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See detailAcetaldehyde-related pathology: bridging the trans-disciplinary divide
Quertemont, Etienne ULg

in Novartis Foundation (Ed.) Acetaldehyde-related pathology: bridging the trans-disciplinary divide (2007)

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See detailThe psychostimulant and rewarding effects of cocaine in histidine decarboxylase knockout mice do not support the hypothesis of an inhibitory function of histamine on reward
Brabant, Christian ULg; Quertemont, Etienne ULg; Anaclet, Christelle et al

in Psychopharmacology (2007), 190(2), 251-263

RATIONALE AND OBJECTIVES: Lesion studies have shown that the tuberomammillary nucleus (TM) exerts inhibitory effects on the brain reward system. To determine whether histamine from the TM is involved in ... [more ▼]

RATIONALE AND OBJECTIVES: Lesion studies have shown that the tuberomammillary nucleus (TM) exerts inhibitory effects on the brain reward system. To determine whether histamine from the TM is involved in that reward inhibitory function, we assessed the stimulant and rewarding effects of cocaine in knockout mice lacking histidine decarboxylase (HDC KO mice), the histamine-synthesizing enzyme. If histamine actually plays an inhibitory role in reward, then it would be expected that mice lacking histamine would be more sensitive to the behavioral effects of cocaine. MATERIALS AND METHODS: The first experiment characterized spontaneous locomotion and cocaine-induced hyperactivity (0, 8, and 16 mg/kg, i.p.) in wild-type and HDC KO mice. The rewarding effects of cocaine were investigated in a second experiment with the place-conditioning technique. RESULTS: The first experiment demonstrated that histidine decarboxylase mice showed reduced exploratory behaviors but normal habituation to the test chambers. After habituation to the test chambers, HDC KO mice were slightly, but significantly, less stimulated by cocaine than control mice. This finding was replicated in the second experiment, when cocaine-induced activity was monitored with the place-conditioning apparatus. Furthermore, a significant place preference was present in both genotypes for 8 and 16 mg/kg cocaine, but not for 2 and 4 mg/kg. CONCLUSIONS: Our data confirm previous results demonstrating that HDC KO mice show reduced exploratory behaviors. However, contrary to the hypothesis that histamine plays an inhibitory role in reward, histamine-deficient mice were not more responsive to the psychostimulant effects of cocaine. [less ▲]

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See detailPreclinical and clinical pharmacology of alcohol dependence
Tambour, Sophie ULg; Quertemont, Etienne ULg

in Fundamental & Clinical Pharmacology (2007), 21(1), 9-28

In recent years, advances in neuroscience led to the development of new medications to treat alcohol dependence and especially to prevent alcohol relapse after detoxification. Whereas the earliest ... [more ▼]

In recent years, advances in neuroscience led to the development of new medications to treat alcohol dependence and especially to prevent alcohol relapse after detoxification. Whereas the earliest medications against alcohol dependence were fortuitously discovered, recently developed drugs are increasingly based on alcohol's neurobiological mechanisms of action. This review discusses the most recent developments in alcohol pharmacotherapy and emphasizes the neurobiological basis of anti-alcohol medications. There are currently three approved drugs for the treatment of alcohol dependence with quite different mechanisms of action. Disulfiram is an inhibitor of the enzyme aldehyde dehydrogenase and acts as an alcohol-deterrent drug. Naltrexone, an opiate antagonist, reduces alcohol craving and relapse in heavy drinking, probably via a modulation of the mesolimbic dopamine activity. Finally, acamprosate helps maintaining alcohol abstinence, probably through a normalization of the chronic alcohol-induced hyperglutamatergic state. In addition to these approved medications, many other drugs have been suggested for preventing alcohol consumption on the basis of preclinical studies. Some of these drugs remain promising, whereas others have produced disappointing results in preliminary clinical studies. These new drugs in the field of alcohol pharmacotherapy are also discussed, together with their mechanisms of action. [less ▲]

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See detailEffects of cyanamide and acetaldehyde accumulation on the locomotor stimulant and sedative effects of ethanol in mice
Tambour, Sophie ULg; Closon, Catherine; Tirelli, Ezio ULg et al

in Behavioural Pharmacology (2007), 18(8), 777-784

Ethanol administration induces both locomotor stimulant and sedative effects depending upon blood ethanol concentrations. Recent studies in rats and mice suggest that acetaldehyde, the first product of ... [more ▼]

Ethanol administration induces both locomotor stimulant and sedative effects depending upon blood ethanol concentrations. Recent studies in rats and mice suggest that acetaldehyde, the first product of ethanol metabolism, might be involved in the expression of both the stimulant and the sedative effects of ethanol. A number of studies have used the drug cyanamide in an attempt to clarify the role of acetaldehyde in the behavioral effects of ethanol. The results of such studies are, however, difficult to interpret because cyanamide is an inhibitor of the enzymes catalase and aldehyde dehydrogenase, two enzymes with opposite effects on brain acetaldehyde concentrations. This study was aimed at clarifying the effects of cyanamide on ethanol-induced locomotor stimulant and sedative effects in Swiss mice. The locomotor stimulant effects of ethanol were measured in standard activity boxes, whereas the sedative effects of ethanol were quantified using the loss of righting reflex procedure. Cyanamide prevented the locomotor stimulant effects of 2 g/kg ethanol, although this was mainly due to a potentiation of the inhibitory effects of ethanol as evidenced by a prolongation of ethanol-induced loss of righting reflex. Additionally, 4-methylpyrazole, an inhibitor of the enzyme alcohol dehydrogenase, prevented these effects of cyanamide. It is concluded that in vivo the effects of cyanamide are predominantly due to the inhibition of the enzyme aldehyde dehydrogenase, rather than to its effects on catalase. [less ▲]

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See detailAcute and chronic effects of acetaldehyde on learning and memory in mice
Quertemont, Etienne ULg; Tambour, Sophie ULg; Didone, Vincent ULg

in Alcohol & Alcoholism (2007), 42 Suppl. 1

Acetaldehyde has been postulated to mediate several of the behavioral effects of ethanol, including its reinforcing properties. At the highest doses, alcohol disrupts the acquisition and performance of ... [more ▼]

Acetaldehyde has been postulated to mediate several of the behavioral effects of ethanol, including its reinforcing properties. At the highest doses, alcohol disrupts the acquisition and performance of memory tasks, culminating with the blackout experience at high blood alcohol concentrations. However, it remains unknown whether acetaldehyde is involved in such memory impairments induced by acute ethanol. Additionally, chronic alcohol consumption in humans sometimes leads to persistent memory impairments partly due to serious brain damages. The Wernicke-Korsakoff syndrome, characterized by severe anterograde amnesia, is the most serious memory disorder induced by chronic alcohol. The aim of the present study was to show whether acute and chronic treatments with acetaldehyde, the first metabolite of ethanol, lead to similar memory impairments as ethanol in mice. Memory performances of Swiss and C57BL/6J mice were tested in both the passive avoidance task and the fear conditioning procedure. In the first part of the experiments mice were injected with acute acetaldehyde (50 to 300 mg/kg) immediately after the training phase. In the second part of the experiment, mice were tested for memory performance after 10 daily acetaldehyde injections. The first part of the experiments shows that acute acetaldehyde administrations produce a strong amnesic effect in both experimental paradigms. Additionally, the amnesic effects of acetaldehyde were more consistent than those observed after ethanol administration. In the second part of the studies, we show that 10 daily acetaldehyde injections to mice led to a severe and persistent anterograde amnesia in both the pavlovian and the operant learning tasks. In conclusion, acute acetaldehyde produces strong amnesic effects trough yet unknown pharmacological mechanisms. In addition, chronic acetaldehyde administration leads to persistent memory impairments. These results suggest that acetaldehyde might be involved in both the acute amnesic effects of high ethanol doses and the neurotoxic effects of chronic alcohol consumption. [less ▲]

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See detailNeurobiological and genetic aspects of alcohol addiction: a special focus on acetaldehyde, the first metabolite of ethanol
Quertemont, Etienne ULg

Scientific conference (2007)

Although alcoholism is one of the most common forms of addiction, its neurobiological mechanisms still remain unclear. The reinforcing properties of ethanol are mediated by the interaction of multiple ... [more ▼]

Although alcoholism is one of the most common forms of addiction, its neurobiological mechanisms still remain unclear. The reinforcing properties of ethanol are mediated by the interaction of multiple neurotransmitter systems, including dopamine, serotonin, glutamate, GABA, endogenous opioids and endocannabinoids. Additionally, long term changes in these neurotransmitter systems are believed to promote the development of alcoholism, probably through specific alterations of brain regions involved in motivation. In humans, it has been clearly demonstrated that alcohol dependence is a genetically heritable disease, at least to some extent. Twin and adoptions studies indicate that 50-60% of the phenotypic variations in alcohol dependence are accounted for by a genetic component. Among the multiple genes that are possibly involved in the development of alcohol dependence and addiction, there is very strong evidence that genes related to the metabolism of ethanol play a major role. For example, genetic polymorphisms in alcohol and aldehyde dehydrogenase enzymes strongly affect alcoholism susceptibility in humans. In recent years, several studies have also provided evidence that acetaldehyde, the first metabolite of ethanol, contributes to alcohol abuse and alcoholism. In rodents such as rats and mice, low doses of brain acetaldehyde induce reinforcing and stimulant effects, although high concentrations of peripheral blood acetaldehyde produce adverse reactions. These results led to the controversial theory that acetaldehyde mediates or at least contributes to the reinforcing and addictive properties of ethanol. [less ▲]

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See detailEffects of the H-3-receptor inverse agonist thioperamide on the psychornotor effects induced by acutely and repeatedly given cocaine in C57BL/6J mice
Brabant, Christian ULg; Quertemont, Etienne ULg; Tirelli, Ezio ULg

in Pharmacology, Biochemistry & Behavior (2006), 83(4), 561-569

Previous studies have shown that histamine H(3) blockers potentiate the psychomotor and rewarding effects of cocaine. The present study examined the influence of thioperamide, an inverse H(3) receptor ... [more ▼]

Previous studies have shown that histamine H(3) blockers potentiate the psychomotor and rewarding effects of cocaine. The present study examined the influence of thioperamide, an inverse H(3) receptor agonist, on the development of psychomotor sensitization and stereotyped activity induced by acute or intermittent cocaine in C57BL/6J mice. In the first experiment, mice were injected i.p. with saline, 10 or 20mg/kg thioperamide and saline or 8mg/kg cocaine, 10min apart, before being tested for their locomotor activity (providing data on the acute effects of thioperamide on cocaine-induced activity). Subsequently, mice were treated in the same manner every other day over six additional sessions. Sensitization was assessed by the responsiveness to a cocaine challenge (8mg/kg, i.p.) given 2 and 14days following the intermittent treatment. In experiments 2 and 3, we tested the effects of thioperamide (10 or 20mg/kg, i.p.) on gnawing and sniffing induced or affected by relatively high doses of cocaine (24 or 32mg/kg, s.c.), the drugs being given 10min apart. In the first experiment, both doses of thioperamide amplified cocaine-induced psychomotor hyperactivity almost on all experimental sessions. However, the histamine inverse agonist did not affect the induction of a psychomotor sensitization. All cocaine-treated mice showed similar levels of sensitized activity 2 and 14days after the intermittent treatments, whether they received thioperamide or not. The second and the third experiments showed that thioperamide did not affect gnawing and sniffing induced by cocaine. Taken together, these results indicate that H(3) receptors clearly contribute to the neurobiological mechanisms of the locomotor component of cocaine-induced psychomotor activation, but less likely to those underlying the development of cocaine behavioral sensitization or the expression of cocaine-induced oro-facial stereotypies. [less ▲]

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See detailLocomotor effects of ethanol and acetaldehyde after peripheral and intraventricular injections in Swiss and C57BL/6J mice
Tambour, Sophie ULg; Didone, Vincent ULg; Tirelli, Ezio ULg et al

in Behavioural Brain Research (2006), 172(1), 145-154

Several studies have suggested that acetaldehyde, the first product of ethanol metabolism, is involved in the locomotor stimulant effects of ethanol in mice, although it has never been formally tested ... [more ▼]

Several studies have suggested that acetaldehyde, the first product of ethanol metabolism, is involved in the locomotor stimulant effects of ethanol in mice, although it has never been formally tested whether acetaldehyde injected directly into the brain of mice has stimulant properties. Recently, it was also shown in rats that both ethanol and acetaldehyde can induce opposite locomotor effects according to the route of administration. Whereas peripheral administrations of ethanol and acetaldehyde induced locomotor depressant effects, their infusions directly into the brain produced locomotor stimulation. The aim of the present study was to characterize in mice the locomotor effects of ethanol and acetaldehyde injected either peripherally by the intraperitoneal route or centrally into the brain ventricles. Additionally, the effects of ethanol and acetaldehyde were compared in two strains of mice known for their differential sensitivity to the locomotor effects of ethanol, namely Swiss and C57BL/6J mice. Ethanol induced a biphasic effect on locomotor activity in Swiss mice, with stimulant effects at low to moderate doses and depressant effects at higher doses. Such a profile of effects was observed whatever the route of administration, peripheral or central. In C57BL/6J mice, ethanol only induced monophasic depressant effects. In this mouse strain, no evidence of the stimulant effects of ethanol was found after either an i.p. or an i.c.v. administration of ethanol. In contrast to ethanol, acetaldehyde yielded only depressant effects in both strains of mice after both peripheral and central administrations. These results indicate that the route of administration does not alter the locomotor effects of ethanol and acetaldehyde in mice. Additionally, the present study shows that the stimulant properties of acetaldehyde, even after direct infusion into the brain, are not as obvious as previously speculated. [less ▲]

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See detailRole of acetaldehyde in mediating the pharmacological and behavioral effects of alcohol
Quertemont, Etienne ULg; Didone, Vincent ULg

in Alcohol Research & Health : The Journal of the National Institute on Alcohol Abuse & Alcoholism (2006), 29(4), 258-265

Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological ... [more ▼]

Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological properties). Recent studies have shown that the direct administration of acetaldehyde, especially into the brain, induces several effects that mimic those of alcohol. High doses of acetaldehyde induce sedative as well as movement-and memory-impairing effects, whereas lower doses produce behavioral effects (e.g., stimulation and reinforcement) that are characteristic of addictive drugs. When acetaldehyde accumulates outside the brain (i.e., in the periphery), adverse effects predominate and prevent further alcohol drinking. To investigate the role of acetaldehyde in mediating alcohol's effects, investigators have pharmacologically manipulated alcohol metabolism and the production of acetaidehyde within the body (i.e., endogenous acetaldehyde production). Studies manipulating the activity of the enzyme catalase, which promotes acetaldehyde production in the brain, suggest that acetaldehyde contributes to many behavioral effects of alcohol, especially its stimulant properties. However, it remains controversial whether acetaldehyde concentrations obtained under normal physiological conditions are sufficient to induce significant pharmacological effects. Current evidence suggests that the contribution of acetaldehyde to alcohol's effects is best explained by a process in which acetaidehyde modulates, rather than mediates, some of alcohol's effects. [less ▲]

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See detailAnimal models of drug addiction: advantages and limitations
Quertemont, Etienne ULg

in Acta Neurologica Belgica (2006), 106

Various animal models have been developed to investigate the neurobiological and behavioral mechanisms of drug addiction. The most popular of these animal models include the locomotor sensitization ... [more ▼]

Various animal models have been developed to investigate the neurobiological and behavioral mechanisms of drug addiction. The most popular of these animal models include the locomotor sensitization paradigm, the place conditioning procedure and the self-administration technique. With these techniques, it is possible to mimic in rodents the major aspects of human drug addiction. The self-administration procedure is the most widely used and show an excellent natural and predictive validity. In the self-administration protocol, experimental animals, usually rats or mice, are allowed to press a lever in order to gain access to a small dose of an addictive drug. The drug may be given to the animal through the oral, the intravenous or the intracranial route of administration, according to the purpose of the study. In recent years, the classical self-administration procedure has been adapted to study the specific neurobiological basis of drug relapse. In this now called drug reinstatement paradigm, when drug self-administration behaviors are well established, an extinction procedure starts, during which lever pressing is no longer reinforced by drug access. After a number of such extinction sessions, lever pressing gradually declines and eventually stops. Drug-seeking behaviors are therefore said to be extinguished. It is then possible to test various stimuli in order to investigate whether they reinstate drug-seeking behaviors and use such a reinstatement as an animal model of drug relapse. Three types of stimuli have been shown to reinstate drug-seeking behaviors: a small priming dose of drug, drug-associated cues and a stressful stimuli. The effects of these three relapse-triggering stimuli are mediated by different neurobiological mechanisms, leading to the expectation that they may be targeted by different pharmacotherapeutic and behavioral interventions. Despite the high value of the current animal models of drug addiction, there show several limitations. In particular, it is difficult to differentiate between self-controlled and compulsive drug use in animals. As only uncontrolled compulsive drug consumption characterizes drug addiction in humans, such a limitation might explain the high frequency of false positive results in animal experiments. Indeed, it is common that therapeutic interventions successfully developed in animals later proved to be disappointing in humans. [less ▲]

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See detailThe role of acetaldehyde in the neurobehavioral effects of ethanol : a comprehensive review of animal studies
Quertemont, Etienne ULg; Tambour, Sophie ULg; Tirelli, Ezio ULg

in Progress in Neurobiology (2005), 75(4), 247-274

Acetaldehyde has long been suggested to be involved in a number of ethanol's pharmacological and behavioral effects, such as its reinforcing, aversive, sedative, amnesic and stimulant properties. However ... [more ▼]

Acetaldehyde has long been suggested to be involved in a number of ethanol's pharmacological and behavioral effects, such as its reinforcing, aversive, sedative, amnesic and stimulant properties. However, the role of acetaldehyde in ethanol's effects has been an extremely controversial topic during the past two decades. Opinions ranged from those virtually denying any role for acetaldehyde in ethanol's effects to those who claimed that alcoholism is in fact "acetaldehydism". Considering the possible key role of acetaldehyde in alcohol addiction, it is critical to clarify the respective functions of acetaldehyde and ethanol molecules in the pharmacological and behavioral effects of alcohol consumption. In the present paper, we review the animal studies reporting evidence that acetaldehyde is involved in the pharmacological and behavioral effects of ethanol. A number of studies demonstrated that acetaldehyde administration induces a range of behavioral effects. Other pharmacological studies indicated that acetaldehyde might be critically involved in several effects of ethanol consumption, including its reinforcing consequences. However, conflicting evidence has also been published. Furthermore, it remains to be shown whether pharmacologically relevant concentrations of acetaldehyde are achieved in the brain after alcohol consumption in order to induce significant effects. Finally, we review current evidence about the central mechanisms of action of acetaldehyde. (c) 2005 Elsevier Ltd. All rights reserved. [less ▲]

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See detailThe role of acetaldehyde in the central effects of ethanol
Quertemont, Etienne ULg; Grant, Kathleen A.; Correa, Merce et al

in Alcoholism, Clinical & Experimental Research (2005), 29(2), 221-234

This article represents the proceedings of a symposium at the 2004 annual meeting of the Research Society on Alcoholism in Vancouver, Canada. The symposium was organized by Etienne Quertemont and chaired ... [more ▼]

This article represents the proceedings of a symposium at the 2004 annual meeting of the Research Society on Alcoholism in Vancouver, Canada. The symposium was organized by Etienne Quertemont and chaired by Kathleen A. Grant. The presentations were (1) Behavioral stimulant effects of intracranial injections of ethanol and acetaldehyde in rats, by Merc Correa, Maria N. Arizzi and John D. Salamone; (2) Behavioral characterization of acetaldehyde in mice, by Etienne Quertemont and Sophie Tambour; (3) Role of brain catalase and central formed acetaldehyde in ethanol's behavioral effects, by Carlos M.G. Aragon; (4) Contrasting the reinforcing actions of acetaldehyde and ethanol within the ventral tegmental area (VTA) of alcohol-preferring (P) rats, by William J. McBride, Zachary A. Rodd, Avram Goldstein, Alejandro Zaffaroni and Ting-Kai Li; and (5) Acetaldehyde increases dopaminergic transmission in the limbic system, by Milena Pisano and Marco Diana. [less ▲]

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See detailThe H(3) antagonist thioperamide reveals conditioned preference for a context associated with an inactive small dose of cocaine in C57BL/6J mice
Brabant, Christian ULg; Charlier, Yana ULg; Quertemont, Etienne ULg et al

in Behavioural Brain Research (2005), 160(1), 161-168

The histaminergic system has been speculated to be involved in the inhibitory control of drug reward, H-1 and H-2 antagonists having been found to potentiate conditioned place preference induced by ... [more ▼]

The histaminergic system has been speculated to be involved in the inhibitory control of drug reward, H-1 and H-2 antagonists having been found to potentiate conditioned place preference induced by morphine or cocaine. In contrast, the role of H-3 receptors in cocaine-induced place preference is still unknown. The present study tested the effects of thioperamide (0, 10 and 20 mg/kg, i.p.), an H-3 autoreceptor antagonist, on the development of a conditioned place preference induced by cocaine (0, 2 and 8 mg/kg, i.p.) in C57BL/6J mice. Thioperamide was injected 10 min before each cocaine-pairing session. The activity scores recorded on the first cocaine-pairing session were also used to test the effects of thioperamide on cocaine-induced locomotor activity. Thioperamide alone had no reinforcing effects and did not affect the conditioned place preference induced by 8 mg/kg cocaine. However, thioperamide dose-dependently revealed a conditioned place preference induced by 2 mg/kg cocaine, a dose that was inactive per se. Finally, thioperamide dose-dependently potentiated the stimulant effects of cocaine, in spite of its slight hypolocomotor effect when given alone. Our results strongly suggest that H3 antagonists potentiate the stimulant and reinforcing effects of cocaine in mice. © 2004 Elsevier B.V. All rights reserved. [less ▲]

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See detailIs ethanol a pro-drug? Acetaldehyde contribution to brain ethanol effects
Quertemont, Etienne ULg; Eriksson, Peter C. J.; Zimatkin, Sergey M. et al

in Alcoholism, Clinical & Experimental Research (2005), 29(8), 1514-1521

This article presents the proceedings of a symposium at the 2004 meeting of the International Society for Biomedical Research on Alcoholism, held in Mannheim, Germany. The symposium was organized by ... [more ▼]

This article presents the proceedings of a symposium at the 2004 meeting of the International Society for Biomedical Research on Alcoholism, held in Mannheim, Germany. The symposium was organized by Etienne Quertemont and chaired by C. J. Peter Eriksson. The presentations were (1) Brain ethanol metabolism and its behavior consequences, by Sergey M. Zimatkin and P. S. Pronko; (2) Acetaldehyde increases dopaminergic neuronal activity: a possible mechanism for acetaldehyde reinforcing effects, by Marco Diana and Milena Pisano; (3) Contrasting the reinforcing actions of acetaldehyde and ethanol within the ventral tegmental area (VTA) of alcohol-preferring (P) rats, by Zachary A. Rodd and Richard R. Bell; (4) Molecular and biochemical changes associated with acetaldehyde toxicity, by Roberta J. Ward; and (5) Role of acetaldehyde in human alcoholism and alcohol abuse, by C. J. Peter Eriksson [less ▲]

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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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