Reduction of Cocaine-Induced Locomotor Effects by Enriched Environment Is Associated with Cell-Specific Accumulation of ΔFosB in Striatal and Cortical Subregions

Background: Early exposure to enriched environments has been shown to decrease the locomotor effects induced by repeated injections of cocaine and modify basal and cocaine-induced total protein levels of the transcription factor ΔFosB in the whole striatum of mice. In this study, we aimed at characterizing whether the profile of ΔFosB accumulation induced by enriched environments and cocaine would be similar or different in terms of brain areas and cell type. Methods: We used mice expressing the eGFP protein in D1 receptor positive (D1R(+)) neurons to determine whether ΔFosB induced by enriched environment or cocaine injections (5×15 mg/kg) would occur in selective subpopulations of neurons in several subregions of the striatum and prefrontal cortex. Results: We found that: (1) exposure to enriched environment reduces cocaine-induced locomotor activation, confirming our previous findings; (2) exposure to enriched environment by itself increases the accumulation of ΔFosB mostly in D1R(-) cells in the shell part of the nucleus accumbens and dorsal striatum, whereas in the nucleus accumbens core, ΔFosB accumulates in both D1R(+) and D1R(-) neurons; (3) in standard environment mice, cocaine induces accumulation of ΔFosB selectively in D1R(+) cells in the nucleus accumbens, dorsal striatum, and infralimbic cortex; and (4) the effects of enriched environments and cocaine on accumulation of ΔFosB were reciprocally blocked by their combination. Conclusions: Altogether, these results suggest that the enriched environment-induced reduction in behavioral effects of cocaine might result from 2 distinct effects on ΔFosB in striatal medium-sized spiny neurons belonging to the direct and indirect pathways

Persistent Neuroadaptations in the Expression of Genes Involved in Cholesterol Homeostasis Induced by Chronic, Voluntary Alcohol Intake in Rats

Alcohol use disorder (AUD) is associated with persistent adaptations in the brain that are believed to participate in the long-lasting vulnerability to relapse after abstinence. Cholesterol, the major sterol compound found in the central nervous system (CNS), plays a major role in maintenance of neuronal morphology, synaptogenesis and synaptic communication and may be involved in alcohol-induced neuroadaptations. In this study, we investigated whether alcohol consumption in a two-bottle choice paradigm followed by 3 weeks of abstinence could alter the expression of genes encoding proteins involved in cholesterol homeostasis in brain regions involved in addiction and relapse, namely the prefrontal cortex (PFC), the nucleus accumbens (NAc), the mesencephalon and the amygdala. We found that voluntary alcohol intake followed by 3 weeks of forced abstinence produces changes in the transcription of several genes encoding proteins directly involved in cholesterol synthesis such as 3-hydroxyl-3-methylglutaryl-coenzyme A (HMGCoA) reductase, farnesyl-diphosphate farnesyltransferase 1 (FDFT1) and farnesyl diphosphate synthase (FDPS) and in its regulation such as sterol regulatory element-binding factor-2 (SREBF2), in cholesterol transport such as ATP-binding cassette subfamily A member 1 (ABCA1) and in cholesterol degradation such as CYP46A1. Interestingly, these changes appeared to be region-specific and suggest that previous chronic exposure to alcohol might durably increase cholesterol metabolism in the PFC, the NAc and the mesencephalon and decrease cholesterol metabolism in the amygdala. Altogether, these results suggest that alcohol consumption leads to durable deregulations in cholesterol metabolism in key areas involved in loss of control over drug use and addiction. These long-term neuroadaptations may participate in the changes in brain structure and functioning that are responsible for the long-lasting risks of relapse to alcohol

A MECHATRONIC TOOL FOR REVEALING INVERSE RELATIONSHIPS AMONG HEART’S STROKE VOLUME AND HEAD’S LINEAR ACCELERATION INDUCED BY MOORED BOATS ROLLING IN ELDERLY SAILORS WITH UNCHANGED BODY SIZES: A NON-DRUG ANTI-HYPERTENSIVE ADVANTAGE?

Three aged and skilled sailors, being in a good condition of cardio metabolic compensation, took a seven days coastal sailing cruise. They daily underwent a cardiodynamic assessment by a impedance cardigraphy tool while staying seated on the moored boat. They showed a statistically significant inverse linear regression of beat-to-beat left ventricular stroke volume (LSV) versus the component of the head acceleration along the spatial X-axis, positioning the subject’s head so that the X-axis lay along the nose-ocipital direction. In fact, the temporally corresponding values of LSV inversely changed of about 11 ml on average, with an interindividual difference ranging from a minimum of about 6 ml to a maximum of about 14 ml, for each unitary head acceleration change. Since the reduction of left ventricular stroke volume may be due to the already observed vestibulo-sympathetic reflex from which limbs muscle vasodilation may occur, and considering that LSV falling induces a reduction in arterial blood pressure, it is hypothesized that the slow rolling of moored boat might also act as a non-invasive arterial blood pressure attenuator effect

Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid

In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuana’s main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by re-exposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse

Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: Study protocol for a randomized controlled trial

Background: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria. Methods/design: In this study, 206 spontaneously breathing infants born at 24+0-27+6 weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation. Discussion: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge. Trial registration: ClinicalTrials.gov identifier: NCT02482766. Registered on 1 June 2015

A modified self-adjusting delay discounting procedure for the study of choice impulsivity in rats

International audienceRATIONALE:Delay-discounting procedures involving choice between small immediate rewards and large delayed rewards are used to study impulsivity in rodents. Improving existing procedures may provide new insights into the neurobiological mechanisms underlying decision-making processes.OBJECTIVES:To develop a novel delay-discounting procedure that adjusts the delay value within individual sessions based on the rat's most recent choices.METHODS:Compared to previously developed procedure, we required a more consistent demonstration of preference, five consecutive choices of the large or small reward, a criterion that is more likely to reflect deliberate choice by the animal, as opposed to two consecutive choices. In addition, delays were changed in steps of 5 s (rather than 1 s), because 5-s increments should be more easily discriminated and may produce a more distinct effect on choice. We characterized the procedure behaviorally by manipulating the duration of the session and the consecutive choice criterion, and we investigated the stability of the behavior upon interruption of training. We also characterized the procedure pharmacologically by investigating the effects of dopaminergic compounds.RESULTS:Our procedures allowed obtaining two complementary measures of delay discounting: (1) the percentage of choices of the delay option and (2) the mean adjusting delay, an index of the delay that animals choose more frequently. We found that our procedure rapidly establishes a baseline of choice behavior that remains stable over time and is highly sensitive to manipulations of the dopaminergic system.CONCLUSIONS:This procedure may provide a useful tool for investigating the neurobiology of inter-temporal choice and decision-making

Stratégies environnementales et pharmacologiques du traitement de la rechute à la cocaïne (du comportement à la neurobiologie)

L'addiction est une maladie psychiatrique chronique caractérisée par des comportements répétitifs et compulsifs plus ou moins nuisibles pour la santé. L'une des caractéristiques fondamentales à prendre en considération est la rechute, c'est-à-dire la reprise de la consommation de drogue, pouvant survenir après des années d'abstinence. Etudier les déterminants favorisant l'abstinence et diminuant la rechute est indispensable non seulement pour mieux comprendre la toxicomanie mais aussi pour développer des modalités thérapeutiques centrées sur la prévention à long terme. Dans cette optique, l'objectif principal de ma thèse a été l'étude de l'influence de l'environnement enrichi (EE) sur la rechute à la cocaïne. L'EE consiste à fournir aux animaux de laboratoire une stimulation des fonctions sensorielles, cognitives et motrices. Ainsi, l'EE est considéré comme un modèle animal pour étudier les conséquences des conditions de vie positives sur les maladies du cerveau. Par l'utilisation de différents modèles animaux d'addiction à la cocaïne, nous avons mis en évidence que l'EE possède des propriétés curatives, une fois les comportements relatifs à l'addiction installés. Nous avons démontré que l'EE est capable d'éliminer les conséquences comportementales induites par des injections répétées de drogue chez la souris par l'utilisation du modèle animal de sensibilisation comportementale. Nous avons mis en évidence le rôle curatif de l'EE sur la rechute à la cocaïne et sur le comportement de recherche de drogue en général par l'utilisation du modèle animal de préférence conditionnée (PPC). Nous avons ensuite confirmé ensuite le rôle curatif de l'EE chez le rat par l'utilisation du modèle animal de référence pour étudier l'addiction, qui est l'auto-administration de drogue (AA). Ainsi nous avons mis en évidence que l'EE est capable de réduire significativement la rechute induite par les stimuli environnementaux associés à la drogue, la rechute induite par le stress ainsi que de manière plus générale le comportement de recherche de cocaïne après une période de sevrage. Par l'utilisation de la technique d'immunohistochimie de c-Fos, utilisée comme marqueur d'activation neuronale, nous avons amorcé l'étude de la compréhension des mécanismes neurobiologiques qui sous-tendraient les effets bénéfiques de l'EE et nous avons mis en évidence que le rôle curatif de l'EE est parallèle à une inhibition de l'activation des régions cérébrales impliquées dans la rechute. Nous avons mis en avant l'hypothèse selon laquelle les effets anti-stress de l'EE représenteraitent un mécanisme clef dans l'établissement de ses propriétés curatives. Selon cette hypothèse, l'EE réduirait l'état émotionnel négatif des individus et les rendrait moins sensibles aux stimuli environnementaux associés à la drogue et réduirait de manière significative la rechute. Mes travaux de thèse ont donc permis de mettre en évidence le rôle curatif de l'EE, en plus de son rôle préventif déjà décrit, en démontrant qu'il diminue le risque de rechute après une période de sevrage. De plus, mes travaux représentent le premier pas vers la compréhension des mécanismes neurobiologiques impliqués dans les effets de l'EE sur la rechute. Ainsi ces travaux ouvrent la voie vers de nouvelles stratégies thérapeutiques, comportementales et pharmacologiques pour le traitement de l'addiction, centrées sur la prévention à long terme des risques de rechute.Addiction is a chronic psychiatric disorder caracterised by compulsive and repetitive behaviours, which can have negative influences on health. One of the main characteristic of addiction is relapse even after a long period of withdrawal. Studying factors that can have positive effects on withdrawal and consequently can reduce relapse is of an urgent necessity in order to better understand the phenomenon of addiction but also to develop therapeutic strategies based on long term prevention. In this view, the main goal of my thesis was the study of the influence of environmental enrichment (EE) on relapse to cocaine seeking. EE consists to provide to laboratory animals stimulations of sensory, cognitive and motor functions. With this in mind, EE is considered as a positive animal model to study consequences of positive way of live on brain disorders. By the use of different animal models of addiction, we have shown that EE has curative properties, once related-addiction behaviours are developed. We have demonstrated that EE is able to eliminate behavioural consequences induced by repeated drug injections in mice in an animal model of behavioural sensitization. Moreover, we have shown that EE is also curative in an animal model of conditioned place preference (CPP), as we have demonstrated that EE eliminate the reinstatement of cocaine seeking after exctinction and cocaine seeking behaviour. We have confirmed the curative effects of EE in rats by the use of the animal model of reference to study addiction, self-administration paradigm. With this animal model, we have demonstrated that EE is able to significantly reduced cues- and stress-induced relapse to cocaine seeking and more generally is able to reduce cocaine seeking behaviour after a withdrawal period. By the use of immunohistochemistry technique of c-Fos, a marquor of neuronal activation, we have initiated the understanding of the neurobiological mechanisms underlying the beneficial effects of EE and we have shown that the curative effect of EE is paralleled to an inhibition of activation of brain areas involved in relapse. We hypothesised that the anti-stress effects of EE would represent a pivotal mechanism concerning the curative properties of EE. In this view, EE would reduce the negative emotional state of people rendering them less vulnerable to environmental stimuli associated with drugs et would significantly reduce relapse. In addition to the preventive effect of EE previously described, these works of thesis have higtlighed the curative effect of EE, by demonstrating that EE reduces the risk of relapse after a period of withdrawal. Moreover, my works represent the first step in the understanding of the neurobiological mechanisms involved in the beneficial effect of EE on relapse. In conclusion, these works open the way to new therapeutic, behavioural and pharmacologic therapeutics focused on the long term prevention of risk of relapse.POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Exposure to sucrose during periods of withdrawal does not reduce cocaine-seeking behavior in rats

International audienceConcomitant 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