Publications (14)133.63 Total impact
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Article: Responses to novelty and vulnerability to cocaine addiction: contribution of a multi-symptomatic animal model.
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ABSTRACT: Epidemiological studies have revealed striking associations between several distinct behavioral/personality traits and drug addiction, with a large emphasis on the sensation-seeking trait and the associated impulsive dimension of personality. However, in human studies, it is difficult to identify whether personality/behavioral traits actually contribute to increased vulnerability to drug addiction or reflect psychobiological adaptations to chronic drug exposure. Here we show how animal models, including the first multi-symptomatic model of addiction in the rat, have contributed to a better understanding of the relationships between different subdimensions of the sensation-seeking trait and different stages of the development of cocaine addiction, from vulnerability to initiation of cocaine self-administration to the transition to compulsive drug intake. We argue that sensation seeking predicts vulnerability to use cocaine, whereas novelty seeking, akin to high impulsivity, predicts instead vulnerability to shift from controlled to compulsive cocaine use, that is, addiction.Cold Spring Harbor perspectives in medicine. 01/2012; 2(11). -
Article: A decrease in gamma-synuclein expression within the nucleus accumbens increases cocaine intravenous self-administration in the rat.
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ABSTRACT: Except as a marker of cancer progression, gamma-synuclein (GSyn) had received little attention. Recent data showed however that GSyn modulates cocaine-induced locomotor effects, suggesting that it could also play a role in cocaine reinforcing effects. In the rat, siRNAs targeting GSyn expression were injected in the nucleus accumbens and cocaine reinforcing effects were evaluated by means of intravenous self-administration. A dose-response curve was followed by procedures of progressive ratio, extinction, cocaine- and cue-induced reinstatements. Decrease of GSyn expression increased self-administration over a large range of doses. This effect was associated with an increase in cocaine-induced reinstatement. The present data reveal that GSyn exert a specific negative control on cocaine-induced reinforcing and incentive effects.Addiction Biology 01/2011; 16(1):120-3. · 4.83 Impact Factor -
Article: High-novelty-preference rats are predisposed to compulsive cocaine self-administration.
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ABSTRACT: Sensation/novelty-seeking is amongst the best markers of cocaine addiction in humans. However, its implication in the vulnerability to cocaine addiction is still a matter of debate, as it is unclear whether this trait precedes or follows the development of addiction. Sensation/novelty-seeking trait has been identified in rats on the basis of either novelty-induced locomotor activity (high-responder (HR) trait) or novelty-induced place preference (high-novelty-preference trait (HNP)). HR and HNP traits have been associated with differential sensitivity to psychostimulants. However, it has recently been demonstrated that HR rats do not develop compulsive cocaine self-administration (SA) after protracted exposure to the drug, thereby suggesting that at least one dimension of sensation/novelty seeking in the rat is dissociable from the vulnerability to switch from controlled to compulsive cocaine SA. We therefore investigated whether HNP, as measured as the propensity to choose a new environment in a free choice procedure, as opposed to novelty-induced locomotor activity, predicts the vulnerability to, and the severity of, addiction-like behavior for cocaine. For this, we identified HR/LR rats and HNP/LNP rats before any exposure to cocaine. After 60 days of cocaine SA, each rat was given an addiction score based on three addiction-like behaviors (persistence of responding when the drug is signaled as not available, high breakpoint under progressive ratio schedule and resistance to punishment) that resemble the clinical features of drug addiction, namely inability to refrain from drug seeking, high motivation for the drug and compulsive drug use despite adverse consequences. We show that, as opposed to HR rats, HNP rats represent a sub-population predisposed to compulsive cocaine intake, displaying higher addiction scores than LNP rats. This study thereby provides new insights into the factors predisposing to cocaine addiction, supporting the hypothesis that addiction is sustained by two vulnerable phenotypes: a 'drug use prone' phenotype such as HR which brings an individual to develop drug use and an 'addiction prone' phenotype, such as HNP, which facilitates the shift from sustained to compulsive drug intake and addiction.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2010; 36(3):569-79. · 6.99 Impact Factor -
Article: Transition to addiction is associated with a persistent impairment in synaptic plasticity.
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ABSTRACT: Chronic exposure to drugs of abuse induces countless modifications in brain physiology. However, the neurobiological adaptations specifically associated with the transition to addiction are unknown. Cocaine self-administration rapidly suppresses long-term depression (LTD), an important form of synaptic plasticity in the nucleus accumbens. Using a rat model of addiction, we found that animals that progressively develop the behavioral hallmarks of addiction have permanently impaired LTD, whereas LTD is progressively recovered in nonaddicted rats maintaining a controlled drug intake. By making drug seeking consistently resistant to modulation by environmental contingencies and consequently more and more inflexible, a persistently impaired LTD could mediate the transition to addiction.Science 06/2010; 328(5986):1709-12. · 31.20 Impact Factor -
Article: Mifepristone and spironolactone differently alter cocaine intravenous self-administration and cocaine-induced locomotion in C57BL/6J mice.
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ABSTRACT: Corticosterone, the main glucorticoid hormone in rodents, facilitates behavioral responses to cocaine. Corticosterone is proposed to modulate cocaine intravenous self-administration (SA) and cocaine-induced locomotion through distinct receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), respectively. However, this remains debatable. On one hand, modulation of both responses by the GR was tested in different experimental conditions, i.e. light versus dark nycthemeral phase and naïve versus cocaine-experienced animals. On the other hand, modulation of both responses by the MR was never tested directly but only inferred based on the ability of low plasma corticosterone levels (those for which corticosterone almost exclusively binds the MR) to compensate the effects of adrenalectomy. Our goal here was to test the involvement of the GR and the MR in cocaine-induced locomotor and reinforcing effects in the same experimental conditions. C57Bl/6J mice were trained for cocaine (1 mg/kg/infusion) intravenous SA over 40 SA sessions. The animals were then administered with mifepristone (30 mg/kg i.p.), a GR antagonist, or with spironolactone (20 mg/kg/i.p.), an MR antagonist, 2 hours before either cocaine intravenous SA or cocaine-induced locomotion. In a comparable nycthemeral period and in similarly cocaine-experienced animals, a blockade of the GR decreased cocaine-induced reinforcing effects but not cocaine-induced locomotion. A blockade of the MR decreased both cocaine-induced reinforcing (but to a much lesser extent than the GR blockade) and locomotor effects. Altogether, our results comforted the hypothesis that the GR modulates cocaine-related operant conditioning, while the MR would modulate cocaine-related unconditioned effects. The present data also reveal mifepristone as an interesting tool for manipulating the impact of corticosterone on cocaine-induced reinforcing effects in mice.Addiction Biology 10/2009; 15(1):81-7. · 4.83 Impact Factor -
Article: Pattern of intake and drug craving predict the development of cocaine addiction-like behavior in rats.
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ABSTRACT: Clinical observations suggest that cocaine addiction often emerges with new patterns of use. Whether these changes are a cause of addiction or its consequence is unknown. We investigated whether the development of an addiction-like behavior in the rat is associated with the pattern of cocaine intake and with cocaine craving, a major feature of cocaine addiction. To determine whether changes in the pattern of cocaine use and enhanced craving precede or parallel the onset of addiction, we used a rat addiction model that incorporates core features of human addiction. For this purpose, the pattern of inter-infusion intervals (a measure of pattern of cocaine intake), sensitivity to cocaine-induced reinstatement (a measure of cocaine craving), and addiction-like behaviour were assessed over several months of intravenous cocaine self-administration. We found that, even at early stages of cocaine self-administration, both the pattern of cocaine intake and the intensity of drug-induced reinstatement predict the severity of cocaine use, measured after 75 days of self-administration. Our results identify key predictors of cocaine addiction-intensified pattern of drug use and high drug-induced craving-that may help in the identification of subjects at risk for subsequent development of severe cocaine addiction.Biological psychiatry 05/2009; 65(10):863-8. · 8.93 Impact Factor -
Article: Stress and addiction: glucocorticoid receptor in dopaminoceptive neurons facilitates cocaine seeking.
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ABSTRACT: The glucocorticoid receptor is a ubiquitous transcription factor mediating adaptation to environmental challenges and stress. Selective Nr3c1 (the glucocorticoid receptor gene) ablation in mouse dopaminoceptive neurons expressing dopamine receptor 1a, but not in dopamine-releasing neurons, markedly decreased the motivation of mice to self-administer cocaine, dopamine cell firing and the control exerted by dopaminoceptive neurons on dopamine cell firing activity. In contrast, anxiety was unaffected, indicating that glucocorticoid receptors modify a number of behavioral disorders through different neuronal populations.Nature Neuroscience 04/2009; 12(3):247-9. · 15.53 Impact Factor -
Article: Maternal environment influences cocaine intake in adulthood in a genotype-dependent manner.
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ABSTRACT: Accumulating epidemiological evidence points to the role of genetic background as a modulator of the capacity of adverse early experiences to give rise to mental illness. However, direct evidence of such gene-environment interaction in the context of substance abuse is scarce. In the present study we investigated whether the impact of early life experiences on cocaine intake in adulthood depends on genetic background. In addition, we studied other behavioral dimensions associated with drug abuse, i.e. anxiety- and depression-related behaviors. For this purpose, we manipulated the maternal environment of two inbred mouse strains, the C57BL/6J and DBA/2J by fostering them with non-related mothers, i.e. the C3H/HeN and AKR strains. These mother strains show respectively high and low pup-oriented behavior. As adults, C57BL/6J and DBA/2J were tested either for cocaine intravenous self-administration or in the elevated plus-maze and forced swim test (FST). We found that the impact of maternal environment on cocaine use and a depression-related behavior depends upon genotype, as cocaine self-administration and behavior in the FST were influenced by maternal environment in DBA/2J, but not in C57BL/6J mice. Anxiety was not influenced by maternal environment in either strain. Our experimental approach could contribute to the identification of the psychobiological factors determining the susceptibility or the resilience of certain individuals to develop psychopathologies.PLoS ONE 02/2008; 3(5):e2245. · 4.09 Impact Factor -
Article: Gene-environment interactions in vulnerability to cocaine intravenous self-administration: a brief social experience affects intake in DBA/2J but not in C57BL/6J mice.
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ABSTRACT: Individual differences in cocaine-taking behavior and liability to develop abuse are clearly observed, but underlying mechanisms are still poorly understood. A role for gene-environment interactions has been proposed but remains hypothetical. We investigated whether gene-environment interactions influence intravenous cocaine self-administration (SA) in mice. We tested the effect of a past short group housing experience on cocaine SA in two inbred strains of mice, the C57BL/6J (C57) and DBA/2J (DBA). Adult C57 and DBA mice were individually housed upon arrival in the laboratory. After 3 weeks, half of the animals of each strain were group housed for 19 days. One week after the end of group housing, cocaine SA or measurement of brain cocaine levels took place. Individually and ex-group-housed C57 mice did not differ for cocaine SA. On the contrary, the ex-group-housed DBA mice showed an upward shift in the dose-response curve as compared to individually housed DBA. Differences in brain cocaine levels could not account for the observed behavioral differences. These results demonstrate that vulnerability to cocaine reinforcing effects can be affected by gene-environment interactions. We propose a mouse model for the characterization of gene-environment interactions in the vulnerability to cocaine-taking behavior.Psychopharmacologia 08/2007; 193(2):179-86. · 4.08 Impact Factor -
Article: Preexposure during or following adolescence differently affects nicotine-rewarding properties in adult rats.
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ABSTRACT: Many people come in contact with psychoactive drugs, yet not all of them become addicts. Epidemiology shows that a late approach with cigarette smoking is associated with a lower probability to develop nicotine dependence. Exposure to nicotine during periadolescence, but not similar exposure in the postadolescent period, increases nicotine self-administration in rats, but underlying mechanisms remain poorly understood. We investigated whether exposure to nicotine during or after adolescence would alter rewarding properties of the same drug at adulthood, as assessed by place conditioning. Periadolescent (PND 34-43) or postadolescent (PND 60-69) rats were injected with saline or nicotine (0.4 mg kg(-1)) for 10 days. The rats received three pairings with saline and three pairings with nicotine (0, 0.3, or 0.6 mg kg(-1)) 5 weeks after pretreatment. The rats were then tested for place conditioning in a drug-free state. Upon first exposure to the apparatus, animals pretreated with nicotine during adolescence showed elevated novelty-induced activation. The 0.3 (but not the 0.6) mg kg(-1) dose failed to produce both ongoing locomotor sensitization and place conditioning in animals pretreated with nicotine following adolescence. This suggests a rightward shift in the dose-response curve, namely, a reduced efficacy of nicotine. Conversely, the same dose was effective in saline-pretreated controls and noteworthy in rats pretreated during adolescence. Exposure following the adolescent period might diminish the risk to develop nicotine dependence. As for human implications, findings are consistent with a reduced vulnerability to nicotine addiction in people who start smoking late in their life.Psychopharmacologia 04/2006; 184(3-4):382-90. · 4.08 Impact Factor -
Article: Evidence for addiction-like behavior in the rat.
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ABSTRACT: Although the voluntary intake of drugs of abuse is a behavior largely preserved throughout phylogeny, it is currently unclear whether pathological drug use ("addiction") can be observed in species other than humans. Here, we report that behaviors that resemble three of the essential diagnostic criteria for addiction appear over time in rats trained to self-administer cocaine. As in humans, this addiction-like behavior is present only in a small proportion of subjects using cocaine and is highly predictive of relapse after withdrawal. These findings provide a new basis for developing a true understanding and treatment of addiction.Science 09/2004; 305(5686):1014-7. · 31.20 Impact Factor -
Article: The glucocorticoid receptor as a potential target to reduce cocaine abuse.
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ABSTRACT: Several findings suggest that glucocorticoid hormones are involved in determining the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor. In this study, we show that the selective inactivation of the GR gene in the brains of mice profoundly flattened the dose-response function for cocaine intravenous self-administration and suppressed sensitization, two experimental procedures considered relevant models of addiction. Furthermore, administration of a GR antagonist dose-dependently reduced the motivation to self-administer cocaine. Importantly, the absence of GR did not modify the basal behavioral and molecular effects of cocaine but selectively modified the excessive response to the drug spontaneously present in certain vulnerable individuals or induced by repeated drug exposure in others. In conclusion, we provide the first genetic evidence that the GR gene can modulate cocaine abuse. This suggests that targeting GR function in the brain could provide new therapeutic strategies to treat cocaine addiction for which there is no available treatment.Journal of Neuroscience 07/2003; 23(11):4785-90. · 7.11 Impact Factor -
Article: Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats.
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ABSTRACT: Epidemiological studies indicate that there is an increased likelihood for the development of nicotine addiction when cigarette smoking starts early during adolescence. These observations suggest that adolescence could be a "critical" ontogenetic period, during which drugs of abuse have distinct effects responsible for the development of dependence later in life. We compared the long-term behavioral and molecular effects of repeated nicotine treatment during either periadolescence or postadolescence in rats. It was found that exposure to nicotine during periadolescence, but not a similar exposure in the postadolescent period, increased the intravenous self-administration of nicotine and the expression of distinct subunits of the ligand-gated acetylcholine receptor in adult animals. Both these changes indicated an increased sensitivity to the addictive properties of nicotine. In conclusion, adolescence seems to be a critical developmental period, characterized by enhanced neurobehavioral vulnerability to nicotine.Journal of Neuroscience 07/2003; 23(11):4712-6. · 7.11 Impact Factor -
Article: Influence of cue-conditioning on acquisition, maintenance and relapse of cocaine intravenous self-administration.
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ABSTRACT: Conditioning theories propose that, through a Pavlovian associative process, discrete stimuli acquire the ability to elicit neural states involved in the maintenance and relapse of a drug-taking behaviour. Experimental evidence indicates that drug-related cues play a role in relapse, however, their influence on the development and maintenance of drug self-administration has been poorly investigated. In this report, we analysed the effects of a drug-associated cue light on acquisition, maintenance and reinstatement of intravenous cocaine self-administration. The results show that a cocaine-associated cue light can act as an incentive in absence of the drug, but does not directly modify drug-reinforcing effects. Contingent and non-contingent presentations of a cocaine-associated cue light reinstated an extinguished self-administration behaviour. However, regardless of whether or not a cue light was associated with cocaine infusions, rats acquire cocaine intravenous self-administration reaching the same levels of intake. Furthermore, after self-administration has been acquired in presence of the cue light, the omission of the cue light or its non-contingent presentation did not modify rat behaviour. In conclusion, our work shows that cocaine-associated explicit cues do not directly interfere with the reinforcing effects of the drug.European Journal of Neuroscience 05/2002; 15(8):1363-70. · 3.63 Impact Factor
Top co-authors
Top Journals
Institutions
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2011
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Université de Fribourg
Fribourg, FR, Switzerland
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2007–2010
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University of Bordeaux
Bordeaux, Aquitaine, France
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2003–2008
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Institut national de la santé et de la recherche médicale
Paris, Ile-de-France, France
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2006
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Istituto Superiore di Sanità
Roma, Latium, Italy
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2004
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Université Victor Segalen Bordeaux 2
Bordeaux, Aquitaine, France
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