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.

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.

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.

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.

[Association of Hirschsprung disease, Meckel's diverticulum and gallbladder calculi in a young Down's syndrome patient]. / Association d'une maladie de hirschsprung, d'un diverticule de Meckel et d'une lithiase vésiculaire chez une jeune mongolienne.

Report of a case of Hirschsprung's disease associated with Meckel's diverticulum, gall stones and trisomy 21, in an 18 year old woman, operated for a bowel obstruction due to a volvulus secondary to bowel distention. A brief review of the literature is presented on the association Hirschsprung's disease-trisomy 21.

GABA transmission, but not benzodiazepine receptor stimulation, modulates ethanol intake by rats.

Adult male Long Evans were selected as ethanol preferring rats (DR) during 28 days. After this period, they were daily IP injected during 14 days with one of the next drugs: diazepam 1 mg.kg-1, alprazolam 1 mg.kg-1 (benzodiazepines), progabide 25 mg. kg-1 (GABA A and B agonist), nipecotic acid 150 mg.kg-1 (GABA uptake inhibitor), muscimol 0.2 mg.kg-1 (GABA A agonist), AOAA 10 mg.kg-1 (GABA decarboxylase inhibitor), baclofen 3 mg.kg-1 (GABA B agonist), or NaCl 0.9% (1 ml/200 g). During treatment, rats were isolated, had free access to food, and free choice between ethanol (12%) and water whose respective consumption were daily noted. Among treatments, only AOAA and baclofen were able to decrease significantly ethanol intake, without modifying total liquid intake. The action of these different drugs on GABA transmission and on ethanol intake was discussed. It was concluded that GABA A and benzodiazepine receptors were not implicated in ethanol intake, but that modulation of voluntary ethanol intake could be associated with a modification of GABA metabolism and/or stimulation of GABA B receptors. An intervention of GABA B receptors on noradrenergic pathways was also evoked.

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.

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.

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.

Striatal dopamine does not appear involved in the voluntary intake of ethanol by rats.

Ethanol preferring and non preferring rats were selected. Ethanol preferring rats showed a constant voluntary intake of a 12% ethanol solution during 14 days (about 5 g/kg body weight daily) while the non preferring rats drank less than 1 g/kg body weight daily. Preferring rats were daily IP injected with 5 or 10 mg/kg of nomifensine, an inhibitor of dopamine uptake. Their intake of ethanol solution remained constant during the 14 days of treatment. Dopamine uptake into striatal synaptosomes was identical in ethanol preferring and non preferring rats. These data, as others, led us to suppose that striatal dopamine is not involved in the voluntary intake of ethanol by rats.

Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics.

After they had been weaned off alcohol in hospital 85 severe alcoholics (above 200 g alcohol/day) were included in a double-blind study of calcium bis acetyl homotaurine (Ca AOTA, 25 mg/kg/day), a new gamma-aminobutyric acid agonist, versus placebo. Patients were treated as outpatients during the 3-month study. The only other treatment that patients received was meprobamate, 800 to 1200 mg/day, in the first month. The criterion for success was abstinence at 3 months (with normal gamma-glutamyl transpeptidase being one of the criteria). Of the 70 patients who completed the study, 33 received Ca AOTA and 37 placebo. 20 patients on Ca AOTA did not relapse, compared with 12 on placebo (p less than 0.02 by X2 test). Side-effects were noted by 7 patients on Ca AOTA and 2 on placebo. The results suggest that Ca AOTA may be useful in helping severe alcoholics who have been weaned off alcohol not to relapse.

Isolation and striatal (3H) serotonin uptake: role in the voluntary intake of ethanol by rats.

Ethanol preferring rats were selected and showed a constant voluntary intake of a 12 percent ethanol solution during 14 days (about 5 g/kg body weight daily). Analysis of 3H serotonin uptake by striatal synaptosomes showed that steady state 3H serotonin synaptosomal levels were lower in alcohol preferring rats. Grouping these rats (5 per cage) reduced both voluntary intake of ethanol and synaptosomal 3H serotonin uptake. Furthermore, blocking the serotonin uptake by clomipramine 5 mg X kg-1 or 10 mg X kg-1 also reduces voluntary intake of ethanol. These data are in agreement with the hypothesis of a modulation of the voluntary intake of ethanol both by chemical and housing stimulation of striatal receptors for serotonin.

A homotaurine derivative reduces the voluntary intake of ethanol by rats: are cerebral GABA receptors involved?

The effects of some derivatives of homotaurine (3 APS), the well known GABA agonist, were tested on the voluntary intake of ethanol by rats. Spontaneously ethanol drinking rats (DR) were selected and had a constant voluntary intake of ethanol by rats. Spontaneously ethanol drinking rats (DR) were selected and had a constant voluntary intake of a 12% ethanol solution (VIE) during 14 days (about 5 g/kg body weight daily). Calcium acetylhomotaurine (0.26 and 0.52 mmol/kg daily IP) significantly reduced VIE and this was inhibited by the GABA antagonist bicuculline (2 mg/kg IP). The conditioned aversion test to saccharin was negative. Bicuculline alone did not affect VIE. Other homotaurine (3-APS) derivatives: sodium acetyl homotaurine (Na AOTA), homotaurine (OTA), sodium acetyltaurine (Na A TA) and calcium chloride (CaCl2) did not affect VIE. These data suggest that the gabaergic system could be implicated in VIE. MERAM Lab. patent.