hundred and sixty-nine alcoholics were included in a double-blind placebo-controlled randomized multicenter study of the effects of Acamprosate (calcium acetylhomotaurinate (CA), 1.3 g/day) on indicators of alcoholic relapse after withdrawal. One hundred and eighty-one patients in the CA group versus 175 in the placebo group completed the three-month study. The major efficacy criterion was plasma gamma-glutamyl transpeptidase (GGT), as an indicator of recent alcohol ingestion. This analysis was completed by criteria concordance analysis on a number of indicators of alcohol intake. Patients in both groups were similar initially. After 3 months of treatment, the patients in the CA group had significantly lower GGT (1.4 +/- 1.56 versus 2.0 +/- 3.19 times normal, P = 0.016). All significant differences (P less than 0.05) or trends (0.10 greater than P greater than 0.05) were in favor of a superior effect of CA over placebo. The major side-effect of CA was diarrhea (present in 13% of CA patients versus 7% of placebo, P = 0.04). CA proved superior to placebo on the evolution of markers of alcohol ingestion at three months, in this large-scale multicenter study. It could be a new modality in the drug therapy of alcoholism, not involving an antabuse effect, an antidepressant action, or conditioning.

Acamprosate↗

PubMed1990

Alcohol and GABA: ethanol intake modifies hippocampal nipecotic acid binding in ethanol-preferring and non-preferring rats.

3H-nipecotic acid (3H-NIP) binding to GABA uptake recognition sites was studied in the hippocampus of 3 groups of male, Long Evans rats: Group 1: ethanol-naive rats (ENR); Group II: ethanol-preferring rats (DR) and non-preferring rats (NDR), which had consumed about 5 g.kg-1.d-1 and 1 g-1.d-1 of alcohol respectively in the form of a 12% ethanol solution prior to 3H-NIP binding analysis; Group III: DR and NDR who had had no access to ethanol for 21 d after the initial exposure of ethanol solution (28 d). Binding studies showed that ethanol drunk by both DR and NDR in Group II decreased 3H-NIP binding (Bmax decreased) with an enhancement of affinity (KD decreased). In rats subjected to withdrawal of ethanol (Group III), affinity of 3H-NIP for GABA uptake sites was higher than in controls (Group I), but lower than in Group II, Bmax in this group being higher than in the 2 other groups. In Group III, KD was higher in DR than in NDR. These results showed that ethanol intake, in a free-choice paradigm, altered 3H-NIP binding, and that differences in ethanol intake between DR and NDR were associated with differences in sensitivity of hippocampal GABA uptake sites. These differences in 3H-NIP binding could either precede ethanol intake, or be a direct result from it. The results, together with data from other laboratories suggest that: 1), 3H-NIP binding sites are involved in the regulation of ethanol intake; 2), 1 factor responsible for individual differences in ethanol response is reflected by the GABA uptake system.

Animals↗

PubMed1988

Physicochemical, pharmacological and pharmacokinetic study of a new GABAergic compound, calcium acetylhomotaurinate.

It has been shown that calcium acetylhomotaurinate (Ca AOTA; Meram Patent, France) decreased voluntary ethanol intake in rats (1); this was antagonized by bicuculline. Homotaurine did not have this effect. We thought this was due to a different blood-brain barrier crossing ability for the two drugs. The present study was, therefore, planned to confirm blood-barrier crossing by Ca AOTA and to study the drug's physicochemical and pharmacokinetic characteristics. Both in vitro and in vivo (i.p.) administration of Ca AOTA increased the accumulation of [3H] GABA in rat striatal synaptosomal preparations. The chemical study confirmed Ca AOTA's great stability in biological and hydrophilic media, excluding a "homotaurine-dispensing" effect. The molecule was totally dissociated in such media, but the absence of any detectable acid form at any pH indicates that ion pairs are formed to cross barriers, and/or that a carrier system is used. The pharmacokinetic study showed short half-lives (5 and 30 min for the distribution and elimination phases) and small distribution volumes. However, the elimination phase distribution volume was dose-dependent, a further argument for a carrier transport system. From the present study it appears that Ca AOTA is an extremely stable drug, totally dissociated in hydrophilic media, which acts centrally as a GABA agonist after crossing the blood-brain barrier. It is not a precursor of homotaurine and presumably crosses barriers with the help of a transporter.

Acamprosate↗

PubMed1987

Circling behaviour in rats with unilateral lesions of the nigrostriatum induced by 6-hydroxydopamine: changes induced by oral administration of cytidine-5'-diphosphocholine.

A unilateral administration of 6-hydroxydopamine into the nigrostriatal system of the rat was responsible for ipsiversive circling behaviour in response to administration and, in time, of contraversive circling behaviour in response to L-DOPA and apomorphine. This contraversive circling behaviour appears to be mediated by the development, on the lesioned side, of supersensitivity of postsynaptic dopamine receptors. Subchronic treatment with cytidine-5'-diphosphocholine (p.o.) by itself was devoid of behavioural effects. The CDP-choline did not modify the apomorphine-induced stimulant effect but potentiated the circling behaviour produced by L-DOPA and amphetamine. The data show that the effects of CDP-choline were mediated by a presynaptic mechanism: the potentiation of the effects of L-DOPA cannot be explained by an activation of tyrosine hydroxylase, but seems to be related to an improvement of release of newly synthesized dopamine from exogenous L-DOPA.

Administration, Oral↗

PubMed1987

Noradrenaline and GABA brain receptors are co-involved in the voluntary intake of ethanol by rats.

Stimulation of GABA brain receptors by calcium bis acetyl-homotaurine (a new GABAergic agent) or of noradrenergic brain receptors by metapramine reduces the voluntary intake of ethanol by rats. Bicuculline antagonizes the effects of both drugs. It is suggested that both GABA and noradrenaline are implicated in ethanol intake, and that there is a common final pathway of the two systems to modulate ethanol intake.

Acamprosate↗

PubMed1987

Platelet affinity for serotonin is increased in alcoholics and former alcoholics: a biological marker for dependence?

The kinetics of 3H serotonin platelet uptake were studied in alcoholics and former alcoholics to see whether differences found between alcohol-preferring and non-preferring rats could be reproduced in man. Three groups of patients were studied: 10 dependent alcoholics on admission for treatment; 10 dependent alcoholics after 20 days of treatment; 8 former dependent alcoholics, abstinent for 1-11 years. Controls were non-alcoholics, matched for age and sex. The Km for 3H serotonin uptake in platelets was lower in patients from all three groups compared to 15 controls. This phenomenon could be congenital or induced by the previous excessive intake of alcohol. We believe that this increased platelet affinity for serotonin, in the absence of cirrhosis of the liver and/or depression could be a marker for alcohol dependence, enabling the therapeutic effort to be focussed on these patients.

Adult↗

PubMed1987

Circling behavior in normoxic or hypoxic rats with unilateral 6-OHDA nigrostriatal lesion. Part 1. Effects of apomorphine and L-dopa.

Unilateral administration of 6-hydroxydopamine (6-OHDA) into the rat nigrostriatal system provokes circling behavior in response to apomorphine and L-dopa. This behavior appears to be mediated by the development in the lesioned side of a postsynaptic dopamine receptors supersensitivity. Acute hypobaric hypoxia does not modify the apomorphine-induced stimulant effects, but does oppose the L-dopa-induced circling behavior. Our data suggest that effects of hypoxia are mediated by a presynaptic mechanism. The antagonism of the effects of L-dopa cannot be explained by the inhibition of activity of the oxygen-dependent enzyme tyrosine hydroxylase, but seems to be related to an impairment of the release of newly synthesized dopamine from exogenous L-dopa.

Animals↗

PubMed1987

Circling in normoxic or hypoxic rats with unilateral 6-OHDA nigrostriatal lesion. Part 2. Effects of d-amphetamine.

Unilateral administration of 6-hydroxydopamine into the rat nigrostriatal system induces a unilateral damage of the dopamine (DA) containing neurons. In such lesioned animals, d-amphetamine (AMPH) induces circling behavior (ipsiversive circling) in relation to its DA releasing property in the non-lesioned side. A preexposition to hypoxia potentiates the behavioral effect of AMPH: this can be related to an increase in the amount of substrate available for release, dopamine. Hypoxia occurring just after the administration of AMPH does not initially modify the AMPH induced circling behavior. This suggests that tyrosine hydroxylase inhibition by hypoxia is not a limiting factor of the releasing effect of AMPH. After 20 min of hypoxia, circling decreases. This impairment could be mediated by a decrease of the amount of available DA and/or by a decrease of release.

Animals↗

PubMed1987

Is initial sensitivity to ethanol correlated with alcohol preference in alcohol-drinking and non-drinking rats?

The initial sensitivity to ethanol was determined by hypothermia and sleeping time induced by an injection of ethanol (2.5 g/kg, intraperitoneally) in Long-Evans rats whose response to ethanol was later characterized in drinking, non-drinking and other rats. The response to a nociceptive stimulus (electric shock) in drinking rats and non-drinking rats was also studied. There was no correlation between initial sensitivity to ethanol and ethanol consumption and all rats exhibited the same behaviour towards electric shock. Ethanol elimination was not significantly different in both groups after an i.p. injection of a 2.5 g/kg dose of ethanol. These data indicate that our selected drinking and non-drinking rats differ in their ethanol intake behaviour but not in their initial sensitivity to ethanol or their sensitivity to a nociceptive stimulus. Preference for, and initial sensitivity to, ethanol are therefore not related in our rats.

Alcohol Drinking↗

PubMed1987

Effects of hypoxia and cytidine (5') diphosphocholine on the concentrations of dopamine, norepinephrine and metabolites in rat hypothalamus and striatum.

Experiments were performed in order to determine whether exogenous cytidine (5') diphosphocholine (CDP-choline) opposes the effects of an acute hypobaric hypoxia on the metabolism of catecholamines in rat striatum and hypothalamus. Hypoxia decreased striatal HVA, DOPAC, 3 MT, hypothalamic norepinephrine (NE), and increased both striatal and hypothalamic dopamine (DA). CDP-choline (1000 mg X kg-1 p.o.; 1 or 3 days) was devoid of effects in normoxia, but partially reversed 3 MT, NE and DA changes, potentiated the HVA and DOPAC decrease in hypoxic rats. Our results suggest that hypoxia could impair neurotransmitter release and that treatment with CDP-choline (acute, and especially subacute administration) opposes this impairment.

3,4-Dihydroxyphenylacetic Acid↗