We studied platelet 3H-serotonin uptake in 32 former alcoholics, withdrawn for from 1 month to 22 years, in their descendants ( 21.7+/-1.6 years old, n=17; 10.9 0.7 years old; n=19), and in respective control groups, paired in age and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/30sec.,vs. 0.93+/-0.15pmole/10(8)pl/30sec. Their descendants also showed high platelet serotonin uptake: 3.94+/-1.44 pmoles/10(8)pl/30sec., vs. 0.93+/-0.15 pmoles/10(8)pl/30sec. 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.

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.

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.

* Pharmacologie, UFR Médecine et Pharmacie de Rouen, 76803 Saint Etienne du Rouvray cedex, France ** IRIS, 6 place des Pléiades, 92415 Courbevoie cedex, France

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 alcoholised 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.

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 dependance and suggest that serotonin uptake and paroxetine binding sites may be regulated independently in this pathology.

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.

Summary— 3 H‐nipecotic acid ( 3 H‐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 3 H‐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 3 H‐NIP binding (B max decreased) with an enhancement of affinity ( KD decreased). In rats subjected to withdrawal of ethanol (Group III), affinity of 3 H‐NIP for GABA uptake sites was higher than in controls (Group I), but lower than in Group II, B max 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 3 H‐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 3 H‐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), 3 H‐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.

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.

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.

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.

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.

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.

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.