L’influence de la vitesse d’administration de la cocaïne sur la consommation et motivation pour celle-ci, et l’influence d’un traitement antipsychotique sur la récompense conditionnée

Beaucoup de personnes consomment des drogues d’abus de façon récréative ou expérimentale dans leur vie, mais peu d’entre elles développent une toxicomanie. Nous avons exploré, chez le rat, deux facteurs impliqués dans la transition vers la toxicomanie, soit la vitesse à laquelle la drogue parvient au cerveau et le fait d’être sous traitement antipsychotique. Dans une première étude, notre objectif était de déterminer si augmenter la vitesse de livraison de la cocaïne (0.5 mg/kg) par auto-administration intraveineuse (i.v.; livrée en 5 secondes dans un groupe versus 90 secondes dans l’autre) mènerait à une plus grande consommation de celle-ci lors d’un accès prolongé (6 h/j versus 1 h/j), et à une plus grande motivation à obtenir la drogue telle que mesurée sous un ratio de renforcement progressif à une vitesse différente (10 secondes). Nous avons trouvé que le groupe 5 s consommait plus de cocaïne que le groupe 90 s en accès prolongé, mais aussi en accès limité. Cependant, la motivation des deux groupes était la même à la vitesse de 10 s, ainsi qu’à leurs vitesses initiales. Nous pensons que ceci peut être dû à une forme de plasticité du système méso-cortico-limbique survenue suite à l’auto-administration en accès prolongé en conjonction avec l’augmentation de consommation, chez les deux groupes, rendant impossible une distinction de leur motivation. Dans une deuxième série d’études nous avons émis l’hypothèse que l’antipsychotique typique, halopéridol (HAL, 0.5 mg/kg/j), et non l’atypique, aripiprazole (ARI, 1 mg/kg/j), un modulateur dopaminergique, induirait une augmentation de la poursuite de récompense conditionnée (RC) et de la locomotion (LOCO) en réponse à l’amphétamine (AMPH). Cependant, nous avons trouvé une augmentation chez le groupe HAL, mais non ARI, de la réponse RC, trois semaines, mais non une semaine post traitement, ainsi qu’une augmentation de la LOCO, chez le groupe HAL, mais non ARI, une semaine mais non trois semaines post traitement. L’incohérence des résultats entre les deux tests (RC et LOCO) rend leur interprétation difficile. Ces études restent à être explorées d’avantage afin de pouvoir en tirer des conclusions plus éclairées quant à l’impact de la vitesse d’administration de la cocaïne et du traitement antipsychotique sur le développement d’une toxicomanie.

Atypical neural self-representation in autism

The 'self' is a complex multidimensional construct deeply embedded and in many ways defined by our relations with the social world. Individuals with autism are impaired in both self-referential and other-referential social cognitive processing. Atypical neural representation of the self may be a key to understanding the nature of such impairments. Using functional magnetic resonance imaging we scanned adult males with an autism spectrum condition and age and IQ-matched neurotypical males while they made reflective mentalizing or physical judgements about themselves or the British Queen. Neurotypical individuals preferentially recruit the middle cingulate cortex and ventromedial prefrontal cortex in response to self compared with other-referential processing. In autism, ventromedial prefrontal cortex responded equally to self and other, while middle cingulate cortex responded more to other-mentalizing than self-mentalizing. These atypical responses occur only in areas where self-information is preferentially processed and does not affect areas that preferentially respond to other-referential information. In autism, atypical neural self-representation was also apparent via reduced functional connectivity between ventromedial prefrontal cortex and areas associated with lower level embodied representations, such as ventral premotor and somatosensory cortex. Furthermore, the magnitude of neural self-other distinction in ventromedial prefrontal cortex was strongly related to the magnitude of early childhood social impairments in autism. Individuals whose ventromedial prefrontal cortex made the largest distinction between mentalizing about self and other were least socially impaired in early childhood, while those whose ventromedial prefrontal cortex made little to no distinction between mentalizing about self and other were the most socially impaired in early childhood. These observations reveal that the atypical organization of neural circuitry preferentially coding for self-information is a key mechanism at the heart of both self-referential and social impairments in autism.

Inverse agonism of the antipsychotic drugs at the D-2 dopamine receptor

The antipsychotic drugs had been assumed to act as antagonists at D-2 dopamine receptors but recently these drugs have been shown to possess inverse agonist properties at this receptor. Inverse agonism may be demonstrated from the ability of these drugs to potentiate forskolin-stimulated cAMP accumulation or to suppress agonist-independent [S-35]GTPgammaS binding. The antipsychotic drugs tested generally appear as full inverse agonists in these assays regardless of chemical or therapeutic class. The mechanism of inverse agonism of the antipsychotic drugs is still unclear but may involve stabilisation of the ground state of the D-2 receptor. (C) 2003 Elsevier Science B.V All rights reserved.

Antipsychotic drug action: antagonism, inverse agonism or partial agonism

The positive, psychotic symptoms of schizophrenia can be treated by antipsychotic drugs and it has been assumed that these are antagonists at the D-2 and D-3 dopamine receptors in the brain. Recently, the D-2/D-3 partial agonist aripiprazole has been introduced as an antipsychotic drug. It has also been realized that, using in vitro assays, the other antipsychotic drugs are in fact inverse agonists at D-2/D-3 dopamine receptors. This raises questions about how these disparate drugs can achieve a similar clinical outcome. In this review, I shall consider the efficacies of these drugs in signalling assays and how these efficacies might affect treatment outcomes. It seems that the treatment outcome might depend on the overall level of cell stimulation, which is in turn dependent on the level of residual dopamine and the efficacy of the drug in signalling assays.

A novel experimental method for measuring vergence and accommodation responses to the main near visual cues in typical and atypical groups

Binocular disparity, blur, and proximal cues drive convergence and accommodation. Disparity is considered to be the main vergence cue and blur the main accommodation cue. We have developed a remote haploscopic photorefractor to measure simultaneous vergence and accommodation objectively in a wide range of participants of all ages while fixating targets at between 0.3 and 2 m. By separating the three main near cues, we can explore their relative weighting in three-, two-, one-, and zero-cue conditions. Disparity can be manipulated by remote occlusion; blur cues manipulated by using either a Gabor patch or a detailed picture target; looming cues by either scaling or not scaling target size with distance. In normal orthophoric, emmetropic, symptom-free, naive visually mature participants, disparity was by far the most significant cue to both vergence and accommodation. Accommodation responses dropped dramatically if disparity was not available. Blur only had a clinically significant effect when disparity was absent. Proximity had very little effect. There was considerable interparticipant variation. We predict that relative weighting of near cue use is likely to vary between clinical groups and present some individual cases as examples. We are using this naturalistic tool to research strabismus, vergence and accommodation development, and emmetropization.

Exploring block construction and mental imagery: evidence of atypical orientation discrimination in Williams syndrome

The visuospatial perceptual abilities of individuals with Williams syndrome (WS) were investigated in two experiments. Experiment I measured the ability of participants to discriminate between oblique and between nonoblique orientations. Individuals with WS showed a smaller effect of obliqueness in response time, when compared to controls matched for nonverbal mental age. Experiment 2 investigated the possibility that this deviant pattern of orientation discrimination accounts for the poor ability to perform mental rotation in WS (Farran, Jarrold, & Gathercole, 2001). A size transformation task was employed, which shares the image transformation requirements of mental rotation, but not the orientation discrimination demands. Individuals with WS performed at the same level as controls. The results suggest a deviance at the perceptual level in WS, in processing orientation, which fractionates from the ability to mentally transform images.

Perceptual grouping and distance estimates in typical and atypical development: comparing performance across perception, drawing and construction tasks

Perceptual grouping is a pre-attentive process which serves to group local elements into global wholes, based on shared properties. One effect of perceptual grouping is to distort the ability to estimate the distance between two elements. In this study, biases in distance estimates, caused by four types of perceptual grouping, were measured across three tasks, a perception, a drawing and a construction task in both typical development (TD: Experiment 1) and in individuals with Williams syndrome (WS: Experiment 2). In Experiment 1, perceptual grouping distorted distance estimates across all three tasks. Interestingly, the effect of grouping by luminance was in the opposite direction to the effects of the remaining grouping types. We relate this to differences in the ability to inhibit perceptual grouping effects on distance estimates. Additive distorting influences were also observed in the drawing and the construction task, which are explained in terms of the points of reference employed in each task. Experiment 2 demonstrated that the above distortion effects are also observed in WS. Given the known deficit in the ability to use perceptual grouping in WS, this suggests a dissociation between the pre-attentive influence of and the attentive deployment of perceptual grouping in WS. The typical distortion in relation to drawing and construction points towards the presence of some typical location coding strategies in WS. The performance of the WS group differed from the TD participants on two counts. First, the pattern of overall distance estimates (averaged across interior and exterior distances) across the four perceptual grouping types, differed between groups. Second, the distorting influence of perceptual grouping was strongest for grouping by shape similarity in WS, which contrasts to a strength in grouping by proximity observed in the TD participants. (c) 2008 Elsevier Inc. All rights reserved.

Formation of atypical podosomes in extravillous trophoblasts regulates extracellular matrix degradation

Throughout pregnancy the cytotrophoblast, the stem cell of the placenta, gives rise to the differentiated forms of trophoblasts. The two main cell lineages are the syncytiotrophoblast and the invading extravillous trophoblast. A successful pregnancy requires extravillous trophoblasts to migrate and invade through the decidua and then remodel the maternal spiral arteries. Many invasive cells use specialised cellular structures called invadopodia or podosomes in order to degrade extracellular matrix. Despite being highly invasive cells, the presence of invadapodia or podosomes has not previously been investigated in trophoblasts. In this study these structures have been identified and characterised in extravillous trophoblasts. The role of specialised invasive structures in trophoblasts in the degradation of the extracellular matrix was compared with well characterised podosomes and invadopodia in other invasive cells and the trophoblast specific structures were characterised by using a sensitive matrix degradation assay which enabled visualisation of the structures and their dynamics. We show trophoblasts form actin rich protrusive structures which have the ability to degrade the extracellular matrix during invasion. The degradation ability and dynamics of the structures closely resemble podosomes, but have unique characteristics that have not previously been described in other cell types. The composition of these structures does not conform to the classic podosome structure, with no distinct ring of plaque proteins such as paxillin or vinculin. In addition, trophoblast podosomes protrude more deeply into the extracellular matrix than established podosomes, resembling invadopodia in this regard. We also show several significant pathways such as Src kinase, MAPK kinase and PKC along with MMP-2 and 9 as key regulators of extracellular matrix degradation activity in trophoblasts, while podosome activity was regulated by the rigidity of the extracellular matrix.

Atypical processing of voice sounds in infants at risk for Autism Spectrum Disorder

Adults diagnosed with autism spectrum disorder (ASD) show a reduced sensitivity (degree of selective response) to social stimuli such as human voices. In order to determine whether this reduced sensitivity is a consequence of years of poor social interaction and communication or is present prior to significant experience, we used functional MRI to examine cortical sensitivity to auditory stimuli in infants at high familial risk for later emerging ASD (HR group, N = 15), and compared this to infants with no family history of ASD (LR group, N = 18). The infants (aged between 4 and 7 months) were presented with voice and environmental sounds while asleep in the scanner and their behaviour was also examined in the context of observed parent-infant interaction. Whereas LR infants showed early specialisation for human voice processing in right temporal and medial frontal regions, the HR infants did not. Similarly, LR infants showed stronger sensitivity than HR infants to sad vocalisations in the right fusiform gyrus and left hippocampus. Also, in the HR group only, there was an association between each infant's degree of engagement during social interaction and the degree of voice sensitivity in key cortical regions. These results suggest that at least some infants at high-risk for ASD have atypical neural responses to human voice with and without emotional valence. Further exploration of the relationship between behaviour during social interaction and voice processing may help better understand the mechanisms that lead to different outcomes in at risk populations.

Clonal Relationship among Atypical Enteropathogenic Escherichia coli Strains Isolated from Different Animal Species and Humans

Forty-nine typical and atypical enteropathogenic Escherichia coli (EPEC) strains belonging to different serotypes and isolated from humans, pets (cats and dogs), farm animals (bovines, sheep, and rabbits), and wild animals (monkeys) were investigated for virulence markers and clonal similarity by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The virulence markers analyzed revealed that atypical EPEC strains isolated from animals have the potential to cause diarrhea in humans. A close clonal relationship between human and animal isolates was found by MLST and PFGE. These results indicate that these animals act as atypical EPEC reservoirs and may represent sources of infection for humans. Since humans also act as a reservoir of atypical EPEC strains, the cycle of mutual infection of atypical EPEC between animals and humans, mainly pets and their owners, cannot be ruled out since the transmission dynamics between the reservoirs are not yet clearly understood.