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See detailOntogeny of the stimulant and sedative effects of ethanol in male and female Swiss mice: gradual changes from weaning to adulthood
Quoilin, Caroline ULg; Didone, Vincent ULg; Tirelli, Ezio ULg et al

in Psychopharmacology (2010), 212(4), 501-512

Rationale: The adolescent period is characterized by a specific sensitivity to the effects of alcohol, which is believed to contribute to the enhanced risks of alcohol dependence when drinking is ... [more ▼]

Rationale: The adolescent period is characterized by a specific sensitivity to the effects of alcohol, which is believed to contribute to the enhanced risks of alcohol dependence when drinking is initiated early during adolescence. In adolescent rodents, while the reduced sensitivity to the sedative effects of ethanol has been well characterized, its stimulant effects have not yet been extensively studied. Objectives: The present study characterized the development of the stimulant and sedative effects of acute ethanol in male and female Swiss mice from weaning to early adulthood and tested whether both effects are interrelated. Methods: In a first experiment, mice aged 21, 28, 35, 42 and 60 days were injected with various ethanol doses and tested for ethanol-induced locomotor activity. In an independent experiment, mice of the same groups of age were injected with 4 g/kg ethanol and ethanol-induced sedation was quantified with the loss of righting reflex procedure. Results: In male and female mice, the stimulant effects of ethanol gradually decreased, whereas its sedative effects increased with age. When the sedation was statistically controlled using a covariance analysis, the differences between adult and juvenile mice in the locomotor stimulation were significantly reduced. Conclusions: From weaning to early adulthood, the acute stimulant and sedative effects of ethanol show gradual changes that are similar in male and female mice. Although the initial tolerance to the sedative effects of ethanol contribute to the changes in ethanol-induced locomotor activity, young mice also show a higher sensitivity to the stimulant effects of ethanol. [less ▲]

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See detailAnxiety in adult female mice following perinatal exposure to chlorpyrifos.
Braquenier, Jean-Baptiste; Quertemont, Etienne ULg; Tirelli, Ezio ULg et al

in Neurotoxicology & Teratology (2010), 32

Epidemiologic studies suggested a possible link between prenatal exposure to organophosphate insecticides (OP) and long-term mental delay and some behavioral troubles. Experimental studies in rats and ... [more ▼]

Epidemiologic studies suggested a possible link between prenatal exposure to organophosphate insecticides (OP) and long-term mental delay and some behavioral troubles. Experimental studies in rats and mice have confirmed that a relatively short exposure to low doses of OP such as chlorpyrifos (CPF) during specific perinatal periods decreased anxiety-like behaviors. In the present study, we report that chronic perinatal exposure (GD15-PND14) to low doses of CPF leads to an increase (and not a decrease) in anxiety-like behaviors of female mouse offspring. Pregnant or lactating female mice were exposed to CPF (0.2; 1; or 5 mg/kg day) by oral treatment during 18 consecutive days. Following a recovery period of several weeks, the anxiety of adult female offspring was determined using neurobehavioral tests (elevated plus-maze and light/dark box tests). Our results showed that CPF-exposed female offspring were more anxious than controls. In addition, the magnitude of anxiety profile alterations depended on the level of exposure to CPF during gestation and lactation with a maximal effect observed at the 1 mg/kg day dose. Our results confirm that OP exposure during the perinatal period can induce long-term alterations in mouse anxiety-like behaviors and suggest that the routes of administration and the duration of OP exposure during brain development may be factors to consider when studying the development of anxiety. [less ▲]

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See detailInvolvement of the brain histaminergic system in addiction and addiction-related behaviors: a comprehensive review with emphasis on the potential therapeutic use of histaminergic compounds in drug dependence
Brabant, Christian ULg; Alleva, Livia ULg; Quertemont, Etienne ULg et al

in Progress in Neurobiology (2010), 92

Neurons that produce histamine are exclusively located in the tuberomamillary nucleus of the posterior hypothalamus and send widespread projections to almost all brain areas. Neuronal histamine is ... [more ▼]

Neurons that produce histamine are exclusively located in the tuberomamillary nucleus of the posterior hypothalamus and send widespread projections to almost all brain areas. Neuronal histamine is involved in many physiological and behavioral functions such as arousal, feeding behavior and learning. Although conflicting data have been published, several studies have also demonstrated a role of histamine in the psychomotor and rewarding effects of addictive drugs. Pharmacological and brain lesion experiments initially led to the proposition that the histaminergic system exerts an inhibitory influence on drug reward processes, opposed to that of the dopaminergic system. The purpose of this review is to summarize the relevant literature on this topic and to discuss whether the inhibitory function of histamine on drug reward is supported by current evidence from published results. Research conducted during the past decade demonstrated that the ability of many antihistaminic drugs to potentiate addictionrelated behaviors essentially results from non-specific effects and does not constitute a valid argument in support of an inhibitory function of histamine on reward processes. The reviewed findings also indicate that histamine can either stimulate or inhibit the dopamine mesolimbic system through distinct neuronal mechanisms involving different histamine receptors. Finally, the hypothesis that the histaminergic system plays an inhibitory role on drug reward appears to be essentially supported by place conditioning studies that focused on morphine reward. The present review suggests that the development of drugs capable of activating the histaminergic system may offer promising therapeutic tools for the treatment of opioid dependence. [less ▲]

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See detailEthanol-induced behaviors in mice genetically deficient in MCH1 receptors
Didone, Vincent ULg; Tirelli, Ezio ULg; Quertemont, Etienne ULg et al

in Alcoholism, Clinical & Experimental Research (2010), 34(8), 93-93

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See detailLa dépendance au cannabis : propriétés addictives, tolérance et sevrage
Quertemont, Etienne ULg; Tirelli, Ezio ULg

in Seutin, Vincent; Scuvée, Jacqueline; Quertemont, Etienne (Eds.) Regards croisés sur le cannabis (2010)

En dépit de controverses récurrentes, les données expérimentales récoltées dans de nombreuses études animales et humaines indiquent que le cannabis présente toutes les caractéristiques associées aux ... [more ▼]

En dépit de controverses récurrentes, les données expérimentales récoltées dans de nombreuses études animales et humaines indiquent que le cannabis présente toutes les caractéristiques associées aux autres drogues toxicomanogènes. Le cannabis induit manifestement une dépendance psychologique primaire chez l’homme et les modèles animaux ont démontré qu’il possède des propriétés renforçantes, quoique de moindre intensité que celles d’autres drogues comme la cocaïne ou les opiacés. La consommation chronique de cannabis produit une tolérance envers certains de ses effets, ce qui est susceptible d’entraîner un accroissement des doses utilisées par un utilisateur régulier. On reconnaît aussi au cannabis la capacité d’induire une véritable dépendance physiologique chez les plus gros consommateurs. Cette dépendance physiologique se manifeste par un syndrome de sevrage typique lors de l’arrêt de la consommation. Toutefois, il est clair que la dépendance au cannabis (aussi bien psychologique que physiologique) est moins sévère que celle induite par d’autres drogues majeures comme l’alcool, la cocaïne ou les opiacés. De plus, elle ne concerne qu’une petite fraction des consommateurs de cannabis. Depuis de nombreuses années, on s’interroge sur le risque d’escalade vers la consommation de drogues « plus dures » que produirait la consommation de cannabis. Les études scientifiques ont clairement démontré qu’il existe un lien statistique significatif entre usage de cannabis et consommation d’autres drogues illicites. Toutefois, la nature de cette relation statistique reste controversée. Selon les tenants de « la théorie de la porte d’entrée », le cannabis conduit directement, par des mécanismes biologiques, psychologiques ou sociaux, à une augmentation du risque de consommer des drogues telles que la cocaïne ou l’héroïne. Au contraire, les adeptes de « la théorie du facteur commun » soutiennent que les consommations de cannabis, d’héroïne ou de cocaïne sont expliqués par des facteurs généraux identiques, conduisant ainsi à une relation statistique qui ne serait qu’apparente et en aucun cas de nature causale. A l’heure actuelle, les données expérimentales disponibles ne permettent pas de trancher définitivement entre ces deux théories explicatives. [less ▲]

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See detailAcetaldehyde and the hypothermic effects of ethanol in mice.
Closon, Catherine ULg; Didone, Vincent ULg; Tirelli, Ezio ULg et al

in Alcoholism, Clinical & Experimental Research (2009), 33(11), 2005-14

BACKGROUND: Acetaldehyde, the first metabolite of ethanol, has been suggested to be involved in many behavioral effects of ethanol. However, few studies have investigated the hypothermic effects of ... [more ▼]

BACKGROUND: Acetaldehyde, the first metabolite of ethanol, has been suggested to be involved in many behavioral effects of ethanol. However, few studies have investigated the hypothermic effects of acetaldehyde or the contribution of acetaldehyde to ethanol-induced hypothermia. The aim of the present study is to better understand the hypothermic effects of acetaldehyde and the possible contribution of acetaldehyde in ethanol-induced hypothermia, especially under conditions leading to acetaldehyde accumulation. METHODS: Female Swiss mice were injected intraperitoneally with ethanol and acetaldehyde and their rectal temperatures were measured with a digital thermometer at various time points after the injections. Experiment 1 compared the hypothermic effects of various acetaldehyde doses (0 to 300 mg/kg) with a reference dose of ethanol (3 g/kg). Experiment 2 tested the effects of a pretreatment with the aldehyde dehydrogenase (ALDH) inhibitor cyanamide (25 mg/kg) on ethanol- and acetaldehyde-induced hypothermia. In experiments 3 and 4, mice received a combined pretreatment with cyanamide and the alcohol dehydrogenase (ADH) inhibitor 4-Methylpyrazole (10 mg/kg) before the injection of ethanol or acetaldehyde. RESULTS: Acetaldehyde at doses between 100 and 300 mg/kg induced significant hypothermic effects, but of shorter duration than ethanol-induced hypothermia. The inhibition of ALDH enzymes by cyanamide induced a strong potentiation of both ethanol- and acetaldehyde-induced hypothermia. The pretreatment with 4-MP prevented the potentiation of ethanol-induced hypothermia by cyanamide, but slightly increased the potentiation of acetaldehyde-induced hypothermia by cyanamide. CONCLUSIONS: The results of the present study clearly show that acetaldehyde has hypothermic properties in mice at least at relatively high concentrations. Furthermore, the accumulation of acetaldehyde following ALDH inhibition strongly enhanced the hypothermic effects of ethanol. These latter results confirm the hypothermic properties of acetaldehyde and show that acetate, the next step in ethanol metabolism, is not involved in these hypothermic effects. Finally, the experiment with 4-MP indicates that the potentiating effects of cyanamide are mediated by the peripheral accumulation of acetaldehyde, which then reaches the brain to induce a severe hypothermia. [less ▲]

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See detailThe usefulness of operant conditioning procedures to assess long-lasting deficits following transient focal ischemia in mice.
Ferrara, André ULg; El Bejaoui, Sophie; Seyen, Sandrine ULg et al

in Behavioural Brain Research (2009), 205(2), 525-34

In this study, we examined a number of short and long-term sensorimotor, behavioural and cognitive consequences of an experimental ischemia induced by a 60-min right middle cerebral artery occlusion (MCAO ... [more ▼]

In this study, we examined a number of short and long-term sensorimotor, behavioural and cognitive consequences of an experimental ischemia induced by a 60-min right middle cerebral artery occlusion (MCAO) in 129S2 mice. During 14 days after surgery, a classical sensorimotor assessment was conducted using hanging wire test, negative geotaxis test, grip strength test, accelerated rotarod test and locomotor activity-meter. In order to provide a technique for the assessment of more resistant consequences of ischemia on fine psychomotor control, the peak procedure (a modified version of the operant fixed-interval schedule of reinforcement) was used. This procedure also helped to objectify temporal perception in mice five weeks following surgery. On several sensorimotor tests, ischemic mice showed some degree of impairment which rapidly tended to improve after stroke, a profile of results substantially consistent with previous studies. Five weeks post-surgery, ischemic mice tested with the peak procedure exhibited a moderate but yet significant temporal regulation impairment along with a reduced response rate compared to control mice. The present results suggest that the peak procedure and other derived operant schedules of reinforcement may provide useful and sensitive tools for the long-term assessment of both behavioural and cognitive aspects of the consequences of an experimental ischemia. [less ▲]

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See detailEffects of the H(3) receptor inverse agonist thioperamide on cocaine-induced locomotion in mice: role of the histaminergic system and potential pharmacokinetic interactions.
Brabant, Christian ULg; Alleva, Livia ULg; Grisar, Thierry ULg et al

in Psychopharmacology (2009), 202(4), 673-87

RATIONALE: Previous studies have shown that intraperitoneal injections of thioperamide, an imidazole-based H(3) receptor inverse agonist that enhances histamine release in the brain, potentiate cocaine ... [more ▼]

RATIONALE: Previous studies have shown that intraperitoneal injections of thioperamide, an imidazole-based H(3) receptor inverse agonist that enhances histamine release in the brain, potentiate cocaine-induced hyperlocomotion. The present study examined the involvement of the histaminergic system in these effects of thioperamide in mice. MATERIALS AND METHODS: We investigated whether immepip, a selective H(3) agonist, could reverse the potentiating effects of thioperamide. Moreover, the non-imidazole H(3) inverse agonist A-331440 was tested on the locomotor effects of cocaine. Using high-performance liquid chromatography with ultraviolet detection, cocaine plasma concentrations were measured to study potential drug-drug interactions between thioperamide and cocaine. Finally, thioperamide was tested on the locomotor effects of cocaine in histamine-deficient knockout mice in order to determine the contribution of histamine to the modulating effects of thioperamide. RESULTS: Thioperamide potentiated cocaine-induced hyperlocomotion in normal mice, and to a higher extent, in histamine-deficient knockout mice. A-331440 only slightly affected the locomotor effects of cocaine. Immepip did not alter cocaine-induced hyperactivity but significantly reduced the potentiating actions of thioperamide on cocaine's effects. Finally, plasma cocaine concentrations were more elevated in mice treated with thioperamide than in mice that received cocaine alone. CONCLUSIONS: The present results indicate that histamine released by thioperamide through the blockade of H(3) autoreceptors is not involved in the ability of this compound to potentiate cocaine induced-hyperactivity. Our data suggest that thioperamide, at least at 10 mg/kg, increases cocaine-induced locomotion through the combination of pharmacokinetic effects and the blockade of H(3) receptors located on non-histaminergic neurons. [less ▲]

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See detailParametric analysis of the development and expression of ethanol-induced behavioral sensitization in female Swiss mice: effects of dose, injection schedule, and test context.
Didone, Vincent ULg; Quoilin, Caroline ULg; Tirelli, Ezio ULg et al

in Psychopharmacology (2008), 201(2), 249-60

RATIONALE: Repeated administrations of ethanol induce a progressive and enduring increase in its locomotor stimulant effects, a phenomenon termed behavioral sensitization that has not been systematically ... [more ▼]

RATIONALE: Repeated administrations of ethanol induce a progressive and enduring increase in its locomotor stimulant effects, a phenomenon termed behavioral sensitization that has not been systematically characterized. OBJECTIVE: The aim of the present studies was to characterize the development and expression of ethanol sensitization in female Swiss mice by examining (1) the doses of ethanol that induce behavioral sensitization, (2) the doses of acute ethanol challenges that are necessary to express behavioral sensitization, (3) the effects of the intervals between administrations, and (4) the context dependency of ethanol sensitization. MATERIALS AND METHODS: Mice were i.p. injected for 8 days with various ethanol doses, and locomotion was recorded for 5 min. Two days after the last sensitization session, ethanol sensitization was tested in 30-min test sessions. RESULTS: Mice repeatedly injected with 2.5 g/kg ethanol showed a progressive (200-300%) increase in locomotor activity. In response to a 2.5 g/kg ethanol challenge, the mice repeatedly treated with doses above 1.5 g/kg showed a significant sensitization. Following the induction of sensitization with the maximally effective sensitizing dose (2.5 g/kg), mice showed greater activation after challenges with 1.5, 2.0, 2.5, and 3.0 g/kg ethanol. The intervals (24, 48, or 96 h) between ethanol injections did not affect the induction or expression of sensitization. Finally, sensitization to 2.5 g/kg ethanol was expressed regardless of the context in which it was induced. CONCLUSIONS: Female Swiss mice develop a robust context-independent sensitization after repeated ethanol injections at all doses above 1.5 g/kg, including highly sedative doses such as 4 g/kg. [less ▲]

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See detailDeletion of Melanin-Concentrating Hormone Receptor-1 gene accentuates D-amphetamine-induced psychomotor activation but neither the subsequent development of sensitization nor the expression of conditioned activity in mice
Tyhon, Amélie ULg; Lakaye, Bernard ULg; Grisar, Thierry ULg et al

in Pharmacology, Biochemistry & Behavior (2008), 88

The present study aimed to test the hypothesis that mice lacking the MCHR1 receptor (Melanin-Concentrating Hormone Receptor-1) present an elevated vulnerability towards the neurobehavioural effects of D ... [more ▼]

The present study aimed to test the hypothesis that mice lacking the MCHR1 receptor (Melanin-Concentrating Hormone Receptor-1) present an elevated vulnerability towards the neurobehavioural effects of D-amphetamine, presumably due to previously established up-regulations of dopamine D1 receptors in these mice. We examined the psychomotor effects of five once-daily injections of 1.5 and 3 mg/kg D-amphetamine (i.p.) or ten once-daily injections of 2.25 mg/kg D-amphetamine in knockout (KO) mice lacking the MCHR1 receptor. The first injection of Damphetamine induced a greater psychomotor response amongst the KO mice at 2.25 and 3.0 mg/kg. On all subsequent D-amphetamine injections, KO mice still showed greater levels of psychomotor activity than the WT mice, but with no between-genotype difference in the rate of development of sensitization (similar slopes of the curves). Furthermore, 24 h after the last injection of 2.25 mg/kg D-amphetamine both genotypes exhibited a significant post-sensitization conditioned activity. Thus, MCHR1 receptors are likely not deeply involved in the mechanisms of induction of sensitization and related conditioned activity induced by D-amphetamine, albeit our results confirm a contribution of these receptors to the mechanisms of the acute effects of that drug, possibly via an inhibitory action on the dopaminergic mesolimbic system. Our results do not support the hypothesis of a functional contribution of MCHR1 receptors to the addictive effects of D-amphetamine [less ▲]

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See detailAmphetamine- and cocaine-induced conditioned place preference and concomitant psychomotor sensitization in mice with genetically inactivated melanin-concentrating hormone MCH(1) receptor.
Tyhon, Amélie ULg; Lakaye, Bernard ULg; Adamantidis, Antoine ULg et al

in European Journal of Pharmacology (2008), 599(1-3), 72-80

The melanin-concentrating hormone MCH(1) receptor has been proposed to exert an inhibitory control on monoaminergic (especially dopaminergic) activity within the mesolimbic system, which underpins drug ... [more ▼]

The melanin-concentrating hormone MCH(1) receptor has been proposed to exert an inhibitory control on monoaminergic (especially dopaminergic) activity within the mesolimbic system, which underpins drug seeking and reward. That hypothesis predicts that an inactivation of these receptors should enhance the sensitivity to drug rewarding effects. To test that prediction, we examined the propensity of mice lacking the melanin-concentrating receptor (MCH(1) KO) and their intact counterparts (WT) to form cocaine- and amphetamine-induced conditioned place preference. The conditioned rewarding effects induced by 0.375, 0.75, 1.5 and 3 mg/kg amphetamine were assessed in two sub-experiments and those induced by 1, 2, 4 and 8 mg/kg cocaine in two other sub-experiments. All mice were tested under saline for place preference 24 h following four every-other-day conditioning trials and an initial pre-conditioning session under saline. Most of the cocaine and amphetamine doses induced place preference, but without any genotype difference being revealed. Also, none of the cocaine doses induced psychomotor sensitization during conditioning, whereas amphetamine generated clear-cut dose-dependent sensitization in both genotypes. Albeit MCH(1) KO mice exhibited higher levels of psychomotor activation, the rates of sensitization were comparable across genotypes at 1.5 and 3 mg/kg amphetamine. Moreover, 0.375 and especially 0.75 mg/kg amphetamine produced a slight but yet significant sensitization in MCH(1) KO but not in their WT counterparts. Despite such an effect, the results cannot be considered as unambiguously supportive of the tested prediction. [less ▲]

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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 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 detailMale aromatase knockout mice acquire a conditioned place preference for cocaine but not for contact with an estrous female
Pierman, S.; Tirelli, Ezio ULg; Douhard, Quentin ULg et al

in Behavioural Brain Research (2006), 174(1), 64-69

We have previously shown that male mice carrying a targeted mutation in the Cyp19 gene which encodes the aromatase enzyme (aromatase knockout or ArKO), showed a reduced interest to investigate volatile ... [more ▼]

We have previously shown that male mice carrying a targeted mutation in the Cyp19 gene which encodes the aromatase enzyme (aromatase knockout or ArKO), showed a reduced interest to investigate volatile odors from conspecifics in a Y-maze. We asked here whether the incentive value of reproductively relevant odors is reduced in ArKO males by comparing the ability of male wild-type (WT) and ArKO mice to learn a conditioned place preference using exposure to reproductively relevant odors as incentive stimuli. When the presence of an anesthetized estrous female or soiled bedding from estrous females was used as incentive stimuli, only WT and not male ArKO mice showed conditioned place preference suggesting that the reward value of these stimuli is reduced in ArKO males. However, ArKO males showed conditioned place preference when cocaine was used as incentive stimulus, indicating that ArKO males are able to learn the conditioned place preference procedure. These results thus further confirm the important role of estradiol in sexually related behavioral responses in male mice. [less ▲]

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See detailMice lacking the melanin-concentrating hormone receptor-1 exhibit an atypical psychomotor susceptibility to cocaine and no conditioned cocaine response
Tyhon, Alain ULg; Adamantidis, Antoine ULg; Foidart, Agnès ULg et al

in Behavioural Brain Research (2006), 173(1), 94-103

The present study aimed at characterizing the acute and intermittent psychomotor responsiveness to cocaine in mice lacking the MCHR1 receptor, which is thought to modulate the mesocorticolimbic sytem ... [more ▼]

The present study aimed at characterizing the acute and intermittent psychomotor responsiveness to cocaine in mice lacking the MCHR1 receptor, which is thought to modulate the mesocorticolimbic sytem functioning [Smith DG, Tzavara ET, Shaw J, Luecke S, Wade M, Davis R, et al. Mesolimbic dopamine super-sensitivity in melanin-concentrating hormone-1 receptor deficient mice. J Neurosci 2005;25:914-22]. On a first free-drug session, MCHR1-deficient mice exhibited significantly higher levels of locomotor activity elicited by the novelty of the test chambers than their wild-type counterparts. On the following day session, a first injection of 6 or 12mg/kg cocaine induced comparable dose-related psychomotor activations in both genotypes, without significant difference in the relative increase in locomotion. Over the following eight once-daily test sessions, the slight psychomotor increase induced by 6mg/kg was equivalent in both genotypes and constant over the sessions. At 12mg/kg, cocaine induced a clear-cut incremental responsiveness to cocaine in both genotypes on the three first sessions; on the following sessions, only the wild-types displayed an incremental responsiveness until the last session, a sensitized effect that was confirmed for the wild-types but not for the knockouts on a subsequent sensitization test (cocaine challenge). Finally, the knockouts did not exhibit any sign of cocaine-conditioning (saline challenge), contrarily to the wild-types. It is speculated that MCHR1 may contribute to the neurobiological mechanisms of conditioned cocaine-induced psychomotor effects, possibly to those underpinning sensitization, and to a lesser extent to those sub-serving acute pharmacological cocaine action. [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 detailCocaine-conditioned activity persists for a longer time than cocaine-sensitized activity in mice: Implications for the theories using Pavlovian excitatory conditioning to explain the context-specificity of sensitization
Tirelli, Ezio ULg; Michel, Alexa ULg; Brabant, Christian ULg

in Behavioural Brain Research (2005), 165(1), 18-25

The present study was aimed at testing the prediction of the Pavlovian excitatory conditioning explanation of context-specific sensitization that the sensitized effect (SE) should persist as long as the ... [more ▼]

The present study was aimed at testing the prediction of the Pavlovian excitatory conditioning explanation of context-specific sensitization that the sensitized effect (SE) should persist as long as the post-sensitization conditioned activity (CR). C57BL/6J mice were tested for the expression of cocaine-induced conditioned and sensitized locomotion on several intervals after the establishment of a sensitization in an unchanging context. A group of mice received 10 once-daily injections of 10 mg/kg cocaine (s.c.) in a short time prior to being tested in activity-meters for 60 min sessions (cocaine-pretreated group), mice from a control group receiving saline in the same manner (saline-pretreated group). On the test sessions, taking place 1, 8 and 28 days after cocaine pretreatment, half of the animals of each pretreatment group (n=8) received a challenge test with saline and the other half with 10 mg/kg cocaine in the pretreatment context room (for CR and SE tests, respectively). The CR was significantly expressed on the three successive saline-challenge tests, albeit the activity levels were markedly decreased on the 28-day retention test. In contrast, the SE was significantly expressed only during the first half of the 1-day test session and the first 10 min of the 8-day test session, no SE effect being expressed on the 28-day retention test. The results, suggesting a functional uncoupling of the CR from the SE, disprove the theories of context-specificity of sensitization based completely or partially on Pavlovian excitatory conditioning mechanisms. [less ▲]

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See detailDisrupting the melanin-concentrating hormone receptor 1 in mice leads to cognitive and NMDA response deficit
Grisar, Thierry ULg; Adamantidis, Antoine ULg; Thomas, Elizabeth et al

in Journal of the Neurological Sciences (2005, November 15), 238(Suppl. 1), 288

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See detailDisrupting the melanin-concentrating hormone receptor 1 in mice leads to cognitive deficits and alterations of NMDA receptor function.
Adamantidis, Antoine ULg; Thomas, Elizabeth; Foidart, Agnès ULg et al

in European Journal of Neuroscience (2005), 21(10), 2837-44

In order to investigate the physiological properties of the melanin-concentrating hormone (MCH) we have generated and used mice from which the MCH receptor 1 gene was deleted (MCHR1(Neo/Neo) mice ... [more ▼]

In order to investigate the physiological properties of the melanin-concentrating hormone (MCH) we have generated and used mice from which the MCH receptor 1 gene was deleted (MCHR1(Neo/Neo) mice). Complementary experimental approaches were used to investigate alterations in the learning and memory processes of our transgenic model. The ability of the knockout strain to carry out the inhibitory passive avoidance test was found to be considerably impaired although no significant differences were observed in anxiety levels. This impaired cognitive property prompted us to explore modifications in N-methyl D-aspartate (NMDA) responses in the hippocampus. Intracellular recordings of CA1 pyramidal neurons in hippocampal slices from the MCHR1(Neo/Neo) mice revealed significantly decreased NMDA responses. Finally, using in situ hybridization we found a 15% reduction in NMDAR1 subunit in the CA1 region. These results show for the first time a possible role for MCH in the control of the function of the NMDA receptor. [less ▲]

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