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See detailIs ethanol a pro-drug? The role of acetaldehyde in the central effects of ethanol
Quertemont, Etienne ULg; Tambour, Sophie ULg

in Trends in Pharmacological Sciences (2004), 25(3), 130-134

Acetaldehyde, the first product of ethanol metabolism, has been speculated to be involved in many behavioral effects of ethanol. However, its precise role remains a matter of debate, with some researchers ... [more ▼]

Acetaldehyde, the first product of ethanol metabolism, has been speculated to be involved in many behavioral effects of ethanol. However, its precise role remains a matter of debate, with some researchers suggesting that acetaldehyde has no role in the effects of ethanol and others contending that ethanol is a pro-drug whose pharmacological action is mediated by acetaldehyde. Recent studies support a role for acetaldehyde in the stimulant, reinforcing, hypnotic and amnesic effects of ethanol, and, in particular, alcohol abuse and alcoholism. However, current evidence indicates that acetaldehyde is not involved in some of the major neurochemical effects of ethanol. It is therefore likely that ethanol and acetaldehyde molecules act synergistically to determine the multiple neurochemical and behavioral effects of alcohol consumption. [less ▲]

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See detailBehavioral characterization of acetaldehyde in C57BL/6J mice: locomotor, hypnotic, anxiolytic and amnesic effects
Quertemont, Etienne ULg; Tambour, Sophie ULg; Bernaerts, Pascale et al

in Psychopharmacology (2004), 177(1-2), 84-92

Rationale: Acetaldehyde, the first metabolite of ethanol, was recently suggested to contribute to many behavioral effects of ethanol, although few studies have directly investigated the behavioral effects ... [more ▼]

Rationale: Acetaldehyde, the first metabolite of ethanol, was recently suggested to contribute to many behavioral effects of ethanol, although few studies have directly investigated the behavioral effects of acetaldehyde itself. Objectives: The aim of the present study was to characterize the locomotor, hypnotic, anxiolytic-like and amnesic effects of acetaldehyde in C57BL/6J mice. Methods: Increasing doses of acetaldehyde (0 - 300 mg/kg) were injected intraperitoneally and their effects on a series of representative behaviors were investigated. The locomotor effects of acetaldehyde were measured in activity boxes. The duration of the loss of righting reflex was used as an index of the hypnotic effects of acetaldehyde. The anxiolytic-like effects of acetaldehyde were tested with an elevated plus-maze and the amnesic effects with the one-trial passive avoidance test. Finally, brain and blood acetaldehyde concentrations were assessed. Results: Acetaldehyde induced a significant hypolocomotor effect at 170 mg/kg and higher doses. In addition, the hypnotic effects of acetaldehyde were demonstrated by a loss of righting reflex after the administration of 170 and 300 mg/kg acetaldehyde. The elevated plus-maze showed that acetaldehyde does not possess anxiolytic-like properties. Finally, acetaldehyde ( 100 - 300 mg/kg) dose-dependently altered memory consolidation as shown by a reduced performance in the passive avoidance test. Conclusions: The present results show that acetaldehyde induces sedative, hypnotic and amnesic effects, whereas it is devoid of stimulant and anxiolytic-like properties in C57BL/6J mice. However, the behavioral effects of acetaldehyde after intraperitoneal administration were apparent at very high brain concentrations. The present results also indicate that acetaldehyde is unlikely to be involved in the anxiolytic properties of ethanol in mice. [less ▲]

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See detailResponse to novelty as a predictor for drug effects: the pitfalls of some correlational studies
Quertemont, Etienne ULg; Brabant, Christian ULg; Tirelli, Ezio ULg

in Psychopharmacology (2004), 173(1-2), 221-224

In recent years, an individual's response to novelty has been postulated to predict its response to drugs of abuse and particularly to their addictive properties (Piazza et al. 1990). The hypothesis of a ... [more ▼]

In recent years, an individual's response to novelty has been postulated to predict its response to drugs of abuse and particularly to their addictive properties (Piazza et al. 1990). The hypothesis of a relationship between the response to novelty and the effects of addictive drugs was supported by a number of animal studies that reported correlations between responses to a novel environment and various effects of drugs, such as their locomotor stimulant effects, their reinforcing action or their propensity to be self-administered (Piazza et al. 1990; Klebaur et al. 2001; Carey et al. 2003; Shimosato and Watanabe 2003). Most of these studies concluded that an animal's response to novelty predicts its subsequent response to drug administration. However, correlational studies are sometimes hampered by methodological and statistical weaknesses that preclude a proper interpretation of the results. The two most frequent weaknesses are the lack of consideration for the correlation in the control group and the calculation of spurious correlations. [less ▲]

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See detailGenetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism
Quertemont, Etienne ULg

in Molecular Psychiatry (2004), 9(6), 570-581

Acetaldehyde, the first product of ethanol metabolism, has been speculated to be involved in many pharmacological and behavioral effects of ethanol. In particular, acetaldehyde has been suggested to ... [more ▼]

Acetaldehyde, the first product of ethanol metabolism, has been speculated to be involved in many pharmacological and behavioral effects of ethanol. In particular, acetaldehyde has been suggested to contribute to alcohol abuse and alcoholism. In the present paper, we review current data on the role of acetaldehyde and ethanol metabolism in alcohol consumption and abuse. Ethanol metabolism involves several enzymes. Whereas alcohol dehydrogenase metabolizes the bulk of ethanol within the liver, other enzymes, such as cytochrome P4502E1 and catalase, also contributes to the production of acetaldehyde from ethanol oxidation. In turn, acetaldehyde is metabolized by the enzyme aldehyde dehydrogenase. In animal studies, acetaldehyde is mainly reinforcing particularly when injected directly into the brain. In humans, genetic polymorphisms of the enzymes alcohol dehydrogenase and aldehyde dehydrogenase are also associated with alcohol drinking habits and the incidence of alcohol abuse. From these human genetic studies, it has been concluded that blood acetaldehyde accumulation induces unpleasant effects that prevent further alcohol drinking. It is therefore speculated that acetaldehyde exerts opposite hedonic effects depending on the localization of its accumulation. In the periphery, acetaldehyde is primarily aversive, whereas brain acetaldehyde is mainly reinforcing. However, the peripheral effects of acetaldehyde might also be dependent upon its peak blood concentrations and its rate of accumulation, with a narrow range of blood acetaldehyde concentrations being reinforcing. [less ▲]

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See detailDiscriminative stimulus effects of ethanol: Lack of interaction with taurine
Quertemont, Etienne ULg; Grant, Kathleen A.

in Behavioural Pharmacology (2004), 15(7), 495-501

Recent microdialysis studies showed that ethanol administration increases the release of taurine in various rat brain regions, and it was suggested that this increase in extracellular concentrations of ... [more ▼]

Recent microdialysis studies showed that ethanol administration increases the release of taurine in various rat brain regions, and it was suggested that this increase in extracellular concentrations of taurine might mediate some of the neurochemical effects of ethanol. Previous drug discrimination studies showed that positive modulators of the GABA(A) receptor consistently substituted for ethanol discriminative stimulus effects. Since taurine is also believed to modulate GABA(A) receptor activity, this study addressed the hypothesis that taurine mediates the discriminative stimulus effects of ethanol due to GABA(A) activation. Male Long-Evans rats were trained to discriminate water from either 1 or 2 g/kg ethanol. In a first experiment, various taurine doses (0-500 mg/kg) were tested to investigate whether taurine substitutes for ethanol. In a second experiment, rats were pretreated with either 500 mg/kg taurine or an equivalent volume of saline before testing for ethanol discrimination with various ethanol doses (0-2.0 g/kg). The results showed that taurine does not substitute for ethanol at any tested doses. In addition, taurine pretreatments failed to modify the dose-response curve for ethanol discrimination. These results demonstrate that taurine is not directly involved in mediating the discriminative stimulus effects of ethanol. It is therefore very unlikely that the brain release of taurine observed after ethanol administration is implicated in the major pharmacological effects of ethanol, i.e. positive modulation of GABA(A) receptor, that mediate its discriminative stimulus effects. [less ▲]

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See detailBehavioral characterization of acetaldehyde in mice
Quertemont, Etienne ULg; Tambour, Sophie ULg; Tirelli, Ezio ULg

in Alcoholism, Clinical & Experimental Research (2004), 28(5), 196-196

Acetaldehyde, the first product of ethanol metabolism, has long been speculated to be involved in many of the behavioral effects of ethanol, although its precise role remains a matter of debate. However ... [more ▼]

Acetaldehyde, the first product of ethanol metabolism, has long been speculated to be involved in many of the behavioral effects of ethanol, although its precise role remains a matter of debate. However, most of the results supporting a role for acetaldehyde in ethanol’s effects come from studies in which ethanol metabolism was pharmacologically manipulated, whereas the behavioral properties of acetaldehyde itself are still largely unknown. In the present studies, we have characterized the locomotor, hypnotic, anxiolytic and amnesic effects of both ethanol and acetaldehyde in C57BL/6J and CD1 mice. Several classical behavioral tests were used: the open field, the loss of righting reflex, the plus-maze, the place conditioning and the passive avoidance. The results show that acetaldehyde similarly to ethanol induces sedation and hypnotic effects at high doses. In addition, acetaldehyde displays potent amnesic effects in the passive avoidance test, suggesting that the first metabolite of ethanol might be critically involved in the memory-impairing effects of ethanol. However, in contrast to ethanol, acetaldehyde does not show anxiolytic properties in the plus-maze. In a second part of the present studies, acetaldehyde contribution to ethanol’s behavioral effects was investigated by using several inhibitors of ethanol metabolism (3-amino-1,2,4-triazole, a catalase inhibitor, and disulfiram, an aldehyde dehydrogenase inhibitor). Overall, the present results suggest that acetaldehyde is involved in some of ethanol’s behavioral effects (amnesia, locomotor depression, sedation) but not in others (in particular anxiolysis). [less ▲]

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See detailAlcoolisme ou aldehydisme : Role de l'acetaldehyde dans les effets psychotropes de l'alcool
Quertemont, Etienne ULg

in Alcoologie et Addictologie (2003), 25(1), 33-39

De récentes études ont suggéré que l’acétaldéhyde, premier produit du métabolisme de l’éthanol, participe aux effets psychotropes résultant de la consommation d’alcool. L’acétaldéhyde semble ... [more ▼]

De récentes études ont suggéré que l’acétaldéhyde, premier produit du métabolisme de l’éthanol, participe aux effets psychotropes résultant de la consommation d’alcool. L’acétaldéhyde semble particulièrement impliqué dans les effets renforçants de l’éthanol, ce qui suggère un rôle important pour ce métabolite dans l’abus d’alcool et l’alcoolisme. Cette mise au point passe en revue les preuves expérimentales qui tendent à démontrer le rôle de l’acétaldéhyde dans les effets psychotropes de l’alcool. Les études animales et humaines indiquent que l’acétaldéhyde exerce une action renforçante plus puissante que l’éthanol dans le cerveau. Au contraire, il semble que l’accumulation d’acétaldéhyde dans le sang périphérique provoque des effets désagréables et une aversion pour l’alcool. Les effets hédoniques de l’acétaldéhyde seraient donc déterminés par le lieu, central ou périphérique, de son accumulation principale. Toutefois, l’acétaldéhyde ne doit pas être considéré comme le seul principe actif responsable de tous les effets psychotropes de l’éthanol. Plusieurs études ont par exemple démontré que l’acétaldéhyde ne participe pas significativement aux effets subjectifs de l’éthanol. Si l’acétaldéhyde exerce effectivement un rôle dans les effets renforçants de l’éthanol, il ne doit donc pas être tenu pour responsable de tous les effets pharmacologiques de la consommation d’alcool. [less ▲]

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See detailSystemic osmotic manipulations modulate ethanol-induced taurine release : a brain microdialysis study
Quertemont, Etienne ULg; Devitgh, Audrey; De Witte, Philippe

in Alcohol (2003), 29(1), 11-19

In recent microdialysis studies, increased extracellular concentrations of taurine after high ethanol dose administration were identified in various rat brain regions. The mechanisms by which ethanol ... [more ▼]

In recent microdialysis studies, increased extracellular concentrations of taurine after high ethanol dose administration were identified in various rat brain regions. The mechanisms by which ethanol caused these increases in extracellular taurine concentration remained unclear but could be related to ethanol-induced cell swelling. The aim of the current study was to investigate whether changes in the body osmotic state modulate the effects of ethanol on brain extracellular taurine concentrations. In several groups of rats, brain hypoosmotic or hyperosmotic states were superimposed on acute ethanol (2.0-g/kg) injections, and extracellular taurine concentrations within the nucleus accumbens were assessed by using an intracerebral microdialysis procedure. A hypoosmotic state was obtained by systemic administration of water while hyperosmotic states were induced by intraperitoneal injections of hypertonic saline solutions (1.8% or 3.6% saline). In isoosmotic conditions, ethanol induced an immediate and significant increase in taurine microdialysate content, confirming results of previous studies. However, the effects of ethanol on taurine concentrations were modulated by osmotic manipulations. Hypoosmotic conditions significantly potentiated ethanol-induced taurine release. In contrast, ethanol-induced increases in extracellular taurine levels were attenuated by 1.8% saline injection and totally prevented by 3.6% saline administration. These results strongly argue in favor of a primary role, of osmoregulation in ethanol-induced taurine release. Ethanol-induced cell swelling probably activates volume-sensitive channels, and taurine passively diffuses outside the cells along its concentration gradient. (C) 2003 Elsevier Science Inc. All rights reserved. [less ▲]

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See detailRole of catalase in ethanol-induced conditioned taste aversion : a study with 3-amino-1,2,4-triazole
Quertemont, Etienne ULg; Escarabajal, M. Dolores; De Witte, Philippe

in Drug and Alcohol Dependence (2003), 70(1), 77-83

Recent studies involved acetaldehyde, the first ethanol metabolite, in both the rewarding and aversive effects of ethanol consumption. Brain acetaldehyde is believed to originate mainly from local brain ... [more ▼]

Recent studies involved acetaldehyde, the first ethanol metabolite, in both the rewarding and aversive effects of ethanol consumption. Brain acetaldehyde is believed to originate mainly from local brain metabolism of ethanol by the enzyme catalase. Therefore, the inhibition of catalase by 3-amino-1,2,4-triazole (aminotriazole) may help to clarify the involvement of acetaldehyde in ethanol's hedonic effects. In the present study, multiple doses of both ethanol and aminotriazole were used to investigate the effects of catalase inhibition on ethanol-induced conditioned taste aversion (CTA). A separate microdialysis experiment investigated the effects of aminotriazole pretreatment on the time course of brain ethanol concentrations. Ethanol induced a dose-dependent CTA with a maximal effect after conditioning with 2.0 g/kg ethanol. Aminotriazole pretreatments dose-dependently potentiated the CTA induced by 1.0 g/kg ethanol. However, aminotriazole pretreatments did not alter the CTA induced by higher ethanol doses (1.5 and 2.0 g/kg) probably because a maximal aversion for saccharin was already obtained without aminotriazole. The results of the microdialysis experiment confirmed that the effects of aminotriazole cannot be attributed to local alterations of brain ethanol levels. The present study argues against a role for brain acetaldehyde in ethanol's aversive effects but in favor of its involvement in ethanol rewarding properties. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. [less ▲]

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See detailRole of acetaldehyde in ethanol-induced conditioned taste aversion in rats
Escarabajal, Dolores M.; De Witte, Philippe; Quertemont, Etienne ULg

in Psychopharmacology (2003), 167(2), 130-136

Rationale: In spite of many recent studies on the effects of acetaldehyde, it is still unclear whether acetaldehyde mediates the reinforcing and/or aversive effects of ethanol. Objectives: The present ... [more ▼]

Rationale: In spite of many recent studies on the effects of acetaldehyde, it is still unclear whether acetaldehyde mediates the reinforcing and/or aversive effects of ethanol. Objectives: The present study reexamined the role of acetaldehyde in ethanol-induced conditioned taste aversion (CTA). A first experiment compared ethanol- and acetaldehyde-induced CTA. In a second experiment, cyanamide, an aldehyde dehydrogenase inhibitor, was administered before conditioning with either ethanol or acetaldehyde to investigate the effects of acetaldehyde accumulation. Methods: A classic CTA protocol was used to associate the taste of a saccharin solution with either ethanol or acetaldehyde injections. In experiment 1, saccharin consumption was followed by injections of either ethanol (0, 0.5, 1.0, 1.5 or 2.0 g/kg) or acetaldehyde (0, 100, 170 or 300 mg/kg). In experiment 2, the rats were pretreated with either saline or cyanamide (25 mg/kg) before conditioning with either ethanol or acetaldehyde. Results: Both ethanol and acetaldehyde induced significant CTA. However, ethanol produced a very strong CTA relative to acetaldehyde that induced only a weak CTA even at toxic doses. Cyanamide pretreatments significantly potentiated ethanol- but not acetaldehyde-induced CTA. Conclusions: The present results indicate that ethanol-induced CTA does not result from brain acetaldehyde effects. In contrast, it is suggested that the reinforcing effects of brain acetaldehyde might actually reduce ethanol-induced CTA. Our results also suggest that the inhibition of brain catalase activity may contribute to the potentiating effects of cyanamide on ethanol-induced CTA. [less ▲]

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See detailDiscriminative stimulus effects of ethanol with a conditioned taste aversion procedure: lack of acetaldehyde substitution
Quertemont, Etienne ULg

in Behavioural Pharmacology (2003), 14(4), 343-350

Acetaldehyde has been suggested to mediate a number of the pharmacological and behavioural effects of ethanol. Recently, several studies investigated the role of acetaldehyde in the subjective effects of ... [more ▼]

Acetaldehyde has been suggested to mediate a number of the pharmacological and behavioural effects of ethanol. Recently, several studies investigated the role of acetaldehyde in the subjective effects of ethanol, but obtained conflicting results. With the discriminative taste aversion (DTA) procedure, high acetaldehyde doses were shown to substitute for the discriminative stimulus effects of ethanol. In contrast, the operant drug discrimination protocol failed to show any substitution effect of acetaldehyde. Several methodological differences between the two procedures could explain these discrepancies, and particularly the absence of an individual discrimination criterion in the DTA procedure. In the present study, the DTA procedure was adapted to introduce such a criterion. In addition, the effects of acetaldehyde were compared with those of other drugs, for which the substitution effects for ethanol are well known. Rats were trained to discriminate 1.0 g/kg ethanol from saline in a DTA protocol. When the rats met the criterion of ethanol discrimination, various doses of several drugs were tested for their ethanol stimulus substitution effects: ethanol, acetaldehyde, dizocilpine, diazepam and nicotine. The results showed a clear dose-dependent discrimination of ethanol stimulus effects. In addition, dizocilpine fully substituted for ethanol, while diazepam only partially substituted. In contrast, both acetaldehyde and nicotine failed to substitute for ethanol. These results show that acetaldehyde is not significantly involved in the subjective and discriminative stimulus effects of ethanol. Acetaldehyde up to toxic doses did not substitute for the ethanol discriminative stimulus in the DTA protocol, when non-specific effects were carefully controlled. [less ▲]

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See detailBrain ethanol concentrations and ethanol discrimination in rats : effects of dose and time
Quertemont, Etienne ULg; Green, Heather L.; Grant, Kathleen A.

in Psychopharmacology (2003), 168(3), 262-270

Rationale. In drug discrimination procedures, the substitution pattern for ethanol of various receptor ligands is dependent upon ethanol training dose, presumably reflecting functionally different ... [more ▼]

Rationale. In drug discrimination procedures, the substitution pattern for ethanol of various receptor ligands is dependent upon ethanol training dose, presumably reflecting functionally different concentrations of ethanol in the brain. The discriminative stimulus effects of ethanol are also time-dependent, although very few studies have investigated the time course of ethanol discriminations. Objectives. The present study investigated the relationship between brain ethanol concentrations (BrEC), as measured by intracranial microdialysis of the nucleus accumbens, and the time course of ethanol discriminative effects. Methods. Two groups of rats were trained to discriminate either 1.0 or 2.0 g/kg ethanol from water following a 30-min post-ethanol interval. Following training, the time course of the discriminative stimulus was assessed using a series of abbreviated testing trials at 20-min intervals for 5 h after the administration of various ethanol doses (0, 0.5, 1.0 and 2.0 g/kg). The rats were then fitted with microdialysis probes and the time course of BrECs were determined under conditions similar to the behavioral assessments. Results. BrECs were significantly above zero at 4 min post-gavage and attained peak concentrations of 16 mmol/l, 24 mmol/l and 42 mmol/l at 9 min, 16 min and 95 min after IG administration of 0.5, 1.0 and 2.0 g/kg ethanol, respectively. BrECs were similar in ethanol-naive and ethanol-trained rats, indicating a lack of pharmacokinetic tolerance under these discrimination procedures. The discriminative stimulus effects of ethanol were dose- and time-dependent, with a threshold concentration of approximately 12 mmol/l achieved at 5 min after 1.0 g/kg ethanol gavage in rats trained to discriminate 1.0 g/kg ethanol. Acute tolerance to the discriminative stimulus effects of ethanol was evident from BrECs 2-5 h post-ethanol gavage. Conclusions. Ethanol given intragastrically results in a rapid increase in BrEC, independent of ethanol exposure history. The discriminative stimulus effects of ethanol trained at 30 min post-gavage reflect a specific range of BrEC, and depend on the training dose. These data suggest that qualitatively different stimulus effects of ethanol reflect both different ranges of BrEC, as well as within dose acute tolerance to the discriminative stimulus effects. [less ▲]

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See detailBehavioral characterization of acetaldehyde in C57BL/6J mice: Locomotor, hypnotic and ataxic effects
Quertemont, Etienne ULg; Tambour, Sophie ULg; Tirelli, Ezio ULg

in Behavioural Pharmacology (2003), 14(Suppl. 1), 69-69

Acetaldehyde, the first ethanol metabolite, was recently suggested to play a major role in many behavioral effects of ethanol. However, no studies have directly investigated the behavioral effects of ... [more ▼]

Acetaldehyde, the first ethanol metabolite, was recently suggested to play a major role in many behavioral effects of ethanol. However, no studies have directly investigated the behavioral effects of acetaldehyde after acute administration. Therefore, the aim of the present study was to characterize the locomotor, hypnotic and ataxic effects of acetaldehyde in C57BL/6J mice. Various acetaldehyde doses (0-300 mg/kg) were injected intraperitoneally and their effects were investigated with several classical behavioral tests. The locomotor effects of acetaldehyde were measured in standard activity boxes. In addition, the loss of righting reflex was used to assess the hypnotic effects of acetaldehyde. Finally, the ataxic effects of acetaldehyde were studied with the horizontal wire test. The results show that acetaldehyde induced a significant hypolocomotor effect at 170 mg/kg and higher doses. In addition, the hypnotic effects of acetaldehyde were evidenced by a loss of righting reflex in doses between 170 and 300 mg/kg. However, the locomotor and hypnotic effects of acetaldehyde were very brief relative to what is observed after ethanol administration. After 170 mg/kg acetaldehyde, normal activity was recovered in less than 30 minutes and the loss of righting reflex lasted only an average of 6.14 ± 1.29 minutes after the administration of 300 mg/kg acetaldehyde, the highest testable dose before lethality. Ataxic effects were observed with lower doses that did not significantly affect locomotor activity. These results show that acetaldehyde, like ethanol, possesses sedative, hypnotic and ataxic properties and therefore indicate that the first product of ethanol metabolism might be involved in these ethanol effects. [less ▲]

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See detailBehavioral characterization of acetaldehyde in C57BL/6J mice: Anxiolytic, amnesic and hedonic effects
Tambour, Sophie ULg; Quertemont, Etienne ULg; Tirelli, Ezio ULg

in Behavioural Pharmacology (2003), 14(Suppl. 1), 68-69

It has been postulated that a number of central effects of ethanol are mediated through the action of its first metabolite, acetaldehyde. In particular, acetaldehyde might be involved in the anxiolytic ... [more ▼]

It has been postulated that a number of central effects of ethanol are mediated through the action of its first metabolite, acetaldehyde. In particular, acetaldehyde might be involved in the anxiolytic and hedonic effects of ethanol and is therefore believed to play an important role in alcohol abuse. In agreement with this assumption, previous studies indicated that acetaldehyde is mainly reinforcing in rats, which have been shown to readily self-administer acetaldehyde both peripherally and centrally. However, the hedonic effects of acetaldehyde have never been tested in mice, and the possible amnesic and anxiolytic effects of acetaldehyde remain to be elucidated. Therefore, the present studies were aimed at characterizing the anxiolytic, hedonic and amnesic effects of acetaldehyde after its acute peripheral administration to C57BL/6J mice. The effects of intraperitoneal acetaldehyde (0-300 mg/kg) injections were assessed in several classical behavioral tests. The anxiolytic effects were tested with the elevated plus maze, the hedonic effects with the place conditioning procedure and the amnesic effects with the passive avoidance apparatus. Our results show that acetaldehyde dose-dependently altered memory consolidation as evidenced by a reduced performance in the passive avoidance test when acetaldehyde was injected immediately after training at doses between 100 and 300 mg/kg. The elevated plus-maze showed that acetaldehyde, in contrast to ethanol, does not possess anxiolytic properties. Finally, the results of the place conditioning experiment confirmed that acetaldehyde displays significant hedonic properties. The present results add further support to the role of acetaldehyde in ethanol amnesic and hedonic effects but interestingly suggest that acetaldehyde is not involved in ethanol anxiolytic effects. [less ▲]

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See detailDifferential taurine responsiveness to ethanol in high- and low-alcohol sensitive rats : a brain microdialysis study
Quertemont, Etienne ULg; Linotte, Sylvie; De Witte, Philippe

in European Journal of Pharmacology (2002), 444(3), 143-150

Several microdialysis studies have investigated the effects of acute ethanol on extracellular amino acids in various rat brain regions, However, these studies led to conflicting results, suggesting that ... [more ▼]

Several microdialysis studies have investigated the effects of acute ethanol on extracellular amino acids in various rat brain regions, However, these studies led to conflicting results, suggesting that individual differences between rat strains and lines may play an important role. In the present study, high-alcohol sensitive (HAS) and low-alcohol sensitive (LAS) rats were used to investigate the possible relationship between ethanol sensitivity and the concentrations of extracellular amino acids in the nucleus accumbens. Several groups of HAS and LAS rats were injected with either saline or ethanol (1.0, 2.0 or 3.0 g/kg, i.p.) and the concentrations of amino acids in the nucleus accumbens microdialysates were assayed by electrochemical detection. Acute ethanol induced a dose-dependent increase in extracellular taurine concentrations. However, this increase was significantly reduced at 2,0 and 3.0 g,,kg ethanol in HAS rats relative to LAS rats. Since the biological functions of taurine suggest its implication in the reduction of ethanol adverse effects, a higher increase in taurine concentrations may contribute to the lower ethanol sensitivity of LAS rats. Although 2.0 and 3.0 g/kg ethanol did not affect extracellular glutamate concentrations, a significant increase in glutamate was observed after 1.0 g/kg ethanol to HAS rats but not to LAS rats. Such an effect remains unexplained but suggests that discrepancies between the results of previous microdialysate studies may be related to differences in the ethanol sensitivities of various rat strains. (C) 2002 Elsevier Science B.V All rights reserved. [less ▲]

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See detailRole of acetaldehyde in the discriminative stimulus effects of ethanol
Quertemont, Etienne ULg; Grant, Kathleen A

in Alcoholism, Clinical & Experimental Research (2002), 26(6), 812-817

Background: Acetaldehyde has been suggested to mediate some of the effects of ethanol. Acetaldehyde can be produced by the enzyme catalase within the brain after ethanol administration. The catalase ... [more ▼]

Background: Acetaldehyde has been suggested to mediate some of the effects of ethanol. Acetaldehyde can be produced by the enzyme catalase within the brain after ethanol administration. The catalase inhibitor 3-amino-1,2,4-triazole (AT) reduces the production of acetaldehyde, and AT administration can reduce a number of ethanol-induced behavioral effects; this suggests the involvement of acetaldehyde in these behaviors. However, a role for acetaldehyde in mediating the discriminative stimulus effects of ethanol remains unclear. Methods: The contribution of acetaldehyde to the discriminative stimulus effects of ethanol was investigated by use of a two-lever drug discrimination paradigm with food reinforcement. Male Long-Evans rats were trained to discriminate water from either 1.0 or 2.0 g/kg ethanol. Stimulus substitution tests were conducted with ethanol (0 –2.5 g/kg by gavage) and acetaldehyde (0–300 mg/kg intraperitoneally). A cumulative dose-response procedure was then used to investigate the effects of pretreatments with AT (0.5 and 1.0 g/kg intraperitoneally) on ethanol discrimination. Results: Acetaldehyde up to doses that decreased response rates (300 mg/kg) did not substitute for the discriminative stimulus effects of 1.0 or 2.0 g/kg ethanol. In addition, AT pretreatment did not affect the dose-response curves for ethanol discrimination. Conclusions: These results show that exogenous acetaldehyde administration does not produce discriminative stimulus effects that are similar to those of ethanol. Also, pretreatment with the catalase inhibitor did not affect the dose-response curve for ethanol discrimination, and this suggests that endogenously produced acetaldehyde does not contribute to the discriminative stimulus effects of ethanol. Together these results suggest that acetaldehyde does not mediate the discriminative stimulus effects of 1.0 to 2.0 g/kg ethanol. [less ▲]

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See detailAcamprosate reduces context-dependent ethanol effects
Quertemont, Etienne ULg; Brabant, Christian ULg; De Witte, Philippe

in Psychopharmacology (2002), 164(1), 10-18

Rationale: Previous studies have indicated that the conditioned effects of environmental stimuli contribute to ethanol tolerance and abuse. Acamprosate was recently suggested to reduce the effects of ... [more ▼]

Rationale: Previous studies have indicated that the conditioned effects of environmental stimuli contribute to ethanol tolerance and abuse. Acamprosate was recently suggested to reduce the effects of environmental stimuli previously associated with ethanol administrations. This action is believed to contribute to the clinical benefits of acamprosate treatment in alcoholics. Objectives: In the present experiment, a classical drug-conditioning paradigm was used to test whether acamprosate modulates the effects of ethanol-paired environmental stimuli on spontaneous motor activity. Methods: Wistar rats were divided into three groups: cued, uncued and control. The cued group daily received ethanol injections (2.0 g/kg, IP) in a specific testing environment. The uncued group daily received ethanol injections (2.0 g/kg, IP) in their home cage but never experienced ethanol in the testing environment. The control group was injected with saline and never experienced ethanol. After 8 conditioning days, the rats were IP injected with various ethanol doses (saline, 1.0, 1.5 or 2.0 g/kg) and their spontaneous motor activity in the testing environment was recorded to investigate their respective tolerance to ethanol inhibitory effects. In the second part of the study, the same procedure was repeated with chronically acamprosate-treated rats. The chronic acamprosate treatment (400 mg/kg per day) started 2 weeks before the conditioning procedure by diluting acamprosate in the drinking bottles and was maintained throughout the whole experiment. Results: The cued rats showed a significant environment-dependent tolerance to ethanol inhibitory effects relative to the uncued and control rats. This higher ethanol tolerance of the cued rats was mainly due to a faster recovery from ethanol's inhibitory effects on spontaneous activity. Furthermore, the cued rats showed a higher level of activity in the testing environment after the saline injection. However, it is not clear whether this hyperactivity is a conditioned compensatory response or an increased exploratory behavior. Acamprosate totally abolished the environment-dependent tolerance to ethanol, whereas it did not alter the hyperactivity of the cued rats in the testing environment. Conclusions: The results of the present study suggest that acamprosate reduces ethanol-conditioned effects. Such an action may be of importance to explain the anti-relapse effects of acamprosate. [less ▲]

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See detailEffet placebo, effet nocebo: comment la science explique les guérions miraculeuses
Quertemont, Etienne ULg

Scientific conference (2002)

L’effet placebo est habituellement considéré comme l’ensemble des réponses psychologiques et physiologiques des patients à une substance inerte. On parle d’effet placebo lorsque cette réponse constitue un ... [more ▼]

L’effet placebo est habituellement considéré comme l’ensemble des réponses psychologiques et physiologiques des patients à une substance inerte. On parle d’effet placebo lorsque cette réponse constitue un effet bénéfique pour la santé et d’effet nocebo lorsque les conséquences sont néfastes. Cependant, les phénomènes placebo/nocebo recouvrent plus largement tous les effets du contexte environnemental qui ne résultent pas spécifiquement du traitement médical administré. Une partie de ce qu’on nomme effet placebo/nocebo peut s’expliquer par des mécanismes de conditionnement pavlovien. Des effets placebo résultant du conditionnement pavlovien sont ainsi régulièrement mis en évidence sur des animaux de laboratoire. Au conditionnement pavlovien s’ajoute également chez l’être humain un facteur plus spécifiquement psychologique : l’effet des croyances et des attentes (expectancies). De nombreuses études ont ainsi démontré que les croyances et les attentes des patients exercent des effets objectifs sur leur santé qui se traduisent par des modifications biologiques. Nous examinerons plus particulièrement les mécanismes qui permettent à ces influences psychologiques de modifier l’état biologique d’un sujet. Parmi ceux-ci, le système immunitaire ainsi que les opiacés endogènes qui régulent la douleur semblent particulièrement influencés par l’état psychologique. Finalement nous montrerons comment les phénomènes placebo/nocebo apportent une explication rationnelle à plusieurs exemples de guérisons miraculeuses ou pseudo-scientifiques. Parmi ces exemples nous examinerons plus particulièrement le rôle important que joue l’effet placebo dans l’homéopathie. [less ▲]

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See detailEthanol-conditioned withdrawal syndrome
Quertemont, Etienne ULg; De Witte, Philippe

in Proceedings of the 22nd European Winterconference on Brain Research (2002)

The withdrawal syndrome is closely related to the concepts of tolerance and physical dependence. The chronic consumption of a drug is believed to induce adaptive changes that are designed to oppose the ... [more ▼]

The withdrawal syndrome is closely related to the concepts of tolerance and physical dependence. The chronic consumption of a drug is believed to induce adaptive changes that are designed to oppose the acute effects of the drug. Such adaptive changes increase the tolerance to acute drug effects but lead to physical dependence, which is revealed by withdrawal symptoms when the drug is cleared from the body. However, another form of adaptive response to repeated drug consumption has been identified. This adaptive response appears after the intermittent repeated administration of a drug in association with the same set of environmental stimuli. After several associations, these environmental stimuli become able to induce a conditioned adaptive response. Such response leads to the phenomenon of “environment-dependent tolerance” that was observed with many drugs of abuse. However, if the drug is not administered, the conditioned stimuli alone may induce a “conditioned withdrawal syndrome”. Although less studied than the classical withdrawal syndrome, this conditioned withdrawal syndrome may be of importance for the development of drug dependence. In our experiments, we have studied the development of a conditioned withdrawal syndrome after repeated associations of a specific set of environmental stimuli with ethanol injections in Wistar rats. After repeated administrations of ethanol, the rats showed a clear environmental-dependent tolerance to ethanol. Furthermore, these conditioned stimuli induced behavioral (hyperexcitation) and neurochemical (increase glutamate release) responses similar to those observed after chronic alcohol withdrawal. [less ▲]

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See detailTime-course of brain ethanol levels and the acoustic startle response in the rat following the acute administration of ethanol
Williams, S. A.; Quertemont, Etienne ULg; Green, Heather et al

in Alcoholism, Clinical & Experimental Research (2001), 25

It is known that ethanol administration inhibits the acoustic startle response, but whether this sensitivity varies within-session has not been investigated. The purpose of the present study was to ... [more ▼]

It is known that ethanol administration inhibits the acoustic startle response, but whether this sensitivity varies within-session has not been investigated. The purpose of the present study was to compare the time-course of ethanol levels in brain with alterations in the acoustic startle response. Three experiments were conducted in adult male Sprague-Dawley rats. 1) Ethanol concentrations in brain were determined by microdialysis following the acute administration of 0.3, 1.0 and 3.0 g/kg ig of ethanol. 2) The effect of ethanol on the acoustic startle response was determined after the same doses. 3) The acoustic startle response was determined during two time periods, at 2-18 and 30-46 minutes, after ethanol administration to evaluate periods of ascending and descending ethanol levels. In expt. 1, brain levels of ethanol rose rapidly, peaking within 4-8 minutes following all doses. In expt. 2, ethanol administration reduced the acoustic startle response in a dose-related manner; all doses significantly reduced the response. In expt. 3, prepulse inhibition was diminished by ethanol during a very short period immediately after ethanol administration, whereas the acoustic startle response was inhibited only during later times. These data indicate that the acoustic startle response was exquisitely sensitive to ethanol, even at doses as low as 0.3 g/kg. In addition, prepulse inhibition was selectively disrupted immediately after ethanol administration, which suggests that this phenomenon may accompany the short-lived ascending limb of the brain ethanol curve. Supported by AA 12356 (DL) and AA11997. [less ▲]

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