Reduction of aggression during benzodiazepine withdrawal: effects of flumazenil.

Benzodiazepine withdrawal has been associated with hostile and aggressive behavior. The benzodiazepine antagonist flumazenil has reduced, increased or not affected hostility and aggression in animal and human studies. In the present study we analyzed data collected in a placebo-controlled study of the effects of the benzodiazepine antagonist flumazenil in patients previously treated for benzodiazepine dependency, and healthy controls. The aim was to analyze the effects of flumazenil on hostility and aggression. Ten patients and 10 controls received, on two separate occasions, cumulative doses of flumazenil (0.05, 0.1, 0.25, 0.5 and 1mg at 15min intervals) or placebo. Withdrawal symptoms were rated after each injection. Patients had been free from benzodiazepines for 47 (4-266) weeks on the first occasion. A three-way interaction (groupxtreatmentxdose) was found, and was explained by: 1) patients rating aggression and hostility higher than controls at all times during placebo, while 2) during the flumazenil provocation i) the initial significant difference between patients and controls was no longer significant above the 0.5mg dose, and ii) patients rated aggression and hostility significantly lower above the 0.5mg dose compared to base-line. The results suggest that self-rated aggression and hostility in patients treated for benzodiazepine dependency was reduced by the partial benzodiazepine agonist flumazenil.

Gender-related differences in response to placebo in benzodiazepine withdrawal: a single-blind pilot study.

RATIONALE: Benzodiazepines have dependency-producing properties, and the majority of patients who are prescribed benzodiazepines and are treated for benzodiazepine dependency are women. Inability to cope with withdrawal symptoms may lead to continued consumption of benzodiazepines, often with the development of tolerance and dose escalation as a consequence. OBJECTIVE: In the present study we analyzed gender-related differences in reactions to placebo injections in a placebo-controlled study of the effects of the benzodiazepine antagonist flumazenil among patients previously treated for benzodiazepine dependency and healthy controls. METHODS: Ten patients and ten controls (five males and five females in each group) received two placebo injections (separated by 15 min) on two separate occasions (1-13 weeks apart). The patients had been benzodiazepine free for 47 (4-266) weeks on the first occasion. Subjective ratings of symptoms, thought to be important during/after withdrawal of benzodiazepines, were made before and after each injection, as well as registrations of blood pressure and heart rate. RESULTS: An overall difference existed between previously benzodiazepine-dependent subjects and healthy controls, with patients scoring higher on negative and somatic aggregates and lower on a positive aggregate. A four-way interaction (group x gender x occasion x time) was found for negative and somatic aggregates, which could mainly be explained by the reactions of female patients. Thus, females had the highest base-line ratings and were the only group that showed a significant reduction in symptom ratings after placebo injections on the first occasion. Gender differences were also found for systolic and diastolic blood pressure. There was no significant response to placebo among male patients or for controls (males or females) for ratings of any variable. CONCLUSIONS: The results suggest that there might be gender-specific differences in reactions to placebo injections, with female patients being more affected. Arguments for and against explanatory factors such as expectation, provider factors, habituation, regression toward the mean, and reduction of anxiety are presented.

Acute tolerance during intravenous infusion of alcohol: comparison of performance during ascending and steady state concentrations--a pilot study.

Although acute tolerance (AT) to alcohol has been demonstrated in many single-dose studies, the existence of AT at steady state concentrations of alcohol has been questioned. In the present study, six subjects were examined as (1) 7.5% alcohol or (2) placebo was administered intravenously (IV). The order of the infusions was randomized. The alcohol infusions were designed to result in similar blood alcohol concentrations at 20, 60, and 140 min (approximately 0. 7 per thousand). At 20 min, the concentrations were rising; the steady state (+/-0.10 per thousand) was reached after 60 min and continued until 140 min. Three reaction time (RT) tests from the automated psychological test system were used (simple RT, two-choice RT, and two-choice RT with auditory inhibition). When the performance of the subjects was compared at rising and steady-state concentrations of alcohol, AT was shown for the most complex task requiring parallel processing, i.e., RT with failed inhibition, test. However, at steady state (i.e., 60 vs. 140 min), AT was not found for any of the tests. Further, the analysis showed that the test results of different individuals were related to their estimated normal alcohol consumption and that these differences presumably influenced the test results in accordance with our earlier findings.

Prediction of single episodes of drinking during the treatment of alcohol-dependent patients.

Drinking episodes during the treatment (relapses or lapses) of alcohol-dependent patients is predicted from clinical ratings of patients and individual background data such as alcohol drinking history and social status. The probability of these relapses (or lapses) is determined up to three days in advance using a logistic regression procedure. The study group consisted of 33 male alcohol-dependent persons, who participated in a treatment program. Clinical ratings were performed three times a week by a trained person during a visit to the clinic. The questionnaire contained 23 different items about irritation, craving for alcohol. sleep disturbances, etc. The relapses were either self-reported or detected by a biochemical marker in a urine sample that was taken daily. The most important factor for a relapse in alcohol drinking was shown to be if the patient already had had one relapse during the treatment. Other important clinical factors were the levels of irritation and autonomic disturbances. None of the variables measuring mood shifts was significant. Family conditions during childhood were the most important background variables. The predictions turned out to have a rather high specificity, but the sensitivity was lower. Half of the relapses were not predicted by an increased probability for relapse. Self-reported relapses were predictable from preceding interviews and were also less frequent compared to those detected objectively by the biochemical markers.

Rated well-being in relation to plasma concentrations of l- and d-methadone in satisfied and dissatisfied patients on methadone maintenance treatment.

RATIONALE: One of the major problems in methadone maintenance treatment is to find optimal individual doses for the patients. OBJECTIVE: The present study investigated whether the use of rating scales together with enantioselective analysis of l-methadone might facilitate dose adjustments in a clinical situation. METHODS: Rating scales were used to evaluate subjective and objective signs of well-being in relation to plasma methadone concentrations in two groups of patients receiving methadone maintenance treatment. The first group (n = 25) was well-adjusted according to clinical observations and were satisfied with their methadone doses (86.2+/-4.3 mg). The second group (n = 25) was in need of the methadone dose adjustment; they complained of low dosing, despite a dose level of 69.2+/-4.0 mg/day. RESULTS: Results indicated a significant correlation between dose and methadone concentration among dissatisfied patients only. The trough levels of d,l-methadone and l-methadone, as well as their elimination rates, were similar in the two groups of patients. There was a variable predominance of l- over d-methadone in plasma (ratio approximate to 1.2; range 0.7-3.6). Illicit use of drugs by the patients was related to the methadone dose and to satisfaction with the dose received. Increased illicit drug use among dissatisfied patients was successfully eliminated by raising the methadone dose. Subjective and objective ratings of the satisfied patients were quite stable throughout the evaluation period, whereas the ratings of the dissatisfied patients were unstable. These patients seemed to be more sensitive to low trough levels of methadone than the satisfied patients. Associations between the subjective and objective ratings and plasma methadone, along with background characteristics, were characterized by multiple regression analyses. The plasma concentrations of l-methadone were one of the most important explanatory variables in these analyses. Associations between well-being and methadone concentrations in plasma were stronger for l-methadone than for d,l-methadone. CONCLUSIONS: Selective measurements of the active isomer and the use of rating scales should be of clinical value when monitoring methadone maintenance treatment patients.

Patient perceptions of psychological and physiological withdrawal symptoms and positive factors associated with gradual withdrawal from methadone maintenance treatment: a prospective study.

Psychological and physiological withdrawal symptoms and some positive factors were studied in 10 methadone maintenance treatment patients during methadone dose reduction. The subjective ratings were made during a period of 10 days around each reduction occasion, 3 days before dose reduction and 7 days after (i.e., within the periods). To permit comparisons of the subjects' ratings between earlier and later stages of the dose reduction process, a division has been made between the first half and the second half of the total reduction occasions (i.e., between the periods). Three of the patients completed the dose reduction, while the others interrupted their withdrawal attempts. The results show that the aggregate psychological symptoms were rated low, but that, as expected, they increased significantly from the first to the second half of the dose reduction. A significant increase of the psychological symptoms also occurred from the days before each reduction to the days after. The aggregate physiological symptoms were rated very low. A significant increase in rated withdrawal intensity is found within the reduction occasions. There were no significant changes with regard to the aggregate positive factors, either within or between the reduction occasions.

Acute alcohol tolerance in social drinkers: changes in subjective effects dependent on the alcohol dose and prior alcohol experience.

Using subjective ratings of the degree of alcohol intoxication, the interaction between the drinking history of the subjects, the alcohol dose, and acute alcohol tolerance were examined in light and moderate alcohol consumers (N = 10). Both groups of subjects were tested with doses of alcohol corresponding to 0.5 and 1.0 g/kg. Dose order was random and tests were carried out with an interval of 1 week. Reports of the subjects' previous experience with these doses of alcohol indicated that the moderate consumers ingested the lower (but not the higher) of the doses quite regularly, whereas light consumers were rather inexperienced with both of the doses. Comparison of blood alcohol concentrations as measured by breath and blood analysis yielded slightly different results, the concentrations being significantly higher as measured by breath analysis. This result was mainly associated with the initial phases, where this difference was greatest. Acute tolerance was assessed by comparing the ratings at equal concentrations of alcohol on the ascending and the descending limbs of the alcohol concentration curve. Due to the lag in the measurements of breath and blood alcohol concentrations, the outcome of the evaluations of acute tolerance was also influenced by whether breath or blood alcohol concentrations were used to obtain similar concentrations in both phases. Results based on the breath alcohol concentrations showed that in light alcohol consumers, acute tolerance was demonstrated for both of the doses. In moderate alcohol consumers only the higher of the doses produced evidence for acute tolerance. However, if comparisons are based on blood alcohol concentrations, moderate alcohol consumers also show an apparent acute tolerance for the lower of the doses tested. The present results clearly demonstrate the complexity of the acute tolerance phenomenon, and emphasize the fact that the results are dependent on the dose of alcohol, the subjects' prior experience with alcohol as well as the procedure used for measuring alcohol concentration.

Effects of flumazenil in the treatment of benzodiazepine withdrawal--a double-blind pilot study.

Flumazenil, a partial benzodiazepine agonist with low intrinsic activity, was tested for potential use in patients experiencing withdrawal symptoms after traditional treatment for benzodiazepine dependency. On two occasions, separated by 1-13 weeks, ten patients treated for benzodiazepine dependency and ten controls received cumulative doses of flumazenil (0.05, 0.10, 0.25, 0.50 and 1.00 mg at 15-min intervals) or placebo, with assessments of withdrawal symptoms and physiological variables after each dose. As expected, there was an overall difference between patients and controls, with patients scoring higher on negative and somatic items and lower on positive psychological items. Flumazenil reduced symptoms thought to be important in withdrawal in patients treated for benzodiazepine dependency. In contrast to the patient group, controls reacted in the opposite direction with increases in negative experience when given flumazenil. Further research may develop flumazenil as a therapeutic option in the treatment of benzodiazepine withdrawal.

Abstinence fear in methadone maintenance withdrawal: a possible obstacle for getting off methadone.

The present study attempts to shed light on methadone maintenance patients expectations regarding withdrawal symptoms during voluntary methadone detoxification. The study includes two groups of subjects; one group who have tried on their own initiative to terminate their methadone maintenance treatment (Group 1) and one group that contains rehabilitated patients who have not tried to quit using methadone (Group 2). Two main results have emerged. Group 1 has negative expectations beforehand about the intensity of withdrawal which significantly exceed the later, actual experience. Group 2 has negative expectations about the intensity of withdrawal that significantly exceed the negative expectations of Group 1. The clinical implications of these results are discussed.

Acute alcohol tolerance in cognitive and psychomotor performance: influence of the alcohol dose and prior alcohol experience.

Using tests for cognitive performance (the Pauli test) and psychomotor coordination (the Pursuit Rotor test), the interaction between the drinking history of the subjects, the alcohol dose, and acute alcohol tolerance were examined in light and moderate alcohol consumers (N = 10). Both groups of subjects were tested with doses of alcohol corresponding to 0.5 and 1.0 g/kg. Dose order was random and tests were carried out at an interval of 1 week. Reports of the subjects' previous experience with alcohol indicated that the moderate consumers ingested alcohol in higher quantities than the light consumers. The light consumers were rather inexperienced with frequent alcohol consumption at the quantities investigated, as were the moderate consumers for the higher of the alcohol doses used. Acute tolerance was assessed by comparing performance at equal concentrations of alcohol on the ascending and the descending limbs of the alcohol concentration curve. In the test for cognitive performance, both doses of alcohol in light alcohol consumers yielded significant differences between the ascending and descending limbs of the alcohol concentration curve, suggesting the existence of acute tolerance. In the moderate alcohol consumers, only a tendency to acute tolerance was observed for the higher of the doses tested. In the test for the psychomotor performance, both of the measures of frequency (of misses) and duration (of time outside the target area) were used. The results showed that in the light consumers, acute tolerance was seen for both of the doses, and to some extent for both of the dependent measures (frequency and duration) investigated. However, in the moderate alcohol consumers, acute tolerance was only observed for the higher of the doses and only for the duration measure. Given the difference in drinking history between the two groups of subjects, the implication would be that when the dose of alcohol exceeds the subjects' prior experience, acute tolerance seems inevitable. The present results clearly demonstrate the complexity of the acute tolerance phenomenon, and emphasize the fact that the results are dependent on the subjects' prior experience with alcohol as well as the dose of alcohol ingested, and consequently suggest the interaction between acute and chronic alcohol tolerance.

Effects of long-term abstinence on psychological functioning: a prospective longitudinal analysis comparing alcohol-dependent patients and healthy volunteers.

Using a prospective longitudinal design, differences between abstinent alcohol-dependent patients (n = 15) and abstinent healthy volunteers (n = 11) were determined with respect to their psychological functioning and alcohol consumption patterns following abstinence. Results showed no differences in alcohol consumption. In 20% of the patients and 9% of the controls more than 10% of protocols indicated alcohol intake, and in 27% of the patients and 27% of the controls less than 10% of protocols indicated alcohol intake. Total abstinence was reported by 53% of the patients and by 64% of the controls. For patients, validation of self-reported alcohol consumption was carried out via biological markers. Patients and controls differed in terms of increased sleep, euphoria, concentration, initiative, anxiety, negative and positive craving, pessimistic thoughts, autonomic disturbances, and humour. A gradual normalization back to baseline levels was observed for some symptoms. These results suggest that affective/mood states may be unstable for alcoholics, and further, that these symptoms may be related to the protracted withdrawal syndrome or may represent residual symptomatology.

Sub-populations of alcohol-dependent patients: differences in psychological functioning between high- and low-frequency alcohol consumers.

The purpose of the present study was to examine the processes underlying relapse to drinking using objective biological validation of self-reported recent alcohol consumption, using the ratio of 5-hydroxytryptophol to 5-hydroxyindol-3-ylacetic acid (5-HTOL/5-HIAA), a new biological marker to detect single episodes of drinking, in a sample of 38 male alcohol-dependent patients (DSM-III-R) who were assessed prospectively in terms of their clinical symptomatology over a 6-month treatment period. Results showed that nearly all patients obtained positive 5-HTOL/5-HIAA samples during the course of treatment. However, upon closer inspection, results revealed a bimodal distribution for alcohol intake with high and low frequency of consumption episodes. Results showed that high frequency consumers obtained higher ratings of clinical symptoms as measured by the Comprehensive Psychopathological Rating Scale (CPRS) and by the St Göran's Semi-structured Interview (SGSI) compared to low frequency alcohol consumers on symptoms of inner tension, lack of initiative, risk of relapse (as rated by therapists and as rated by patients themselves), dysphoria, negative craving for alcohol, and positive craving for alcohol. The present results provided evidence for the existence of two sub-populations of alcoholics, those who have frequent lapses and those who have low frequency of sporadic lapses. Further, these two sub-populations were shown to differ with respect to overall psychological functioning, and craving for alcohol. In conclusion, the present findings have important treatment implications in that reliable identification of patients' consumption patterns using biological markers would allow for the design of individually tailored treatment needs.

Factors associated with successful withdrawal from methadone maintenance treatment in Sweden.

Two groups have been compared with each other with respect to the possible influence of a number of possible predictors of success in voluntary methadone withdrawal-one group that succeeded in terminating their methadone maintenance treatment and one group that did not manage to quit, despite serious attempts. Each of the groups contains 25 subjects. The possible predictors were subdivided into Conditions and Interventions. The results show that few Conditions exhibit any predictive value, while a larger proportion of the studied Interventions are associated with success.

Neuropsychological changes during steady-state drug use, withdrawal and abstinence in primary benzodiazepine-dependent patients.

Impairment on neuropsychological tests during steady-state drug use and withdrawal, and after discontinuation of benzodiazepines, was studied in primary benzodiazepine-dependent patients. One group of patients was tested before and the other group after the initiation of a gradual tapering-off of the drug, and both groups were tested approximately 1 year later. At the initial assessment, both groups of patients showed impairment on most of the tests of general intelligence and on several of the tests in the Halstead-Reitan battery, as well as on a test of nonverbal memory, in comparison with healthy controls. At follow-up the patient groups had reached the level of the control group. This study confirmed earlier observations of neuropsychological deficits in long-term benzodiazepine-using patients and demonstrated that these changes are at least partly reversible by discontinuing drug intake.

Subjective and objective symptoms in relation to plasma methadone concentration in methadone patients.

Two rating scales, which were originally developed for measurements of objective and subjective signs of opiate withdrawal, were used to evaluate potential estimates (correlates) of methadone effects in relation to plasma methadone concentrations. Patients participating in our regular methadone maintenance treatment project were studied during 24 h after the intake of the daily methadone dose. Methadone concentrations in plasma were compared to the subjective (estimated by the patients) and objective (estimated by the investigator) signs of the drug effects before, and 2.5, 5, 9 and 24 h after intake of methadone. Some new items possibly related to rising methadone concentrations were added to the subjective scale. Results indicated that, for subjective ratings, the majority of the items investigated corresponded well with the plasma methadone concentrations. The most significant associations were found for the following items: low psychomotor speed, alertness, running nose, yawning and anxiety. For objective ratings, only the items rhinorrhea, piloerection and signs of anxiety were significantly associated with the methadone concentrations. These rating scales may, together with plasma methadone determinations, be of considerable value when making dose adjustments for methadone maintenance patients. Further work is, however, needed to establish concentration-effect relationships.

Detection of relapses in alcohol-dependent patients: comparison of carbohydrate-deficient transferrin in serum, 5-hydroxytryptophol in urine, and self-reports.

In this study, detection of relapses in male alcohol-dependent patients by biochemical markers and self-reports of alcohol consumption were examined. The patients were trying to stay abstinent from alcohol for 6 months. Four of 15 patients dropped out from treatment after 50-110 days. Ratios of urinary 5-hydroxytryptophol (5-HTOL)/5-hydroxyindole-3-acetic acid and 5-HTOL/creatinine were measured daily and serum carbohydrate-deficient transferrin (CDT) once a week. Clinical ratings and self-reports about alcohol consumption were performed three times a week. According to the self-reports, 3 of the patients drank alcohol frequently, 5 of them sporadically, and 7 of the patients reported no alcohol intake at all. According to the 5-HTOL marker, 4 of the patients drank alcohol frequently, and 11 of them sporadically. No one had all urinary levels of 5-HTOL marker below the reference level. According to the CDT, 3 of the patients drank alcohol frequently, 3 sporadically, and in 9 of the patients no elevated levels of CDT were found. Elevated levels of CDT were preceded by increased values of 5-HTOL marker. The combined results suggested that no one of the patients was totally abstinent from alcohol during the treatment period. The 5-HTOL marker seemed to be useful to reveal recent alcohol drinking, and CDT proved to be useful to validate the patients' self-reports. Together the two biochemical markers showed complementary properties in early detection of relapse and treatment monitoring.

Discriminative stimulus effects and receptor binding of enantiomeric pairs of cannabinoids in rats and pigeons; a comparison.

The cannabimimetic activity of two enantiomeric pairs of compounds structurally different from the classical cannabinoids was evaluated in rats and pigeons, trained to discriminate between the presence and absence of (-)-delta-9-tetrahydrocannabinol (THC). One pair of enantiomers [compounds (+)-HU-249 and (-)-HU-250] has a 5-membered oxygen-containing benzofuran ring; the second pair [(+)-HU-253 and (-)-HU-254] does not have an oxygen-containing ring. The onset of cannabimimetic activity was slower, and duration of action was longer for the test compounds than for THC. HU-250 exhibited cannabimimetic activity with a potency similar to THC in both species; HU-249 was 22 times less active than THC. The pattern of response rate and THC-like responding obtained with HU-249 were dissociated; THC-like responding occurred during the later test intervals when suppression of response rate was reduced. HU-250 bound to the cannabinoid receptor with a Ki of 47.6 nM, essentially identical to that of THC. HU-249 was much less active, with a Ki of 28.3 microM. The triacetate enantiomers, HU-253 and HU-254, occasioned THC-like responding in both species, HU-254 being about 4.5 times less potent than THC and 3 to 4 times more potent than HU-253. In binding, HU-253 was also less potent than HU-254. The corresponding triols were considerably more potent than the acetates; (-)-HU-256 had a Ki of 198 nM, whereas (+)-HU-255 had a Ki of 43.8 nM, comparable to that of THC.

Acute and chronic ethanol tolerance: operant behaviour in naive and ethanol tolerant rats.

The relationship between tolerance to ethanol and acute tolerance to ethanol was examined. One group of rats was given 1.8 g/kg ethanol, and another group was administered 18 ml/kg saline for 26 days after sessions. Animals responded under a fixed ratio ten (FR-10) schedule of food reinforcement. Thereafter, various doses of ethanol (1.3-2.5 g/kg) were examined to assess the influence of the ethanol treatment on the expression of acute tolerance. Acute tolerance was assessed by comparing the performance at equal concentrations of ethanol on the ascending and the descending limbs of the ethanol concentration curve. This was achieved by varying the time between behavioural tests since ethanol administration. Ethanol concentrations were estimated using a rebreathed air procedure. Equal concentrations of ethanol were achieved with doses of i) 1.3 g/kg (10 min post-injection, PI), and 1.8 g/kg (60 min PI), as well as with doses of ii) 2.0 g/kg (10 min PI), and 2.5 g/kg (60 min PI). Acute tolerance was demonstrated for the initially ethanol naive animals. For the animals given ethanol chronically, only doses of ethanol higher than the chronically administered dose produced evidence for acute tolerance. When the chronically dosed animals had been off ethanol for 67 days, there was evidence for acute tolerance. The present data add to the generality of the acute ethanol tolerance phenomenon, and emphasize both the appearance as well as the loss of tolerance for this effect.

Cannabimimetic activity of novel enantiomeric, benzofuran cannabinoids.

The synthesis of the (2R,3R,4S,6R)-7/(2S,3S,4R,6S)-8 enantiomeric pair of benzofuran cannabinoids is reported together with the 1H and 13C NMR spectral parameters. In benzofuran 8 the configurational arrangement of ligated groups at the stereogenic C(3) atom (through which the terpene moiety is connected to the aromatic ring) is very similar to that of the corresponding atom in natural (3R,4R)-delta 1-tetrahydrocannabinol (delta 1-THC), although their respective Cahn-Ingold-Prelog descriptors are different. In drug-discrimination tests in pigeons and rats, benzofuran 8 is as active as delta 1-THC; in the mouse ring test compound 8 is more active than delta 6-THC. Enantiomer 7 is considerably less active than enantiomer 8 in both tests. These results can be explained by the fact that both 7 and 8 have a dimethylheptyl side chain (which is known to enhance cannabimimetic activity) and that delta 1-THC and benzofuran 8 have closely related conformations, as determined by molecular mechanics.

Acute tolerance to ethanol using drug discrimination and open-field procedures in rats.

This study examined the phenomenon of acute tolerance to ethanol (ETOH) using drug discrimination learning (DDL), and open-field (OF) procedures. In DDL, rats were trained to discriminate between ETOH (1.2 g/kg) and saline. Doses of ETOH lower (0.6 and 0.9 g/kg), or higher (1.8 and 2.4 g/kg) than the training dose were tested to examine possible influence of ETOH pretreatment doses on the expression of acute tolerance. To assess concentrations of ETOH in the organism, a rebreathed air procedure was used. Equal concentrations after different ETOH doses were achieved by postponing the tests until sufficient time had elapsed. Only doses of ETOH higher than the training dose produced acute tolerance in the DDL procedure. For the response-time data no acute tolerance was observed. In the OF experiment, the occurrence of acute tolerance was examined for different spontaneous behaviours in drug-naive animals. At equal ETOH concentrations, the group examined during the descending phase of intoxication (1.8 g/kg, 60 min post-injection), reared significantly more than the group tested during the ascending phase (1.5 g/kg, 10 min post-injection). Other OF behaviours did not differ significantly between the two time intervals. Thus, it is suggested that acute tolerance is seen both in ETOH naive and in ETOH pre-exposed rats. However, in DDL acute tolerance was observed only when doses higher than training dose of ETOH were evaluated.