Réduire et contrôler les émissions de gaz à effet de serre générés par les activités industrielles, tel que le CO2, est un enjeu majeur. Afin de limiter ces rejets, une des solutions développées est le captage en postcombustion utilisant une solution aqueuse d'amine. A l'heure actuelle, l’amine de référence est la Monoethanolamine (MEA). Cependant, la forte énergie de régénération requise est unhandicap à son utilisation industrielle. Il est donc nécessaire de trouver de nouvelles structuresd’amines ayant des propriétés thermodynamiques plus favorables.L'objectif de la thèse est d'établir une relation entre la structure des amines et leurs propriétés thermodynamiques afin d'apporter une compréhension générale. Devant le nombre conséquent destructures possibles, des données sont obtenues via l'utilisation d'une expérimentation à haut débit (E.H.D.). Par l’utilisation d’une nouvelle représentation permettant d'étudier les mono- et multiamines et de la dérivée des isothermes d’absorption, nous avons mis en évidence deux grandes familles: la famille Aet la famille B qui a un comportement atypique non mis en évidence dans la littérature. Ces résultatsont permis d’orienter nos travaux afin d’obtenir un modèle général pour chacune de ces deux familles afin de déterminer des données thermodynamiques à partir des isothermes d’absorption (famille A:pKa*, pKc*, capacité cyclique - famille B: pKaIII, pKcI, capacité cyclique). Ces données thermodynamiques ont ensuite permis d'établir une série de relations structure/propriétés et d'identifier les caractéristiques structurales d'amines potentiellement performantes pour le captage du CO2. / The reduction of greenhouse gas emissions generated by industrial activities is a major challenge to prevent global warming effect. A large amount of these emissions comes from coal-fired power station generating important quantities of CO2. Post-combustion CO2 capture is one of the most mature solution developed to reduce these CO2 emissions. The benchmark molecule of the process ismonoethanolamine (MEA), where this primary amine displays a high reactivity toward CO2absorption. However, the corresponding process usually suffers from high energy requirement,corrosion, and degradation. There is a need to optimize the solvent structure in order to identify themost efficient amine moleculesSeveral classes of molecules can be found. The objective of this work is to correlate the thermodynamic properties with the amine structure obtained by High Throughput Screening (HTS) experiment. By using a new data representation of absorption capacity alpha* and the derivative dlnPCO2/dalpha*, weidentify two families: family A and family B. These results are used to built a thermodynamic modelfor each family in order to determine thermodynamic properties (family A: pKa*, pKc*, cycliccapacity and family B : pKaIII, pKcI and cyclic capacity). These thermodynamic data are used to establish a structure/properties relationship to identify structures which are interesting for CO2 capture.

Le modèle de sensibilisation comportementale permet d'étudier les changements neuronaux induits par les drogues. Chez les rongeurs, l'activité locomotrice augmente au fur et à mesure des injections et se maintient à long terme. En parallèle à cette sensibilisation, on observe une sensibilisation neurochimique des transmissions noradrénergique (NA) et sérotoninergique (5-HT) jusqu'à un mois après la dernière injection. Cette sensibilisation neurochimique, qui se traduit par des libérations de NA et de 5-HT potentialisées mesurées au niveau du cortex préfrontal, est commune à toutes les drogues et fortement corrélée à la sensibilisation comportementale. Le but de ce travail était d'identifier les mécanismes qui maintiennent à long terme cette hyper-réactivité. Nous avons tout d'abord montré que la réponse locomotrice potentialisée à l'amphétamine se maintient durant le premier mois de sevrage, et décroit de 60% entre 2 et 4 mois. Toutefois les souris restent plus vulnérables à la drogue et ce, même après de longs sevrages. Nous avons également démontré que l'hyper-réactivité des systèmes se maintient à long terme notamment grâce à une désensibilisation fonctionnelle persistante des récepteurs ?2A- adrénergiques et 5-HT1A, responsables du rétrocontrôle inhibiteur des transmissions NA et 5-HT. On observe une diminution de l'expression des protéines G?i couplées à ces récepteurs, dans le locus coeruleus et dans le raphé dorsal, respectivement. La même altération des rétrocontrôles ayant été mesurée chez les animaux sensibilisés au MDMA, les résultats suggèrent que les récepteurs ?2A-adrénergiques et 5-HT1A pourraient être des cibles indirectes des psychostimulants. / The behavioral sensitization model allows the study of the neuronal changes induced by drugs of abuse. In rodents, the locomotor activity increases progressively with the injections of drug, and stays long-lastingly potentiated. Concurrent with this sensitization, a neurochemical sensitization of noradrenergic and serotonergic transmissions is developed until one month after the last injection. This sensitization, quantified through potentiated noradrenergic and serotonergic releases in the prefrontal cortex, was shown to be common to almost all drugs of abuse and highly correlated to behavioral sensitization. The aim of this study was to identify the mechanisms sustaining this hyper-reactivity. We first showed that the potentiated response persists after the first month of withdrawal, and decreases to 40% of the response after 2 to 4 months of withdrawal. However, all mice remain more vulnerable to the drug, even after long (4 months) withdrawals. We also showed that the systems? hyper-reactivity is sustained in the long term by a functional and persistent desensitization of the ?2A-adrenergic and 5-HT1A receptors, responsible for the inhibitory feed-back of noradrenergic and serotonergic transmissions. We observed a decreased expression of G?i proteins coupled receptors in the locus coeruleus and the dorsal raphe.The same feed-back dysfunctions were found in animals sensitized to MDMA, which suggests that ?2A-adrenergic and 5-HT1A receptors are indirect targets of psychostimulant drugs

Il existe une comorbidité entre douleur et dépression. Si les antidépresseurs inhibiteurs de recapture de monoamines représentent le traitement de première intention des troubles dépressifs unipolaires, certains d’entre eux sont également recommandés en première ligne de traitement des douleurs neuropathiques. L’objectif de ce travail a été d’étudier les propriétés analgésiques de ces antidépresseurs dans des modèles animaux co-exprimant des éléments de phénotypes douloureux et dépressifs. Pour cela nous avons développé des tests d’évaluation comportementale de la douleur chez la souris. Ces tests permettent de décrire la sensibilité douloureuse des animaux et d’évaluer les effets pharmacologiques de substances de référence et innovantes.Nous avons ainsi démontré que la fluoxétine, inhibiteur sélectif de la recapture de sérotonine (ISRS), possède des effets antalgiques sur les altérations de sensibilité d’un modèle d’anxiété/dépression chez la souris : le modèle CORT. La caractérisation d’un phénotype douloureux chronique chez ces souris renforce la pertinence de ce modèle neuropsychopharmacologique, puisqu’il exprime une des comorbidités fréquentes des pathologies dépressives. De plus, l’efficacité antalgique de la fluoxétine dans ce modèle plaide en faveur d’une modulation de la composante affective de la douleur par les ISRS.De plus, nous avons caractérisé l’effet antalgique d’une nouvelle classe d’antidépresseurs monoaminergiques, les triples inhibiteurs de recapture des monoamines capables d’augmenter à la fois les concentrations intracérébrales de sérotonine, noradrénaline et dopamine. Pour ce faire, nous avons développé un modèle de douleurs induites par injections répétées d’oxaliplatine chez la souris et comparé l’efficacité de différents traitements sur ces douleurs. Les souris « oxaliplatine » développent une hyperalgie mécanique, ainsi qu’une allodynie et hyperalgie au froid. Ces altérations de la sensibilité douloureuse sont corrigées par l’administration aigüe d’un triple bloqueur (indatraline) en faisant intervenir des mécanismes probablement supra-spinaux. La composante dopaminergique de ces substances apporte un intérêt dans le profil antalgique. Par ailleurs, les souris « oxaliplatine » développent des traits caractéristiques d’un phénotype anxio-dépressif et l’indatraline semble avoir des effets antidépresseurs dans ce modèle, ouvrant la possibilité d’une participation de la DA à la composante affective de la douleur et plus d’effets sur l’influx somatosensoriel. L’ensemble de nos travaux fait ressortir l’importance du développement et de l’utilisation de modèles animaux co-exprimant douleurs et anxiété/dépression afin de mieux définir les mécanismes liant ces pathologies et d’optimiser les critères de développement des futurs antidépresseurs et analgésiques. / High comorbidity is described between depression and pain disorders. Monoaminergic reuptake inhibitors represent the first choice of treatment for depression and serotonin and norepinephrin reuptake inhibitors are also recommended for the treatment of neuropathic pain disorders. We aims at evaluating analgesic effects of these drugs in animal models sharing anxio-depressive and painful phenotype. We first developed tests to assess pain sensitivity in mice and analgesic properties of pharmacological compounds. Depressive phenotype was assessed using various behavioural paradigms of anxiety/depression.We thus show that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), provide antinociceptive effects in a mice model of anxiety-depression: the CORT model. Fluoxetine may thus exert its analgesic effect by modulating the affective aspect of pain in addition to a putative influence on sensory mechanisms. Moreover we characterized analgesic effects of a new generation of antidepressant, the triple reuptake inhibitors, which simultaneously potentialisate serotoninergic, noradrenergic and dopaminergic neurotransmission, in a mice model of oxaliplatin-induced neuropathy. Our results support that indatraline provide a better analgesic profile than escitalopram and venlafaxine in pain relief in oxaliplatin-treated mice. Although other investigations are required to quantify the putative involvement of DA in the therapeutic action of indatraline, the benefit can be attributed to this additional component. Indeed, reinforcement of descending control pathways though 5-HT and NE systems has been proposed to participate in the analgesic properties of dual reuptake inhibitors. The fact that indatraline was able to enhance dopaminergic transmission in the Anterior Cingulate Cortex argues in favor of a more potent action upon this inhibitory descending control of pain. Results with indatraline in the depression paradigm cannot rule out the possibility that the antidepressant property of the TRI accounts for its analgesic effect.This work provides a support for the need of animal models sharing anxio/depressive and painful phenotype in order to define mechanism responsible for such co-mobidity and optimize the development of newer antidepressants and pain killers.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O Transtorno de DÃficit de AtenÃÃo/ Hiperatividade (TDAH) Ã um transtorno prevalente e debilitante, diagnosticado com base em persistentes nÃveis de hiperatividade, desatenÃÃo e impulsividade. FÃrmacos estimulantes tÃm sido eficazes no tratamento desse transtorno, sendo que o metilfenidato (MFD) Ã o agente terapÃutico mais prescrito e seu uso aumentou significativamente nos Ãltimos anos, entretanto, as conseqÃÃncias da sua utilizaÃÃo ainda sÃo pouco conhecidas. O MFD foi avaliado em modelos animais clÃssicos para screening de drogas com atividade em ansiedade, depressÃo e convulsÃo, tais como, labirinto em cruz elevado (LCE), campo aberto, rota rod, nado forÃado e convulsÃo induzida por pilocarpina, e em estudo neuroquÃmico, atravÃs da concentraÃÃo de monoaminas, tais como dopamina (DA), noradrenalina (NE) e 5-hidroxitriptamina (5-HT), alÃm da atividade da enzima Acetilcolinesterase (AChE). O MFD foi administrado de forma aguda em todos os testes, nas doses de 2,5; 5; 10 e 20 mg/Kg, atravÃs da via oral (v.o.) em camundongos jovens (21 dias) e adultos. Os resultados mostraram que o MFD apresentou efeito ansiolÃtico nos modelos LCE, pois aumentou todos os parÃmetros analisados no LCE, como NEBA, PEBA, TPBA e PTBA nas doses de 10 e 20mg/Kg nos animais jovens e apenas na de 20mg/Kg nos animais adultos. No teste do campo aberto, foi observado aumento na atividade locomotora em todas as doses nos animais jovens e apenas nas doses maiores (10 e 20mg/Kg) nos animais adultos. NÃo alterou o nÃmero de grooming e rearing. O MFD apresentou efeito antidepressivo no Sistema Nervoso Central (SNC), pois no teste do nado forÃado diminuiu o tempo de imobilidade nas doses de 10 e 20 mg/Kg nos animais jovens e apenas na dose de 20mg/Kg nos animais adultos. A avaliaÃÃo neuroquÃmica comprovou o efeito antidepressivo do MFD, pois se verificou um aumento da concentraÃÃo das monoaminas. No teste da convulsÃo induzida por pilocarpina, o metilfenidato diminuiu a latÃncia de convulsÃo, bem como a latÃncia de morte nos animais jovens e adultos, sugerindo que o MFD apresenta atividade proconvulsivante. O estudo sobre os efeitos sobre o sistema de neurotransmissÃo colinÃrgica demonstrou que o prÃ-tratamento com MFD reduziu a atividade da AChE apenas no corpo estriado. Em conclusÃo, esses efeitos mostraram que o MFD apresenta efeito ansiolÃtico, efeito antidepressivo e atividade proconvulsivante. / Attention-deficit hyperactivity disorder (ADHD) is a prevalent and debilitating disorder diagnosed on the basis in persistent levels of overactivity, inattention and impulsivity. Stimulant drugs have been effective in treating this disorder, and methylphenidate (MPH) is the most widely prescribed therapeutic agent and its use has increased significantly in recent years, however, the consequences of its use are still poorly known. The MFD was assessed in classical animal models to the screening of drugs with activity in anxiety, depression and convulsion, such as elevated plus maze (EPM), open field, rota rod, forced swimming and pilocarpine-induced seizures and a neurochemistry study, through the level of monoamines, such as dopamine (DA), norepinephrine (NE) and 5-hidroxytriptamine (5-HT) but the activity of the enzyme acetylcholinesterase (AChE). The MPH was administered acutely in all tests at doses of 2,5; 5; 10 e 20 mg/Kg, through the oral via (p.o.) in young mice (21 days) and adults. Results showed that the MPH presented an anxyolitic effects in the models of EPM, since increased all the parameters analyzed in the EPM, such as NEOA, PEOA, TPOA, PTOA, at doses of 10 and 20 mg/Kg in young animals, and only in animals of 20 mg/Kg in adults. In the open field, we observed an increase in locomotor activity at all doses in young animals and only at higher doses (10 e 20 mg/Kg) in adult animals. Not was observed no alteration the number of rearing and grooming. MPH presented antidepressant effect of Central Nervous System (CNS), since in the forced swimming, decreases the time of immobility in doses of 10 and 20 mg/Kg in young animals and only at a dose of 20 mg/Kg in adult animals. The neurochemistry evaluation comproved the antidepressant effect do MPH, because there was an increased concentration of monoamines. The test of the seizure by pilocarpine, MPH did decrease the latency of convulsion and latency of death in young and adult animals, suggesting that the MPH has proconvulsivante activity. The study of the effects of the cholinergic neurotransmission system has show that pretreatment with MPH reduced AChE activity only in the striatum. In conclusion, these effects showed that MPH presented anxiolitic effect, antidepressant effect and proconvulsivante activity.

<p>Animals show a great variety in physiological and behavioural responses to stressors. These responses are often bimodally distributed within populations and show consistency on an individual level over time and across situations, which in terrestrial vertebrates have been identified as proactive and reactive stress coping strategies. Proactive animals show lower cortisol responses, higher sympathetic activation and brain serotonergic activity compared to reactive animals. Behaviourally, proactive animals are more aggressive, more active in avoiding stressors, they form routines and show fewer cases of conditioned immobility compared to reactive animals. Our aim has been to reveal if such stress coping strategies exist in fish. Our results show that rainbow trout with high (HR) or low (LR) cortisol responses to stressors differs in sympathetic activation and brain serotonin turnover in the same manner as proactive and reactive mammals. HR fish showed less locomotor activity when reared in large groups (30 individuals) compared to LR fish. When reared in isolation there were no differences between HR and LR fish when exposed to stressors within a familiar environment. The adaption of a proactive coping style among reactive coping individuals when they are challenged within a familiar environment has previously been shown to be distinction between proactive and reactive coping mammals. However, when they were transferred to unfamiliar environments a behavioural difference between the two lines was observed indicating different stress coping strategies akin to those described in mammals. Finally, we observed a consistency over time in the cortisol response of an unselected line of rainbow trout. Fish from this line also demonstrated a correlation between behavioural responses to different stressors. However, there was no apparent connection between these behavioural responses and the cortisol response. Overall, the results of this thesis have strengthened the hypothesis that different stress coping strategies exist in teleost fish.</p>

<p>This thesis shows that socially subordinate Arctic charr (<i>Salvelinus alpinus</i>) display elevated brain serotonergic (5-HT) and norepinephric activity along with a chronic activation of the hypothalamic-pituitary-interrenal (HPI) axis, including elevated plasma concentrations of á-MSH. Furthermore, subordinate fish showed an inhibition of aggressive behaviour and darker body coloration, skin darkness being positively correlated with plasma á-MSH. Fish kept on dark background, and thus being darker in body colour, were less aggressive than conspecifics interacting on white background, supporting the hypothesis that skin darkening could signal social submission. The 5-HT_1A-receptor agonist 8-OH-DPAT stimulated HPI axis activity in non-stressed fish, but if administrated to stressed fish it inhibited HPI axis activity, suggesting that 5-HT_1A receptors may act as both post- and pre-synaptic receptors. 8-OH-DPAT also induced skin darkening in both non-stressed and stressed fish. Stimulation of brain dopaminergic activity by L-dopa treatment counteracted the stress-induced inhibition of aggressive behaviour, and stress related effects on brain 5-HT activity and plasma levels of cortisol. In conclusion, social subordination in Arctic charr results in skin darkening and an inhibition of aggressive behaviour. Stress-induced effects, that could be mediated by elevated brain 5-HT activity, and serve as a way of signalling social position and coping with stress.</p>

This thesis shows that socially subordinate Arctic charr (Salvelinus alpinus) display elevated brain serotonergic (5-HT) and norepinephric activity along with a chronic activation of the hypothalamic-pituitary-interrenal (HPI) axis, including elevated plasma concentrations of á-MSH. Furthermore, subordinate fish showed an inhibition of aggressive behaviour and darker body coloration, skin darkness being positively correlated with plasma á-MSH. Fish kept on dark background, and thus being darker in body colour, were less aggressive than conspecifics interacting on white background, supporting the hypothesis that skin darkening could signal social submission. The 5-HT1A -receptor agonist 8-OH-DPAT stimulated HPI axis activity in non-stressed fish, but if administrated to stressed fish it inhibited HPI axis activity, suggesting that 5-HT1A receptors may act as both post- and pre-synaptic receptors. 8-OH-DPAT also induced skin darkening in both non-stressed and stressed fish. Stimulation of brain dopaminergic activity by L-dopa treatment counteracted the stress-induced inhibition of aggressive behaviour, and stress related effects on brain 5-HT activity and plasma levels of cortisol. In conclusion, social subordination in Arctic charr results in skin darkening and an inhibition of aggressive behaviour. Stress-induced effects, that could be mediated by elevated brain 5-HT activity, and serve as a way of signalling social position and coping with stress.

Animals show a great variety in physiological and behavioural responses to stressors. These responses are often bimodally distributed within populations and show consistency on an individual level over time and across situations, which in terrestrial vertebrates have been identified as proactive and reactive stress coping strategies. Proactive animals show lower cortisol responses, higher sympathetic activation and brain serotonergic activity compared to reactive animals. Behaviourally, proactive animals are more aggressive, more active in avoiding stressors, they form routines and show fewer cases of conditioned immobility compared to reactive animals. Our aim has been to reveal if such stress coping strategies exist in fish. Our results show that rainbow trout with high (HR) or low (LR) cortisol responses to stressors differs in sympathetic activation and brain serotonin turnover in the same manner as proactive and reactive mammals. HR fish showed less locomotor activity when reared in large groups (30 individuals) compared to LR fish. When reared in isolation there were no differences between HR and LR fish when exposed to stressors within a familiar environment. The adaption of a proactive coping style among reactive coping individuals when they are challenged within a familiar environment has previously been shown to be distinction between proactive and reactive coping mammals. However, when they were transferred to unfamiliar environments a behavioural difference between the two lines was observed indicating different stress coping strategies akin to those described in mammals. Finally, we observed a consistency over time in the cortisol response of an unselected line of rainbow trout. Fish from this line also demonstrated a correlation between behavioural responses to different stressors. However, there was no apparent connection between these behavioural responses and the cortisol response. Overall, the results of this thesis have strengthened the hypothesis that different stress coping strategies exist in teleost fish.

Réduire et contrôler les émissions de gaz à effet de serre générés par les activités industrielles, tel que le CO2, est un enjeu majeur. Afin de limiter ces rejets, une des solutions développées est le captage en postcombustion utilisant une solution aqueuse d'amine. A l'heure actuelle, l'amine de référence est la Monoethanolamine (MEA). Cependant, la forte énergie de régénération requise est unhandicap à son utilisation industrielle. Il est donc nécessaire de trouver de nouvelles structuresd'amines ayant des propriétés thermodynamiques plus favorables.L'objectif de la thèse est d'établir une relation entre la structure des amines et leurs propriétés thermodynamiques afin d'apporter une compréhension générale. Devant le nombre conséquent destructures possibles, des données sont obtenues via l'utilisation d'une expérimentation à haut débit (E.H.D.). Par l'utilisation d'une nouvelle représentation permettant d'étudier les mono- et multiamines et de la dérivée des isothermes d'absorption, nous avons mis en évidence deux grandes familles: la famille Aet la famille B qui a un comportement atypique non mis en évidence dans la littérature. Ces résultatsont permis d'orienter nos travaux afin d'obtenir un modèle général pour chacune de ces deux familles afin de déterminer des données thermodynamiques à partir des isothermes d'absorption (famille A:pKa*, pKc*, capacité cyclique - famille B: pKaIII, pKcI, capacité cyclique). Ces données thermodynamiques ont ensuite permis d'établir une série de relations structure/propriétés et d'identifier les caractéristiques structurales d'amines potentiellement performantes pour le captage du CO2.

<p>Diss. (sammanfattning) Umeå : Umeå universitet, 1980, härtill 5 uppsatser.</p> / digitalisering@umu