The Impact of Catechol-O-Methyltransferase and Dopamine D4 Receptor Genotypes on Neurophysiological Markers of Performance Monitoring

Dynamic adaptations of one"s behavior by means of performance monitoring are a central function of the human executive system, that underlies considerable interindividual variation. Converging evidence from electrophysiological and neuroimaging studies in both animals and humans hints atthe importance ofthe dopaminergic system forthe regulation of performance monitoring. Here, we studied the impact of two polymorphisms affecting dopaminergic functioning in the prefrontal cortex [catechol-O-methyltransferase (COMT) Val108/158Met and dopamine D4 receptor (DRD4) single-nucleotide polymorphism (SNP)-521] on neurophysiological correlates of performance monitoring. We applied a modified version of a standard flanker task with an embedded stop-signal task to tap into the different functions involved, particularly error monitoring, conflict detection and inhibitory processes. Participants homozygous for the DRD4 T allele produced an increased error-related negativity after both choice errors and failed inhibitions compared with C-homozygotes. This was associated with pronounced compensatory behavior reflected in higher post-error slowing. No group differences were seen in the incompatibility N2, suggesting distinct effects of the DRD4 polymorphism on error monitoring processes. Additionally, participants homozygous for the COMTVal allele, with a thereby diminished prefrontal dopaminergic level, revealed increased prefrontal processing related to inhibitory functions, reflected in the enhanced stop-signal-related components N2 and P3a. The results extend previous findings from mainly behavioral and neuroimaging data on the relationship between dopaminergic genes and executive functions and present possible underlying mechanisms for the previously suggested association between these dopaminergic polymorphisms and psychiatric disorders as schizophrenia or attention deficit hyperactivity disorder.

Catechol-O-methyltransferase, dopamine, and sleep-wake regulation.

NlmCategory="UNASSIGNED">Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and environment. The catechol-O-methyltransferase (COMT) gene is an interesting candidate, being one of the major mammalian enzymes involved in the catabolism of catecholamines. The activity of COMT enzyme is genetically polymorphic due to a guanine-to-adenine transition at codon 158, resulting in a valine (Val) to methionine (Met) substitution. Individuals homozygous for the Val allele show higher COMT activity, and lower dopaminergic signaling in prefrontal cortex (PFC) than subjects homozygous for the Met allele. Since COMT has a crucial role in metabolising dopamine, it was suggested that the common functional polymorphism in the COMT gene impacts on cognitive function related to PFC, sleep-wake regulation, and potentially on sleep pathologies. The COMT Val158Met polymorphism may predict inter-individual differences in brain electroencephalography (EEG) alpha oscillations and recovery processes resulting from partial sleep loss in healthy individuals. The Val158Met polymorphism also exerts a sexual dimorphism and has a strong effect on objective daytime sleepiness in patients with narcolepsy-cataplexy. Since the COMT enzyme inactivates catecholamines, it was hypothesized that the response to stimulant drugs differs between COMT genotypes. Modafinil maintained executive functioning performance and vigilant attention throughout sleep deprivation in subjects with Val/Val genotype, but less in those with Met/Met genotype. Also, homozygous Met/Met patients with narcolepsy responded to lower doses of modafinil compared to Val/Val carriers. We review here the critical role of the common functional COMT gene polymorphism, COMT enzyme activity, and the prefrontal dopamine levels in the regulation of sleep and wakefulness in normal subjects, in narcolepsy and other sleep-related disorders, and its impact on the response to psychostimulants.

GREUB, Yan. 'Les mots régionaux dans les farces françaises. Étude lexicologique sur le Recueil Tissier (1450-1550). Strasbourg: Société de Linguistique Romane, 2003.

El volum que presentem és el segon de la col.lecció «Bibliothèque de Linguistique Romane» (BiLiRo), que va iniciar la seva singladura el 2002 amb el Trésor étymologique des mots de la Franche-Comté de Colette Dondaine. La col.lecció es publica sota el patrocini de la Société de Linguistique Romane i és dirigida per l"infatigable Gilles Roques.

The influence of genetic and environmental factors among MDMA users in cognitive performance

This study is aimed to clarify the association between MDMA cumulative use and cognitive dysfunction, and the potential role of candidate genetic polymorphisms in explaining individual differences in the cognitive effects of MDMA. Gene polymorphisms related to reduced serotonin function, poor competency of executive control and memory consolidation systems, and high enzymatic activity linked to bioactivation of MDMA to neurotoxic metabolites may contribute to explain variations in the cognitive impact of MDMA across regular users of this drug. Sixty ecstasy polydrug users, 110 cannabis users and 93 non-drug users were assessed using cognitive measures of Verbal Memory (California Verbal Learning Test, CVLT), Visual Memory (Rey-Osterrieth Complex Figure Test, ROCFT), Semantic Fluency, and Perceptual Attention (Symbol Digit Modalities Test, SDMT). Participants were also genotyped for polymorphisms within the 5HTT, 5HTR2A, COMT, CYP2D6, BDNF, and GRIN2B genes using polymerase chain reaction and TaqMan polymerase assays. Lifetime cumulative MDMA use was significantly associated with poorer performance on visuospatial memory and perceptual attention. Heavy MDMA users (>100 tablets lifetime use) interacted with candidate gene polymorphisms in explaining individual differences in cognitive performance between MDMA users and controls. MDMA users carrying COMT val/val and SERT s/s had poorer performance than paired controls on visuospatial attention and memory, and MDMA users with CYP2D6 ultra-rapid metabolizers performed worse than controls on semantic fluency. Both MDMA lifetime use and gene-related individual differences influence cognitive dysfunction in ecstasy users.

Genetic Factors in the Regulation of Striatal and Extrastriatal Dopamine D2 Receptor Expression

Positron emission tomography (PET) studies on healthy individuals have revealed a marked interindividual variability in striatal dopamine D2 receptor density that can be partly accounted for by genetic factors. The examination of the extrastriatal lowdensity D2 receptor populations has been impeded by the lack of suitable tracers. However, the quantification of these D2 receptor populations is now feasible with recently developed PET radioligands. The objective of this thesis was to study brain neurobiological correlates of common functional genetic variants residing in candidate genes relevant for D2 receptor functioning. For this purpose, healthy subjects were studied with PET imaging using [₁₁C]raclopride and [₁₁C]FLB457 as radioligands. The candidate genes examined in this work were the human D2 receptor gene (DRD2) and the catechol-Omethyltransferase gene (COMT). The region-specific genotypic influences were explored by comparing D2 receptor binding properties in the striatum, the cortex and the thalamus. As an additional study objective, the relationship between cortical D2 receptor density and a cognitive phenotype i.e. verbal memory and learning was assessed. The main finding of this study was that DRD2 C957T genotype altered markedly D2 receptor density in the cortex and the thalamus whereas in the striatum the C957T genotype affected D2 receptor affinity, but not density. Furthermore, the A1 allele of the DRD2-related TaqIA polymorphism showed increased cortical and thalamic D2 receptor density, but had the opposite effect on striatal D2 receptor density. The DRD2 –141C Ins/Del or the COMT Val158Met genotypes did not change D2 receptor binding properties. Finally, unlike previously reported, cortical D2 receptor density did not show any significant correlation with verbal memory function. The results of this study suggest that the C957T and the TaqIA genotypes have region-specific neurobiological correlates in brain dopamine D2 receptor availability in vivo. The biological mechanisms underlying these findings are unclear, but they may be related to the region-specific regulation of dopamine neurotranssion, gene/receptor expression and epigenesis. These findings contribute to the understanding of the genetic regulation of dopamine and D2 receptor-related brain functions in vivo in man. In addition, the results provide potentially useful endophenotypes for genetic research on psychiatric and neurological disorders.

Itinéraire et observations militaires sur la communication de Pontarlier à Blamont

Ancien possesseur : Argenson, Antoine-René de Voyer (1722-1787 ; marquis de Paulmy d')

ALBUM AMICORUM de Jean Durand (1583-1592). In-8 de 2 f. lim. et 380 p., mar. r., comp. de mos. de mar. v., riche dorure à petits fers, tr. dor. et ciselée. (Rel. du XVIe siècle.)

Durand (Jean). Album amicorum (1583-1592)

Recueil de pièces, manuscrites et imprimées, mémoires, actes royaux, comptes, suppliques, etc., concernant le Béarn, la Navarre, le pays de Soule, le Dauphiné, la Bresse, la Bourgogne, la Lorraine, le Ponthieu, la Normandie et le Berry.

Contient : Pièces relatives au Béarn, et principalement à la réunion du Béarn à la Couronne de France (f. 1), — et au pays de Soule (f. 45). — Navarre, etc. : Supplique orig. des députés des Trois États de la Basse-Navarre (f. 77) ; Pièces diverses, comptes, etc., concernant le domaine de Navarre, notamment : « Estat des sommes que le Roy veult et entend estre doresnavant paiées aux gens de son Conseil d'Estat et privé de ses maison et finances de Navarre et ancien domaine...», 1607 ; « Advis de ce qui se peult faire pour la réduction des officiers de la maison de Navarre et Béarn... » ; Baux du domaine de Navarre ; Pièces relatives aux revenus ecclésiastiques du Béarn ; « Estat de la recepte et despence du domaine de la maison de Navarre, pour l'année 1619 » ; « Mémoire du nomé Du BOURG, touchant les forests de l'antien domaine de Navarre, au resort de Thoulouze » ; Copies d'actes de Henri IV ; Mémoire orig., signé Hurault « de Maisse », concernant une adjudication de l'ancien domaine de Navarre ; Pièces relatives à Bayonne (f. 218), — à Tartas (f. 222), — à Saint-Béat (f. 224), — à Blaye (f. 226). — Dauphiné : « Extrait d'un Registre aux archifs de la Chambre des Comptes et Cour des Finances du Dauphiné, institué [intitulé] Homagia Chalançonis , 1489 et 1490 » (f. 250) ; Pièces relatives à la Bresse (f. 260). — Bourgogne : « Du duché de Bourgogne, et de ceux qui l'ont tenue et possédée... » (f. 282). — Lorraine : « Mémoire au Roy..., des choses qui ce sont passées au gouvernement et ville de Toul » [contre le sieur de Vannes], orig. signé « Vuiry » (f. 294) ; « Remonstrances qu'il fault faire au Roy, pour conserver la ville de Toul en son obéissance... » ; Copie d'un acte de Charles-Quint, 1521 ; Pièces relatives à l'évêché de Metz (f. 316), — notamment, actes orig. de Georges de Bade, évêque de Metz, 1473 (f. 318 et 351) ; « Articles proposez au nom du Roy par Mr [Louis] d'Auzance à Mr le cardinal de Lorraine, pour le suject de la ville et ecclésiastiques de Metz, avec les responses dudict cardinal..., 1565 » ; « Mémoire pour la ville de Verdun, et comme elle est venue souz l'obéissance du Roy... » ; Pièce concernant Épinal, 1463 (f. 349). — Ponthieu : Extraits relatifs à l'abbaye de Sain t-Josse-aux-Bois (f. 352) ; Prisée du comté de Boulogne, 1477 (f. 356). — Normandie : Copie d'un arrêt du Parlement de Rouen, 1643 (f. 374). — Berry : Copie d'un acte de Charles VII pour Issoudun, 1423 (f. 440)