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See detailInfluence of the dose and the number of drug-context pairings on the magnitude and the long-lasting retention of cocaine-induced conditioned place preference in C57BL/6J mice
Brabant, Christian ULg; Quertemont, Etienne ULg; Tirelli, Ezio ULg

in Psychopharmacology (2005), 180(1), 33-40

Rationale: The place conditioning procedure is increasingly used to study relapse in drug seeking in mice. However, the retention course of drug-induced place preference has not been systematically ... [more ▼]

Rationale: The place conditioning procedure is increasingly used to study relapse in drug seeking in mice. However, the retention course of drug-induced place preference has not been systematically characterized. Methods: The effects of cocaine doses and number of conditioning trials on both the magnitude and the persistence of cocaine-induced conditioned place preference (CPP) were investigated in C57BL/6J mice. Twelve groups of animals were injected with saline, 4, 8 or 12 mg/kg cocaine (i.p.) and submitted to an unbiased counterbalanced place conditioning protocol including one, two or four drug-pairing sessions. Subsequently, the animals were tested at various time intervals after the last conditioning session. Results: One cocaine-pairing session was insufficient to induce a CPP. Two and four pairing sessions resulted in significant place preferences of similar magnitude for all tested doses of cocaine, the place preference induced by the greatest number of pairing sessions being the strongest. In the two-pairing groups, place preference lasted less than 14 days for any tested dose of cocaine. In contrast, all four-pairing groups still showed significant place preference 28 days after the last conditioning session. However, the magnitude of cocaine place preference slowly declined at a rate that was dependent upon cocaine dose. On the 35-day post-conditioning interval, only the 12-mg/kg cocaine group still displayed a significant place preference, whereas place preference was undetectable at 42 and 56 days post-conditioning for all groups. Conclusions: The number of cocaine-pairing sessions, but not cocaine dose, affected the magnitude of cocaine place preference in mice when tested 1 day after the last conditioning session. In contrast, both cocaine doses and the number of pairing sessions affected the persistence of cocaine place preference. Overall, these results demonstrate that cocaine-induced place preference is a long lasting phenomenon that is strongly affected by the number of drug-pairing trials. [less ▲]

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See detailDissociation between the locomotor and anxiolytic effects of acetaldehyde in the elevated plus-maze : evidence that acetaldehyde is not involved in the anxiolytic effects of ethanol in mice
Tambour, Sophie ULg; Didone, Vincent ULg; Tirelli, Ezio ULg et al

in European Neuropsychopharmacology (2005), 15(6), 655-662

Acetaldehyde, the first product of ethanol metabolism, has been suggested to play a major role in many behavioral effects of ethanol. However, very few studies have directly tested the behavioral effects ... [more ▼]

Acetaldehyde, the first product of ethanol metabolism, has been suggested to play a major role in many behavioral effects of ethanol. However, very few studies have directly tested the behavioral effects of the acute administration of acetaldehyde. In particular, the role of this metabolite in ethanol-induced anxiolytic effects has never been extensively tested. The aim of the present study was to characterize the anxiolytic effects of acetaldehyde in two strains of mice, C57BL/6J and CD1 mice with the elevated plus-maze procedure. The results show that acute injections of ethanol (1-2 g/kg) induced significant dose-dependent anxiolytic effects in both strains of mice. In contrast, acetaldehyde failed to produce any anxiolytic effect, although it induced a significant hypolocomotor effect at the highest doses. In an independent experiment, cyanamide, an aldehyde dehydrogenase inhibitor, prevented the locomotor stimulant effects of ethanol, although it failed to alter its anxiolytic effects. Together, the results of the present study indicate that acetaidehyde is not involved in ethanol-induced anxiolytic effects, although it may be involved in its sedative/hypolocomotor effects. (c) 2005 Elsevier BX and ECNP. All fights reserved. [less ▲]

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See detailEvidence that the relations between novelty-induced activity, locomotor stimulation and place preference induced by cocaine qualitatively depend upon the dose: A multiple regression analysis in inbred C57BL/6J mice
Brabant, Christian ULg; Quertemont, Etienne ULg; Tirelli, Ezio ULg

in Behavioural Brain Research (2005), 158(2), 201-210

It has been speculated that an individual's response to novelty is a reliable predictor of its vulnerability to develop addiction. However, the relationships between response to novelty and the ... [more ▼]

It has been speculated that an individual's response to novelty is a reliable predictor of its vulnerability to develop addiction. However, the relationships between response to novelty and the development of drug-induced conditioned place preference are still unclear. The present study investigates the relationships between locomotor responses to novelty, cocaine-induced locomotor stimulation and conditioned place preference in C57BL/6J mice with multiple regression analyses. Four groups of mice receiving saline, 4, 8 or 12 mg/kg cocaine (i.p.) were submitted to an 8-day unbiased counterbalanced place conditioning protocol. Levels of locomotion on the pre-conditioning session were used as a score of locomotor response to a novel environment. The locomotor activity on the first cocaine-pairing session of the conditioning procedure served as a measure of the locomotion-activating response to a single injection of cocaine. Cocaine-induced dose-dependent locomotor stimulant effects and a significant place preference at all tested doses. A positive correlation was found between the locomotor responses to novelty and the locomotor stimulant effects of cocaine, but was significant only for the highest dose of cocaine (12 mg/kg). In contrast, there was a negative correlation between the locomotor response to novelty and the conditioned place preference induced by 4 mg/kg cocaine. Finally, the locomotor stimulant effects of cocaine do not correlate with cocaine-induced conditioned place preference at any tested dose of cocaine. The relationships between locomotor response to novelty and both cocaine-induced stimulant and rewarding effects can be differentially affected by the dose in inbred C57BL/6J mice. (C) 2004 Elsevier B.V. All rights reserved. [less ▲]

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See detailAcetaldehyde and the central effects of alcohol: Beyond the discrepancies between animal and human studies
Quertemont, Etienne ULg

in Alcohol & Alcoholism (2005), 40(Suppl.1), 23

Whereas human studies keep reporting evidence that acetaldehyde accumulation prevents alcohol drinking and alcoholism, animal studies support a rewarding rather than aversive role for acetaldehyde. In ... [more ▼]

Whereas human studies keep reporting evidence that acetaldehyde accumulation prevents alcohol drinking and alcoholism, animal studies support a rewarding rather than aversive role for acetaldehyde. In recent years, the reinforcing properties of acetaldehyde were demonstrated in various rodent strains and using different experimental methods. These results led to the hypothesis that acetaldehyde might be involved in the addictive properties of alcohol. The most recent experimental studies suggest that the apparent discrepancies between animal and human studies might be due to the localization of acetaldehyde accumulation. Whereas peripheral acetaldehyde accumulation leads to adverse reactions and prevents alcohol drinking, brain acetaldehyde is believed to be primarily reinforcing in both rodents and humans. In addition to its possible role in the reinforcing properties of alcohol, there is also evidence that acetaldehyde is involved in many other behavioral effects of ethanol. This presentation reviews the latest results about the behavioral properties of acetaldehyde. In both CD1 and C57BL/6J mice, acetaldehyde induces locomotor depressant, sedative and amnesic effects. These effects are observed when acetaldehyde is administered either in the periphery or directly into the brain. In contrast to previous studies in rats, we found no evidence of the stimulant effects of acetaldehyde over a wide range of doses, whether injected in the periphery or administered intracerebroventricularly. Additional studies with cyanamide, an aldehyde dehydrogenase inhibitor leading to peripheral and central acetaldehyde accumulations after ethanol administration, also confirm the role of acetaldehyde in the locomotor depressant, sedative and amnesic effects of ethanol. However, a key issue remains to be addressed in order to demonstrate the role of acetaldehyde in alcohol abuse. To date, it remains uncertain whether pharmacologically relevant acetaldehyde concentrations are formed in the brain after alcohol consumption in vivo. [less ▲]

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See detailEffects of centrally versus peripherally administered ethanol in C57BL/6J and CD1 mice
Tambour, Sophie ULg; Didone, Vincent ULg; Quertemont, Etienne ULg et al

in Behavioural Pharmacology (2005), 16

Locomotor activation is often reported to occur after a systemic administration of low doses of ethanol in most mouse strains, as for example outbred CD1 mice. However, in some strains of mice, such as ... [more ▼]

Locomotor activation is often reported to occur after a systemic administration of low doses of ethanol in most mouse strains, as for example outbred CD1 mice. However, in some strains of mice, such as the inbred C57BL/6J mice, and in rats, systemic injections of ethanol typically induce only a depression of the locomotor activity. Recently, Correa et al. (2003) showed that direct infusions of ethanol in the brain ventricles of rats induced locomotor stimulant effects. These authors suggested that some undefined peripheral effects of ethanol may mask its central stimulant effects when ethanol is administered intraperitoneally. The aim of the present study was to investigate the locomotor effects of either intraperitoneal and intracerebroventricular ethanol administrations in two strains of mice, outbred CD1 and inbred C57BL/6J, that are respectively characterized by the presence and absence of a locomotor stimulant response to ethanol. The results showed that ethanol at moderate and high doses induced locomotor depressant effects in C57BL/6J mice whatever the route of ethanol administration. In contrast, ethanol induced a biphasic effect on locomotor activity in CD1 mice with a stimulant response at low doses followed by a significant sedation. Such a response to ethanol was observed after both peripheral and central administrations of ethanol. The results of the present study demonstrate that the locomotor effects of ethanol in mice are not affected by the route of administration, i.e. peripheral or central. In these rodents, there is no evidence that unidentified peripheral effects of ethanol mask the stimulant ethanol effects. [less ▲]

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See detailModulatory function of the H3 histaminergic receptor system in addiction: an example with cocaine and ethanol
Brabant, Christian ULg; Didone, Vincent ULg; Tirelli, Ezio ULg et al

Poster (2005)

The histaminergic neurotransmission is involved in many biological functions, including the modulation of arousal, fluid balance, food intake, reinforcement and learning. Recently, the results of several ... [more ▼]

The histaminergic neurotransmission is involved in many biological functions, including the modulation of arousal, fluid balance, food intake, reinforcement and learning. Recently, the results of several studies have also suggested that the central histaminergic system, and particularly the H3 receptors, plays a role in drug addiction. For example, in animal experiments, the administration of H3 agonists and antagonists modulate the self-administration of various drugs including cocaine, amphetamine and alcohol. In the present studies, we used the locomotor stimulant effects of drugs as an index of their abuse potential (most of addictive drugs stimulate locomotor activity, at least at some doses, and this effect is often considered as an intrinsic feature of drug addiction). In two independent experiments, we tested the effects of thioperamide, a histamine H3 antagonist/inverse agonist, on the locomotor stimulant effects of cocaine and ethanol. Our results show that thioperamide modulates the locomotor stimulant effects of both cocaine and ethanol. However, this modulatory effect was surprisingly opposite in direction depending upon the tested drug. Whereas thioperamide potentiated the locomotor stimulant effect of cocaine, it prevented the hyperactivity induced by 2 g/kg ethanol in mice. In the brain, H3 receptors is both a histamine autoreceptor modulating the synaptic release of histamine and a heteroreceptor that modulates the release of other neurotransmitters such as dopamine, acetylcholine and GABA. It is therefore likely that the modulatory action of thioperamide on cocaine and ethanol stimulant effects involves different neurotransmitter system. This conclusion is supported by our preliminary results on knock-out mice genetically devoid of histamine. In such knock-out mice, ethanol retains its stimulant properties, suggesting that histamine release is not involved in this effect. In contrast, these knock-out mice showed a reduced cocaine-induced hyperactivity, indicating that histamine release play a significant role in the stimulant effect of cocaine. [less ▲]

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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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