Ethanol intake after chronic intoxication by inhalation of ethanol vapour in rats: behavioural dependence.

In Wistar rats, which practically avoid ethanol when naive, it is possible to induce a large ethanol intake in a free-choice situation after chronic intoxication by ethanol vapour. In this study, we evaluated the ethanol intake of chronically intoxicated and control rats. The ethanol intake was increased in intoxicated animals but the intensity of the response varied according to individuals without any clear relation to the level of the intoxication. The results clearly showed in intoxicated animals two kinds of responders: alcohol-nonpreferring (27/95) and alcohol-preferring rats (68/95). In the alcohol-preferring rats, ethanol intoxication had induced an alcohol drinking-dependent behaviour; about 75% of the animals of this group drank more than 7 g/kg b.wt. per day and could be considered as behaviourally dependent on alcohol. Furthermore, this group presents most of the criteria of alcoholism that an animal model should ideally satisfy.

Synaptic membrane responses to acute and chronic alcohol intoxication in high alcohol sensitive (HAS) and low alcohol sensitive (LAS) selectively bred rats.

HAS (high alcohol sensitive) and LAS (low alcohol sensitive) lines of rats have been selectively bred based on their differences in ethanol-induced sleep time. In the present study, the two lines were compared to examine another central effect of acute alcohol intoxication: namely, hypothermia. As the disturbances in membrane microorganization have been associated with the nervous system's sensitivity and tolerance to ethanol, the synaptic plasma membrane fluidity and acute sensitivity to ethanol were also evaluated by fluorescence polarization of DPH probes in the HAS and LAS rats. The two lines did not differ in the magnitude of their hypothermic response after acute injection of ethanol (3 g/kg body wt, i.p.). Although membranes in the HAS line were slightly more rigid than in the LAS line, the level of membrane disordering after acute ethanol addition was identical for the two lines in the region examined with the DPH probe. Following the chronic intoxication of the rats, the two lines developed tolerance to the hypnotic and hypothermic effects of ethanol. In the same way, a membrane resistance (i.e. tolerance) to the disordering effect of acute ethanol addition developed in the region probed with DPH. In general, the LAS line showed a more pronounced level of tolerance than the HAS line at both the functional and membrane level. These results suggest that different measures used to assess the depressant action of ethanol, such as sleep time, hypothermia or membrane disordering, may not be related and could indicate different genetic origins.(ABSTRACT TRUNCATED AT 250 WORDS)

Tolerance and dependence in high alcohol sensitivity (HAS) and low alcohol sensitivity (LAS) rats after chronic alcohol intoxication by inhalation.

In rats selected for their differences in sleep time following acute administration of ethanol (high or low alcohol sensitivity: HAS or LAS), alcohol chronic tolerance and behavioural dependence were determined. Tolerance was assessed by calculating the interval between the loss and regain of the righting reflex following an acute administration of ethanol (4 g/kg body wt), after intoxication by inhalation of ethanol vapour for 3 weeks. The importance of behavioural dependence was estimated by measuring the ethanol intake in a free-choice situation water/ethanol (10% v/v), after intoxication by inhalation for 4 weeks. The two HAS and LAS lines did not show any behavioural dependence, while they developed a significant tolerance to the hypnotic effect of ethanol, which was more marked for the LAS line.

[Biophysical membrane correlates of tolerance and dependence on alcohol]. / Corrélats biophysiques membranaires de la tolérance et de la dépendance envers l'alcool.

A large number of studies have given clear indications that ethanol does affect the physicochemical properties of the membrane. Membrane reorganization and adaptation can develop against the acute disordering effect of ethanol during chronic intoxication. Nevertheless, there has been so far no direct evidence of correlations between functional tolerance or dependence and membrane physical states. Membrane physical state can be assessed by fluorescence polarization of DPH in the absence (measure of membrane 'fluidity') or presence (measured of membrane sensitivity) of ethanol added in vitro. Functional tolerance has been already correlated with a reduced synaptic membrane sensitivity to ethanol (membrane tolerance). Behavioural dependence was shown to be quantifiable by measurement of alcohol intake in a free choice situation (water/alcohol) solution). This dependence model allowed us to define a membrane dependence which consists in an increased membrane rigidity (or decrease in 'fluidity') persistent after withdrawal, and which was correlated to the intensity of the behavioural dependence. This biophysical expression of dependence seems rather independent of the biophysical membrane tolerance (resistance to the acute ethanol fluidizing effect), which was found to be rapidly reversible after withdrawal and re-induced by alcohol re-intake, requiring recent periods of current abuse to be expected.

Transferrin microheterogeneity in rats treated chronically with ethanol.

The microheterogeneity of rat serum transferrin was analyzed by isoelectric focusing and immunofixation from Wistar rats chronically treated with ethanol either by inhalation (4 weeks) or by a liquid diet (6 weeks) and from pair-fed controls. In spite of the length of ethanol exposure, a daily ethanol intake of 13-18 g/kg b.wt. and BAC levels of 1.0-4.1 g/l, no transferrin abnormality similar to that found in human alcoholics was observed. It is apparent that these two common animal models for chronic high ethanol consumption are not suitable for experimental studies of ethanol-associated effects on transferrin.

Membrane properties in behaviorally ethanol-dependent rats.

A way of quantifying alcohol behavioral dependence in rats previously developed was used in the present study to get more insight into the relations between neuronal membrane "fluidity", degree of dependence and membrane "sensitivity" (ethanol partitioning and disordering capacities).

Effect of alcohol intoxication during pregnancy on foetal and placental weight: experimental studies.

Recent animal studies have shown that alcohol intoxication in utero leads to a decrease in foetal weight and an increase in that of placenta. These findings are not, however, satisfactorily explained. The object of this study was to investigate these two effects, using inhalation of various concentrations of ethanol vapour as a method of intoxication. Three groups of 12 gravid female rats (treated groups) were intoxicated by permanent exposure to an alcohol atmosphere (19, 20 or 21 mg/l.). Three control groups of 12 gravid females were not intoxicated but had their diet reduced to the same energy intake as the treated groups. On day 21 of pregnancy, foetuses and placentas were surgically removed and individually weighed. The body-weight of foetuses was found to be lower in the treated groups than in the respective controls. Additionally the reduction of foetal weight was directly related to the severity of intoxication. Increases in placental weight were observed in the three intoxicated groups. The differences observed between foetal and placental weights may be interpreted as a foeto-protective phenomenon.

Membrane fluidity and alcohol dependence.

Rats were chronically intoxicated with alcohol by exposing them to increasing concentrations of ethanol vapor over a 4-week period. They were tested for alcohol consumption in a free choice situation of water and 10% (v/v) alcohol. On the basis of their intakes they were divided into alcohol-dependent and nondependent groups. Synaptosome membrane fluidity evaluated by fluorescence polarization was compared between the two groups and against nonintoxicated controls. The intoxicated animals had a lower membrane fluidity than controls, mainly because of a highly significant increase of rigidity in the alcohol-dependent group. Furthermore, membrane fluidity was found to be correlated with the degree of behavioral dependence (i.e., alcohol intake during the free choice period).

Pattern of alcohol administration and physical dependence.

The purpose of this work was to study the influence of the pattern of alcohol administration on the intensity of withdrawal syndrome. Some rats were intoxicated by inhalation of ethanol vapor. The ethanol concentration in atmosphere was increased throughout the whole experiment in such a manner that the blood alcohol concentration (BAC) during the experiment increased as a linear function of time. When the area under BAC curve was varied by changing the duration of alcohol administration and keeping constant the slope of BAC increase, the intensity of withdrawal syndrome increased with the duration of alcohol intoxication. When the duration of alcohol administration and the slopes of the BAC curves were varied in such a manner that the area under the BAC curves was kept constant, the severity of the withdrawal syndrome increased with the slope of the BAC curves.

Alcohol exposure pattern and physical dependence.

Intoxicating animals by inhalation of ethanol vapor allows no possibility of determining accurate daily absorbed doses of ethanol. The daily BAC versus time curve may be considered as a picture of animal intoxication during the experimental period, and the area under the BAC curve (A) indicates the intoxication level of animal. On the other hand, to compensate the development of alcohol tolerance, it is necessary to gradually increase alcohol concentration in the atmosphere (ACA). A protocol was developed to study the withdrawal syndrome intensity (WSI) in rats, based on observations of behavioral alterations. Five successive grades were described and noted in relation to more and more serious WSI. Male rats were intoxicated in various protocols in which the length of alcohol exposure (7-35 days) and the rate of increase in ACA (0.22-0.70 mg/l/day) were changed. In the condition of constant increases of ACA (0.33 mg/l/day in average), WSI varied in relation to the length to alcohol exposure. When A was kept constant, the higher the ACA increase rate was, the higher the WSI was. These results are discussed with regard to patterns of consumption of alcoholic beverages by man.