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See detailStimulant and motivational effects of alcohol: Lessons from rodent and primate models
Brabant, Christian ULg; Guarnieri, Douglas J.; Quertemont, Etienne ULg

in Pharmacology, Biochemistry & Behavior (2014), 122

In several animal species including humans, the acute administration of low doses of alcohol increasesmotor activity. Different theories have postulated that alcohol-induced hyperactivity is causally ... [more ▼]

In several animal species including humans, the acute administration of low doses of alcohol increasesmotor activity. Different theories have postulated that alcohol-induced hyperactivity is causally related to alcoholism.Moreover, a common biological mechanism in the mesolimbic dopamine system has been proposed to mediate the stimulant and motivational effects of alcohol. Numerous studies have examined whether alcohol-induced hyperactivity is related to alcoholism using a great variety of animal models and several animal species. However, there is no review that has summarized this extensive literature. In this article, we present the various experimental models that have been used to study the relationship between the stimulant and motivational effects of alcohol in rodents and primates. Furthermore, we discuss whether the theories hypothesizing a causal link between alcohol-induced hyperactivity and alcoholism are supported by published results. The reviewed findings indicate that animal species that are stimulated by alcohol also exhibit alcohol preference. Additionally, the role of dopamine in alcohol-induced hyperactivity is well established since blocking dopaminergic activity suppresses the stimulant effects of alcohol. However, dopamine transmission plays a much more complex function in the motivational properties of alcohol and the neuronal mechanisms involved in alcohol stimulation and reward are distinct. Overall, the current review provides mixed support for theories suggesting that the stimulant effects of alcohol are related to alcoholism and highlights the importance of animal models as a way to gain insight into alcoholism. [less ▲]

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See detailAmphetamine reward in food restricted mice lacking the melanin-concentrating hormone receptor-1
Geuzaine, A; Tyhon, A; Grisar, Thierry ULg et al

in Behavioural Brain Research (2014), 262

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See detailThe histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice
Brabant, Christian ULg; Charlier, Yana ULg; Tirelli, Ezio ULg

in Behavioural Brain Research (2013), 243

Numerous studies have demonstrated that brain histamine plays a crucial role in learning and memory and histamine H3 receptor inverse agonists (H3R inverse agonists) have been proposed to treat cognitive ... [more ▼]

Numerous studies have demonstrated that brain histamine plays a crucial role in learning and memory and histamine H3 receptor inverse agonists (H3R inverse agonists) have been proposed to treat cognitive disorders. Pitolisant (BF2.649, 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride) was the first H3R inverse agonist that has been tested in human trials and is well tolerated. The present study investigated whether Pitolisant (0.625–20 mg/kg, i.p.) improves consolidation and reconsolidation processes in the fear conditioning task in female C57BL/6J mice. We also tested whether Pitolisant reverses memory deficits induced by the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (MK-801). Our results indicate that post-training systemic injections of Pitolisant facilitated consolidation of contextual fear memory and reversed amnesia induced by an i.p. injection of 0.12 mg/kg dizocilpine. In addition, none of the doses of Pitolisant we have tested after reactivation (reexposure to the context in which training took place 48 h earlier) affected reconsolidation, whereas dizocilpine disrupted it. However, Pitolisant was able to reverse the deficit in reconsolidation induced by 0.12 mg/kg dizocilpine. The present results are the first demonstration that Pitolisant is effective in improving consolidation processes in the fear condition task and add further evidence to its potential for treating cognitive disorders. [less ▲]

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See detailDo excitatory and inhibitory conditioning processes underlie psychomotor sensitization to amphetamine? An analysis using simple and multiple regressions
Brabant, Christian ULg; Tambour, Sophie; Quertemont, Etienne ULg et al

in Behavioural Brain Research (2011), 221

Excitatory or inhibitory conditioning processes have been proposed to account for the context-dependent establishment of amphetamine psychomotor sensitization in rodents. The purpose of this study was to ... [more ▼]

Excitatory or inhibitory conditioning processes have been proposed to account for the context-dependent establishment of amphetamine psychomotor sensitization in rodents. The purpose of this study was to test the predictions of these theories in mice. We first assessed the consequence of the extinction of post-sensitization conditioned activity (CR) on the ulterior expression of sensitization. We also assessed the relations between several measures of sensitization and conditioned hyperactivity revealed on a saline challenge using simple and multiple regression analyses. Context-dependent sensitization was induced via 7 amphetamine injections in the test context given alternately with 7 saline injections in another context in paired mice, unpaired mice receiving the converse pretreatment. Context-dependent sensitization (drug challenge) and the CR (saline challenge) were revealed subsequently. After CR extinction (over 7 every-other-day repetition of the saline challenge), mice were tested again for context-dependent sensitization. Against the excitatory conditioning model, CR extinction spared context-dependent sensitization in paired mice, and regression analyses revealed no significant correlations between the size of the CR and several measures of sensitization. In apparent agreement with the inhibitory conditioning model, unpaired mice expressed higher levels of sensitization in the test context after extinction than before. However, regression analyses did not indicate that activity on the saline challenge was related to measures of sensitization in unpaired mice. Therefore, the present results support neither the excitatory nor the inhibitory conditioning models of context-dependent sensitization, but remain compatible with theories proposing that other inhibitory mechanisms modulate sensitization. [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 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 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 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 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 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 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 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 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 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 detailInfluence of dose on the persistence of conditioned place preference induced by cocaine in C57BL/6J mice
Brabant, Christian ULg; Tirelli, Ezio ULg

in Behavioural Pharmacology (2003, September), 14(Suppl. 1), 54

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See detailQuasi-asymptotic development of conditioned hyperactivity induced by intermittent injections of cocaine in C57BL/6J mice
Brabant, Christian ULg; Tambour, Sophie ULg; Tirelli, Ezio ULg

in Pharmacology, Biochemistry & Behavior (2003), 75(2), 273-280

The emergence of a conditioned cocaine-induced hyperlocomotion was examined in C57BL/6J mice using a procedure that has not been used previously. Two days after a session of preexposure to the test ... [more ▼]

The emergence of a conditioned cocaine-induced hyperlocomotion was examined in C57BL/6J mice using a procedure that has not been used previously. Two days after a session of preexposure to the test chambers under saline, a first group of mice (cocaine-cued) received five once-daily injections of 10-mg/kg sc cocaine every other day (on the odd days of the chronic treatment period) and a saline injection on the 5 days following each cocaine injection day (on the even days of the treatment period), in all cases before being placed in the test chamber. Another group of mice (saline-cued) received 10 injections of saline on both the even and the odd days in the same context, and a third group of mice (cocaine-uncued) received five injections of saline on the even days in the test context and five injections of cocaine on the odd days in an alternative context. On the odd days sessions, the cocaine-cued group showed significant repeated increases in locomotion without behavioural sensitisation being induced, whereas the saline-cued levels of locomotion remained on baseline levels. On the first even session, the three groups did not differ from each other and showed lower levels of locomotion than on the preexposure session. During the two following even sessions, the cocaine-cued group showed an increase in locomotion that levelled off on the two remaining sessions, whereas the saline-cued and the cocame-uncued groups (which presented comparable values) exhibited significantly lower levels of locomotion. That pattern of successive placebo responses resembles the typical S-shaped development of a Pavlovian conditioned response, albeit the increase described here was quite rapid. The protocol used here may provide an additional method for the experimental analysis of stimulant-induced conditioned placebo activity. (C) 2003 Elsevier Science Inc. All rights reserved. [less ▲]

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

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

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

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

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