Impulsive and compulsive behaviors can be induced by opposite GABAergic dysfunctions inside the primate ventral pallidum

Introduction: The ventral pallidum (VP) is central in the limbic Basal Ganglia circuit, controlling both appetitive (approach) and aversive (avoidance) motivated behaviors. Nevertheless, VP involvement in pathological aspects remains unclear, especially in the behavioral expression of different motivational dysfunctions. This study aimed to investigate how the VP contributes to the expression of abnormal behaviors via opposite GABAergic dysfunctions.Methods: Opposite GABAergic dysfunctions were induced by injecting muscimol (a GABAA agonist) and bicuculline (a GABAA antagonist) into monkeys. We determined the effects of both substances on self-initiated behaviors in lab-chair and in free-moving home-cage contexts in six monkeys, and in two animals performing an approach-avoidance task in appetitive and aversive contexts.Results: While the self-initiated behaviors induced by bicuculline injections in VP were characterized by compulsive behaviors such as repetitive grooming and self-biting, muscimol injections induced impulsive behaviors including limb movements in a lab-chair context and exploration behaviors in a free-moving context. More specific behavioral effects were observed in the approach-avoidance task. The muscimol injections induced premature responses and erroneous screen touches, which characterize impulsive and attention disorders, while the bicuculline injections into the VP increased passive avoidance (non-initiated action) and task-escape in an aversive context, suggesting an anxiety disorder.Conclusions: These results show that activating or blocking GABAergic transmission in the VP impairs motivated behaviors. Furthermore, the behavioral expressions produced by these opposite disturbances show that the VP could be involved in anxiety-driven compulsive disorders, such as OCD, as well as in impulsive disorders motivated by attention deficits or reward-seeking, as seen in ADHD or impulse control disorders

Étude des effets de l'administration chronique de substances psychoactives durant la gestation sur la maturation des systèmes monoaminergiques centraux chez le rat

Le but de ce travail a été d'étudier, chez le rat, la maturation des systèmes dopaminergiques et sérotoninergiques en conditions physiologiques, puis suite à une exposition prénatale au 3,4-méthylènedioxyméthamphétamine (MDMA ou ecstasy) et au méthylphénidate (MPH ou ritaline). Des paramètres neurochimiques et comportementaux ont été étudiés de la vie embryonnaire à l'âge adulte. Nous avons montré qu'une exposition prénatale au MDMA ou au MPH avait des conséquences transitoires et à long-terme sur le plan neurochimique et comportemental. Ces altérations concernent le fonctionnement des systèmes dopaminergiques et sérotoninergiques et semblent impliquer plus particulièrement les systèmes de récompense. Ces modèles animaux permettent de mieux comprendre les mécanismes d'action du MDMA et du MPH sur le cerveau en développement et peuvent constituer un outil de choix pour l'étude des mécanismes physiopathologiques impliqués dans les maladies neurodéveloppementales.In this work, we explored dopaminergic and serotonergic systems maturation under physiological conditions and after a prenatal exposure to 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) and methylphenidate (MPH or ritaline) in a rat model. Neurochemical and behavioral parameters were studied from embryonic life to adult ages. We demonstrated that a prenatal exposure to MDMA or MPH induce transient and long-term alterations of dopaminergic and serotonergic systems including neurochemichal and behavioral perturbations related to rewarding systems. These results raise the possibility that prenatal MDMA or MPH exposure in rat could be an interesting model to study developmental disturbances underlying neurodevelopmental disorders.TOURS-BU Sciences Pharmacie (372612104) / SudocSudocFranceF

Image_1_Impulsive and compulsive behaviors can be induced by opposite GABAergic dysfunctions inside the primate ventral pallidum.tif

Introduction: The ventral pallidum (VP) is central in the limbic Basal Ganglia circuit, controlling both appetitive (approach) and aversive (avoidance) motivated behaviors. Nevertheless, VP involvement in pathological aspects remains unclear, especially in the behavioral expression of different motivational dysfunctions. This study aimed to investigate how the VP contributes to the expression of abnormal behaviors via opposite GABAergic dysfunctions.Methods: Opposite GABAergic dysfunctions were induced by injecting muscimol (a GABAA agonist) and bicuculline (a GABAA antagonist) into monkeys. We determined the effects of both substances on self-initiated behaviors in lab-chair and in free-moving home-cage contexts in six monkeys, and in two animals performing an approach-avoidance task in appetitive and aversive contexts.Results: While the self-initiated behaviors induced by bicuculline injections in VP were characterized by compulsive behaviors such as repetitive grooming and self-biting, muscimol injections induced impulsive behaviors including limb movements in a lab-chair context and exploration behaviors in a free-moving context. More specific behavioral effects were observed in the approach-avoidance task. The muscimol injections induced premature responses and erroneous screen touches, which characterize impulsive and attention disorders, while the bicuculline injections into the VP increased passive avoidance (non-initiated action) and task-escape in an aversive context, suggesting an anxiety disorder.Conclusions: These results show that activating or blocking GABAergic transmission in the VP impairs motivated behaviors. Furthermore, the behavioral expressions produced by these opposite disturbances show that the VP could be involved in anxiety-driven compulsive disorders, such as OCD, as well as in impulsive disorders motivated by attention deficits or reward-seeking, as seen in ADHD or impulse control disorders.</p

Image_2_Impulsive and compulsive behaviors can be induced by opposite GABAergic dysfunctions inside the primate ventral pallidum.tif

Introduction: The ventral pallidum (VP) is central in the limbic Basal Ganglia circuit, controlling both appetitive (approach) and aversive (avoidance) motivated behaviors. Nevertheless, VP involvement in pathological aspects remains unclear, especially in the behavioral expression of different motivational dysfunctions. This study aimed to investigate how the VP contributes to the expression of abnormal behaviors via opposite GABAergic dysfunctions.Methods: Opposite GABAergic dysfunctions were induced by injecting muscimol (a GABAA agonist) and bicuculline (a GABAA antagonist) into monkeys. We determined the effects of both substances on self-initiated behaviors in lab-chair and in free-moving home-cage contexts in six monkeys, and in two animals performing an approach-avoidance task in appetitive and aversive contexts.Results: While the self-initiated behaviors induced by bicuculline injections in VP were characterized by compulsive behaviors such as repetitive grooming and self-biting, muscimol injections induced impulsive behaviors including limb movements in a lab-chair context and exploration behaviors in a free-moving context. More specific behavioral effects were observed in the approach-avoidance task. The muscimol injections induced premature responses and erroneous screen touches, which characterize impulsive and attention disorders, while the bicuculline injections into the VP increased passive avoidance (non-initiated action) and task-escape in an aversive context, suggesting an anxiety disorder.Conclusions: These results show that activating or blocking GABAergic transmission in the VP impairs motivated behaviors. Furthermore, the behavioral expressions produced by these opposite disturbances show that the VP could be involved in anxiety-driven compulsive disorders, such as OCD, as well as in impulsive disorders motivated by attention deficits or reward-seeking, as seen in ADHD or impulse control disorders.</p

Serotoninergic neurotransmission is affected by n-3 polyunsaturated fatty acids in the rat

International audienceWe explored the effects of chronic alpha-linolenic acid dietary deficiency on serotoninergic neurotransmission. In vivo synaptic serotonin (5-HT) levels were studied in basal and pharmacologically stimulated conditions using intracerebral microdialysis in the hippocampus of awake 2-month-old rats. We also studied the effects of reversion of the deficient diet on fatty acid composition and serotoninergic neurotransmission. A balanced (control) diet was supplied to deficient rats at different stages of development, i.e. from birth, 7, 14 or 21 days of age. We demonstrated that chronic n-3 polyunsaturated fatty acid dietary deficiency induced changes in the synaptic levels of 5-HT both in basal conditions and after pharmacological stimulation with fenfluramine. Higher levels of basal 5-HT release and lower levels of 5-HT-stimulated release were found in deficient than in control rats. These neurochemical modifications were reversed by supply of the balanced diet provided at birth or during the first 2 weeks of life through the maternal milk, whereas they persisted if the balanced diet was given from weaning (at 3 weeks of age). This suggests that provision of essential fatty acids is durably able to affect brain function and that this is related to the developmental stage during which the deficiency occurs

Longitudinal changes in brain metabolic activity after withdrawal from escalation of cocaine self-administration: Brain metabolic activity during abstinence from cocaine

International audienceThe 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-(18F)fluoro-d-glucose (18FDG) 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

Validation of a global quantitative analysis methodology of tryptophan metabolites in mice using LC-MS

International audienceIn this study, we validated a method for quantifying 20 tryptophan (Trp) catabolites by liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) in 4 different matrices (urine, serum, intestinal contents and liver). The detection limit for all metabolites ranged between 0.015 and 11.25 nmol/L and the dynamic range of the calibration curves were adjusted to allow quantification of metabolites at endogenous levels. Matrix effects were evaluated using isotope labeled internal standards. Reproducibility in the 4 matrices was characterized by CV = 6.2% with an accuracy of 6.6%. Our method has been applied to the determination and quantification of 20 metabolites concentrations in 5 different mouse compartments (plus cecal contents). Our results show that our approach allows for a global exploration of the Trp metabolism by quantifying a large number of Trp metabolites, at the individual level by multi-matrix approach

Optimized spectral clustering for segmentation of dynamic PET images

he quantification of dynamic PET images requires the definition of regions of interest. The manual delineation is a time consuming and unreproducible process due to the poor resolution of PET images. Approaches were proposed in the literature to classify the kinetic profiles of voxels, however, they are generally either sensitive to initial conditions or favor convex shaped clusters. Recently we have proposed a kinetic spectral clustering (KSC) method for segmentation of dynamic PET images that has the advantage of handling clusters with arbitrary shape in the space in which they are identified. However, its use for clinical applications is still hindered by the manual setting of several parameters. In this paper, we propose an extension of KSC to make it automatic (ASC). A new unsupervised clustering criterion is tailored and a global optimization by a probabilistic metaheuristic algorithm is used to select the scale parameter and the weighting factors involved in the method. We validate our approach with GATE Monte Carlo simulations. Results obtained with ASC compare closely with those obtained with optimal manual parameterization of KSC, and outperform those obtained with two other approaches from the literature

Maternal Rat Metabolomics: Amniotic Fluid and Placental Metabolic Profiling Workflows

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