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8 publication(s) since Octobre 2014:

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01/06/2019 | Biol Psychiatry   IF 11.5
Incubation of Cocaine Craving After Intermittent-Access Self-administration: Sex Differences and Estrous Cycle.
Nicolas C, Russell TI, Pierce AF, Maldera S, Holley A, You ZB, McCarthy MM, Shaham Y, Ikemoto S

BACKGROUND: Studies using continuous-access drug self-administration showed that cocaine seeking increases during abstinence (incubation of cocaine craving). Recently, studies using intermittent-access self-administration showed increased motivation to self-administer and seek cocaine. We examined whether intermittent cocaine self-administration would potentiate incubation of craving in male and female rats and examined the estrous cycle's role in this incubation. METHODS: In experiment 1, male and female rats self-administered cocaine either continuously (8 hours/day) or intermittently (5 minutes ON, 25 minutes OFF x 16) for 12 days, followed by relapse tests after 2 or 29 days. In experiments 2 and 3, female rats self-administered cocaine intermittently for six, 12, or 18 sessions. In experiment 4, female rats self-administered cocaine continuously followed by relapse tests after 2 or 29 days. In experiments 3 and 4, the estrous cycle was measured using a vaginal smear test. RESULTS: Incubation of cocaine craving was observed in both sexes after either intermittent or continuous drug self-administration. Independent of access condition and abstinence day, cocaine seeking was higher in female rats than in male rats. In both sexes, cocaine seeking on both abstinence days was higher after intermittent drug access than after continuous drug access. In female rats, incubation of craving after either intermittent or continuous drug access was significantly higher during estrus than during non-estrus; for intermittent drug access, this effect was independent of the training duration. CONCLUSIONS: In both sexes, intermittent cocaine access caused time-independent increases in drug seeking during abstinence. In female rats, the time-dependent increase in drug seeking (incubation) is critically dependent on the estrous cycle phase.

02/04/2018 | Behav Brain Res   IF 2.8
Generalization of effects of environmental enrichment on seeking for different classes of drugs of abuse.
Sikora M, Nicolas C, Istin M, Jaafari N, Thiriet N, Solinas M

BACKGROUND: Addiction is a chronic disease characterized by persistent vulnerability to relapse during abstinence. In animal models of addiction, accumulating evidence suggests that exposure to environmental enrichment (EE) during periods of abstinence can have curative effects on addiction and reduce the risks of relapse. However, until present most studies have mainly focused on cocaine. In this study, we investigated whether EE could have beneficial effects on cue-induced seeking for several psychoactive drugs belonging to different pharmacological classes such as methamphetamine (METH), heroin (HER) and nicotine (NIC). METHODS: After self-administration training of METH, HER and NIC, rats were housed in enriched (EE) or standard environments (SE) for 21-28 days of forced abstinence and then drug-seeking behavior was assessed in the absence of the drug. RESULTS: We found that, compared to SE housing, exposure to EE reduced drug seeking behavior for all drugs tested. CONCLUSIONS: These findings suggest that the anti-craving effects of EE are general for a wide variety of drugs and support the hypothesis that environmental stimulation may be a general intervention for attenuating relapse in humans.

09/2017 | Neuropsychopharmacology   IF 7.2
Longitudinal Changes in Brain Metabolic Activity after Withdrawal from Escalation of Cocaine Self-Administration.
Nicolas C, Tauber C, Lepelletier FX, Chalon S, Belujon P, Galineau L, Solinas M

The chronic and relapsing nature of addiction suggests that drugs produce persistent adaptations in the brain that make individuals with drug addiction particularly sensitive to drug-related cues and stress and incapable of controlling drug-seeking and drug-taking behavior. In animal models, several long-lasting neuroadaptations have been described. However, few studies have used brain-imaging techniques to provide a complete picture of brain functioning in the course of withdrawal from cocaine. In this study, we allowed rats to self-administer cocaine under short-access (1-h/day) or long-access (6-h/day) conditions and used 2-deoxy-2-((18)F)fluoro-d-glucose ((18)FDG) positron emission tomography scanning to investigate the longitudinal changes in metabolic activity 1 and 4 weeks after discontinuation of cocaine self-administration. We found that compared to naive rats, both long-access and short-access rats showed significant disruptions in basal brain metabolic activity. However, compared to short-access, long-access rats showed more intense, and long-lasting neuroadaptations in a network of brain areas. In particular, abstinence from extended access to cocaine was associated with decreased metabolic activity in the anterior cingulate cortex, the insular cortex, and the dorsolateral striatum, and increased metabolic activity in the mesencephalon, amygdala, and hippocampus. This pattern is strikingly similar to that described in humans that has led to the proposal of the Impaired Response Inhibition and Salience Attribution model of addiction. These results demonstrate that extended access to cocaine leads to persistent neuroadaptations in brain regions involved in motivation, salience attribution, memory, stress, and inhibitory control that may underlie increased risks of relapse.

07/2017 | Psychopharmacology (Berl)   IF 3.4
Interaction of chronic food restriction and methylphenidate in sensation seeking of rats.
Talishinsky AD, Nicolas C, Ikemoto S

RATIONALE: It is necessary to understand better how chronic food restriction (CFR) and psychostimulant drugs interact in motivated behavior unrelated to food or energy homeostasis. OBJECTIVES: We examined whether CFR augments methylphenidate (MPH)-potentiated responding reinforced by visual sensation (VS) and whether repeated MPH injections or prolonged CFR further augments such responses. METHODS: Before starting the following experiments, rats on a CFR diet received a limited daily ration in such a way that their body weights decreased to 85-90% of their original weights over 2 weeks. In experiment 1, rats on CFR and ad libitum diet received four injections of varying MPH doses (0, 2.5, 5, and 10 mg/kg). In experiment 2, CFR and ad libitum groups received repeated injections of MPH (2.5 mg/kg). In experiment 3, half of CFR rats received repeated injections of MPH (2.5 mg/kg), and the other half received saline, and following a 7-day abstinence, they all received the 2.5-mg/kg dose of MPH. RESULTS: CFR rats increased VS-reinforced responding more than ad libitum rats when they received MPH. Repeated injections of MPH with prolonged CFR further increased VS-reinforced responding. We found a double dissociation where prolonged CFR (3 vs. 6 weeks) made VS-reinforced responding, but not locomotor activity, more responsive to MPH, whereas repeated MPH injections made locomotor activity, but not VS-reinforced responding, more responsive to MPH. CONCLUSIONS: CFR markedly potentiates effects of MPH on VS-reinforced responding. The present study demonstrates that the longer CFR continues, the greater psychostimulant drugs augment behavioral interaction with salient stimuli.

05/2016 | Neuropsychopharmacology   IF 7.2
Statins Reduce the Risks of Relapse to Addiction in Rats.
Chauvet C, Nicolas C, Lafay-Chebassier C, Jaber M, Thiriet N, Solinas M

Statins are drugs that have been used for decades in humans for the treatment of hypercholesterolemia. More recently, several lines of evidence demonstrate that statins, in addition to their peripheral effects, produce a wide variety of effects in the brain and may be beneficial in neurological and psychiatric conditions. In this study, we allowed rats to self-administer cocaine for several weeks and, at the end of self-administration training, we treated them with low doses of statins daily for a 21-day period of abstinence. Chronic administration of brain-penetrating statins, simvastatin (1 mg/kg) and atorvastatin (1 mg/kg), reduced cocaine seeking compared with vehicle, whereas administration of pravastatin (2 mg/kg), a statin with low brain penetrability, did not. Importantly, the effects of brain-penetrating statins persisted even after discontinuation of the treatment and were specific for drug seeking because drug taking was not altered by simvastatin treatment. Finally, the effects of simvastatin were found to generalize to another drug of abuse such as nicotine, but not to food reward, and to reinstatement of cocaine seeking induced by stress. These results demonstrate that brain-penetrating statins can reduce risks of relapse to addiction. Given their well-known safety profile in humans, statins could be a novel effective treatment for relapse to cocaine and nicotine addiction and their use could be implemented in clinical settings without major health risks.

21/03/2016 | Sci Rep   IF 4
Exposure to sucrose during periods of withdrawal does not reduce cocaine-seeking behavior in rats.
Nicolas C, Lafay-Chebassier C, Solinas M

Concomitant access to drugs of abuse and alternative rewards such as sucrose has been shown to decrease addiction-related behaviors in animals. Here we investigated whether access to sucrose during abstinence in contexts that are temporally and physically distinct from drug-related contexts could reduce subsequent drug seeking. In addition, we investigated whether a history of cocaine self-administration would alter the rewarding effects of sucrose. Rats self-administered cocaine for ten sessions, while yoked-saline rats received only saline injections, and then we subjected them to a 30-day withdrawal period during which they had access to water and sucrose continuously or intermittently according to a schedule that induces binge-drinking behavior. At the end of the withdrawal period, rats were tested for cocaine seeking behavior during a single 6 h session. We found that exposure to cocaine increased sucrose consumption only when rats had intermittent access to sucrose, but exposure to sucrose did not alter drug seeking regardless of the schedule of access. These results suggest that exposure to cocaine cross-sensitizes to the rewarding effects of sucrose, but exposure to sucrose during abstinence, temporally and physically distinct from drug-related environments, does not to reduce drug seeking.

05/12/2014 | Int J Neuropsychopharmacol   IF 4.2
Chronic stimulation of the tone of endogenous anandamide reduces cue- and stress-induced relapse in rats.
Chauvet C, Nicolas C, Thiriet N, Lardeux MV, Duranti A, Solinas M

BACKGROUND: The endogenous cannabinoid system plays an important role in motivation, stress, and drug abuse. Pharmacologically, the endocannabinoid system can be stimulated by either agonists of CB1 receptors or inhibition of metabolic degradation of endogenous cannabinoids and consequent increases in their brain levels. METHODS: Here, we investigated whether chronic administration during a period of withdrawal of the fatty acid amide hydrolase inhibitor URB597, which increases anandamide levels, would decrease the risks of relapse to cocaine seeking. Rats were allowed to self-administer cocaine and then they underwent forced withdrawal for 28 days, during which they were treated with URB597 or vehicle. One day after the last injection, we investigated cocaine seeking in one 6h extinction session and relapse triggered by re-exposure to drug-associated cues or a pharmacological stressor. RESULTS: We found that administration of URB597 significantly decreases cocaine-seeking behavior and cue- and stress-induced relapse. CONCLUSION: These results suggest that stimulation of the endocannabinoid system could be helpful to prevent relapse to cocaine addiction.

31/10/2014 | Int J Neuropsychopharmacol   IF 4.2
Prenatal exposure to methylphenidate affects the dopamine system and the reactivity to natural reward in adulthood in rats.
Lepelletier FX, Tauber C, Nicolas C, Solinas M, Castelnau P, Belzung C, Emond P, Cortese S, Faraone SV, Chalon S, Galineau L

BACKGROUND: Methylphenidate (MPH) is a commonly-used medication for the treatment of children with Attention-Deficit/Hyperactivity Disorders (ADHD). However, its prescription to adults with ADHD and narcolepsy raises the question of how the brain is impacted by MPH exposure during pregnancy. The goal of this study was to elucidate the long-term neurobiological consequences of prenatal exposure to MPH using a rat model. METHODS: We focused on the effects of such treatment on the adult dopamine (DA) system and on the reactivity of animals to natural rewards. RESULTS: This study shows that adult male rats prenatally exposed to MPH display elevated expression of presynaptic DA markers in the DA cell bodies and the striatum. Our results also suggest that MPH-treated animals could exhibit increased tonic DA activity in the mesolimbic pathway, altered signal-to-noise ratio after a pharmacological stimulation, and decreased reactivity to the locomotor effects of cocaine. Finally, we demonstrated that MPH rats display a decreased preference and motivation for sucrose. CONCLUSIONS: This is the first preclinical study reporting long-lasting neurobiological alterations of DA networks as well as alterations in motivational behaviors for natural rewards after a prenatal exposure to MPH. These results raise concerns about the possible neurobiological consequences of MPH treatment during pregnancy.