Catechol-O-methyltransferase (COMT) metabolizes catechols, notably dopamine. The COMT Val158Met polymorphism influences its enzyme activity, and multiple neural correlates of this genotype on dopaminergic phenotypes have been reported, particularly with regards to working memory. COMT activity can also be regulated pharmacologically by COMT inhibitors. The ‘inverted-U’ relationship between dopamine signalling and cognitive performance predicts that the effects of COMT inhibition will differ according to COMT genotype. The goal of this thesis was to better understand COMT’s impact on brain function and behaviour. Here, 33 subjects homozygous for COMT Val158 (‘Val homozygotes’) and 34 homozygous for COMT Met158 (‘Met homozygotes’) were randomly assigned, double-blind, to a single dose of the brain-penetrant COMT inhibitor tolcapone (200mg) or placebo. They completed the N-back task of working memory, an emotional face processing task, and a gambling task, in a magnetoencephalography (MEG) scanner, allowing both behavioural performance and neural activity to be investigated. The data presented in this thesis confirm that COMT activity influences performance on, and neural activity during, the N-back task, in a way consistent with the inverted-U model of dopamine function. The effect on risky decision making is novel, and indicates that COMT plays roles in domains beyond working memory, and that such domains may also follow an inverted-U. Neural activity during the faces task and the gambling task also show COMT-modulated differences. The behavioural results show that the direction of effect of a drug can be influenced by sequence variation in its target gene. They are of translational relevance, since COMT inhibitors are used in the adjunctive treatment of Parkinson’s disease and are under evaluation in schizophrenia and other disorders. The MEG data show that for the three tasks, there are effects of Val158Met genotype, of tolcapone, and their interaction, on neural activity (for example, the P300 during N-back), revealing a complex temporal and spatial pattern which sheds some light on the neural processing underlying these tasks and their previously reported fMRI correlates.

Gen-Umwelt-Interaktionen haben einen wichtigen Stellenwert für das Verständnis der Entstehung psychiatrischer Erkrankungen. Für die Catechol-O-Methyltransferase (COMT)konnte kürzlich gezeigt werden, dass diese die Gehirnaktivität moduliert, während der Verarberitung negativer Stimuli. Für positive Stimuli konnte kein Effekt nachgewiesen werden. In der vorliegenden Arbeit sollte nun geprüft werden, ob Lebensereignisse, als ein Umweltfaktor, für die emotionale Verarbeitung eine Rolle spielen. Um das herauszufinden untersuchten wir 81 gesunde Probanden mittels EEG während der Darbietung positiver und negativer emotionaler Bilder. Wie erwartet moduliert COMT die EPN (early posterior negativity) für negative Bilder, aber nicht für positive. Unter Berücksichtigung der Lebensereignisse konnte der fehlende Effekt der COMT bei der positiven Bedingung aufgelöst werden. Eine hohe Lebensereignis-Last führt dabei zu einer verminderten Gehirnaktivität für positive Stimuli, was sich aber nur für den Met/Met-Genotyp zeigt. Relevant scheint das vor allem für die Entwicklung von Depressionen zu sein, da depressive Patienten häufig ihre Umwelt als weniger positiv bewerten. / The interaction between genes and environment is highly relevant for our understanding of the development of psychiatric disorders. Recently it has been shown that the catechol-O-Methyltransferase genotype (COMT) modulates the brain activity during the processing of negative stimuli, but not for positive stimuli. Here we tested whether life stress, as an environmental factor, modulates this COMT genotype effect. Therefore, we measured the event-related brain potentials in 81 healthy subjects during the processing of positive and negative emotional pictures. As expected, we found that COMT modulates the neural correlates of emotional processing (the early posterior negativity, EPN), but only for negative and not for positive stimuli. Including the factor life stress we could explain this missing COMT effect for positive stimuli. We found that high life stress diminishes the positive evaluation of stimuli but only in subjects with the Met/Met genotype. This might be relevant for the development of depressions, as depressed patients often describe a lost of positive reinforcement.

Das Enzym Catechol-O- Methyltransferase (COMT) spielt eine wichtige Rolle beim Abbau der Neurotransmitter Dopamin, Noradrenalin und Adrenalin. In dessen Gen befindet sich ein Polymorphismus (SNP), der einen Aminosäureaustausch von Valin zu Methionin an Position 158 der membrangebundenden Isoform bewirkt.. In früheren Studien zeigen die verschiedenen Genotypen des Polymorphismus Unterschiede in der emotionalen Verarbeitung, bei der die COMT Einfluss auf die Verarbeitung von negativen, aber nicht von positiven Stimuli zeigt. Neben emotionalen werden durch die COMT aber auch kognitive präfrontale Prozesse beeinflusst. Eine Aufmerksamkeitslenkung auf Bilder führt im Zeitfenster der EPN und LPP zu ähnlichen Effekten wie beim Betrachten emotionaler Bilder In dieser Studie sollte daher untersucht werden, ob die COMT- Effekte auf die Emotionsverarbeitung durch Aufmerksamkeitsprozesse begründet sind und diese unabhängig vom emotionalen Inhalt durch die Aufmerksamkeitsinstruktion auslösbar sind. Dafür wurden bei 48 gesunden und entweder Val/Val oder Met/Met- Homozygoten Probanden während der Präsentation von IAPS Bildern mit positiven, negativen und neutralen Bildern ein EEG abgeleitet. Und es wurde die neuronale Aktivierung bei emotionalen Stimuli, in Interaktion mit der Instruktion, die Aufmerksamkeit auf eine bestimmte emotionale Kategorie zu richten, untersucht. Dabei zeigten sich die erwarteten Emotions- und Aufmerksamkeitseffekte auf EPN und LPP. Keinen Einfluss hatte der COMT-Genotyp. Dies könnte an der Interferenz der Emotionseffekte mit kognitiven Effekten des COMT- Polymorphismus liegen. / The catechol-O-methyltransferase (COMT) is important for the degradation of dopamine and norepinephrine in the prefrontal cortex. It exists a common single nucleotide polymorphism causing a Val to Met substitution at amino acid position 158 with the Met variant displaying lower enzymatic activity. The Val variant is associated with an impaired cognitive performance but seems to provide increased emotional resilience against negative mood states. In previous studies a positive association was found between the number of Met variants and the functional brain activity for unpleasant but not for pleasant stimuli. With regard to the tonic-phasic dopamine model it is hypothesized that this increased reactivity to negative stimuli derives from deficient disengagement from negative stimuli. Processing of emotional cues is associated with similar ERP effects as observes for explicitily directed attention. The aim of this work was therefore to investigate whether the COMT- effects on emotional processing is due to a different allocation of attentional resources. 48 homozygous participants (Met/Met or Val/Val) viewed positive, neutral or negative pictures of the IAPS while recording an EEG and where asked to either count a specific stimoulus category or to simply view the stimuli. The expected effects for emotional and attentional processing was found for the EPN and LPP. No influence was found for the COMT genotype. A possible reason is the strong interaction between emotional processing and cognitive tasks regarding the COMT polymorphism.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 183-205).

Vapor pressure data are vital to understanding impacts that substances, specifically pesticides, may exert on the environment. They enter into atmospheric deposition models for such chemicals which determine the fate and transport of these species in the environment. At normal application temperatures (i.e. room temperature) the vapor pressures of many of these chemicals are too low to be determined by conventional means. An isothermal Knudsen effusion technique was designed and developed in our laboratory for such measurements. The effusion mass as a function of time is measured in our technique using a thickness shear mode (TSM) acoustic wave sensor, which allows for extremely high (few nanograms) sensitivity. This sensitivity allows for much more rapid determination of low vapor pressures (10-1 to 10-5 Pa) than is possible by other Knudsen effusion techniques. Basing the effusion mass measurement on the TSM sensor as in our apparatus eliminates the typically seen dependence on vibration in conventional microbalance-based effusion techniques. Full design details of our apparatus and specifically the Knudsen cell, based on original equations derived by Knudsen, and many corrections that have been noted in the literature for cell and effusion-hole dimensions, are presented. The accuracy of our methodwas tested by a comparison of published vapor pressure data to vapor pressure data acquired in our laboratory with measurements on naphthalene and catechol.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(農学) / 甲第18328号 / 農博第2053号 / 新制||農||1022(附属図書館) / 学位論文||H26||N4835(農学部図書室) / 31186 / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 入江 一浩, 教授 河田 照雄, 教授 保川 清 / 学位規則第4条第1項該当

The effectiveness of catechol, an aromatic vic-diol, in dissolving silicate minerals was studied. A synthetic amorphous magnesium trisilicate, Mg₂Si₃O₈∙5H₂O, as well as the minerals olivine, sepiolite, diopside, augite, and enstatite were used to react with catechol in slightly acidic, basic, and neutral solutions. It was found, depending on the solvent used, that 33-52, 8-17, 14-30, 5-11, 3-6, and 0.5-1 % of the minerals dissolved, respectively. The reaction with Mg₂Si₃0₈·5H₂0 resulted in the formation of crystals of magnesium tris (catecholato) siliconate nonahydrate Mg[Si(Cat)₃]∙9H₂0. Dehydration of the crystals at room temperature resulted in the loss of 6 moles of water to form a trihydrated complex, Mg[Si(Cat)₃]·3H₂0; further dehydration at 100°C gave an anhydrous complex, Mg[Si(Cat)₃]. By adding guanidine hydrochloride, CN₃H₆Cl, to the reaction mixture after filtering, crystals of guanidinium tris (catecholato) siliconate monohydrate, (CN₃H₆)₂[Si(Cat)₃]∙H₂0, were obtained. Infrared and nmr spectra, and analytical and x-ray powder diffraction data are presented. The possible structures of the magnesium salts of tris (catecholato) siliconate are also discussed. The reaction of catechol with the minerals listed above gave a water soluble silicon-catechol complex, Si (Cat)₃⁼, which was isolated as (CN₃H₆)₂[Si(Cat)₃]·H₂0 by adding guanidine hydrochloride to the reaction mixture after filtering. The dissolution of these minerals by catechol to form Si(Cat)₃⁼ leads to the conclusion that aromatic vic-diols in nature may play a role in chemical weathering, in transport of silicon into rivers or seas, in soil development, in interconversion of minerals, and in accumulation of silica in plants.

No description available.