Since the use of opioids started to emerge for analgesic reasons in the 19th century with the synthetization of morphine, opioids have been studied rigorously to better understand its effects on the brain. This thesis shows that both the analgesic effects and the reinforcing effects of opioids are mediated by the same receptor, the mu opioid receptor (MOR). MOR activity has been correlated to both primary and secondary reinforcers and should be considered to cause positive reinforcement together with increases in dopamine transmission for all drugs of abuse, and not only in relation to opioids. Opioid tolerance, dependence and even addiction are to some extent thought to relate to opioids’ acute effect of cyclic adenosine monophosphate (cAMP) superactivation. Based upon these findings, the allostasis theory of addiction is considered to be the most suitable in defining opioid addiction. The theory claims that the mesolimbic dopamine system becomes sensitized, increasing the attractiveness of opioids. This while counteradaptation increases the pleasurable tolerance of opioids, encouraging the user to increase its intake for the same initial reward. Furthermore the theory claims that cAMP superactivation is causing an unfolding effect of neurobiological and neurochemical expressions which leads to the disorder of addiction. cAMP superactivation is mediating the negatively reinforcing aspects of opioid addiction together with changes to corticotropin-releasing factor (CRF) in the brain stress system, such as the hypothalamic-pituitary-adrenal (HPA) axis and the extended amygdala.

Este trabalho apresenta a modelagem matemática e a simulação de potenciais de ação de unidades motoras de músculos de vertebrados visando a posterior simulação do eletromiograma. Para conseguir isso, inicialmente se fez uma compilação de dados existentes para a distribuição das fibras musculares (FBs) nas unidades motoras (MUs) de vários músculos, e as modelagens matemáticas descritos na literatura para o potencial de ação de uma FB (SFAP) e de uma MU (MUAP). Com base nos dados fisiológicos, primeiro se localizou as FBs em um músculo, por meio de uma aproximação de que as FBs estão rodeadas de outras seis no músculo. Para conseguir isto se construiram hexágonos concêntricos por MU, e posteriormente se localizou as FBs nas MUs, cobrindo uma faixa entre 75 e 2000 FBs, o que corresponde a músculos distais de mamíferos. Depois se fez uma aproximação para a distribuição de 170000 FBs nas 272 MUs da cabeça medial do músculo gastrocnêmio (MG) do gato, conseguindo numa primeira simulação localizar cerca de 70% das FBs para cada MU. Com esta localização das FBs no músculo baseados nos dados da literatura se aproximaram os retardos axonais por uma distribuição gaussiana, com média de 2 ms (gato) ou 10 ms (homem) e com desvio padrão de menos de 0,5 ms, desprezando o atraso axonal nas ramificações axonais, que foi estimado no máximo 29 vezes menor. Para a geração do SFAP trabalhou-se com dois modelos, um analítico, o qual resulta em simulações numéricas demoradas, e, outro numérico baseado na convolução da corrente com uma função peso. Para o modelo numérico dobrou-se imaginariamente o comprimento das FBs, para levar em conta o erro computacional de fim de fibra. O modelo numérico resultou em um tempo de simulação 30 vezes menor que o analítico. Adicionalmente, para simular a captação externa (i.e. na pele), fez-se uma aproximação para a função que modela os eletrodos de superfície de secção circular localizados a uma distância maior que 1,79 mm das FBs, mostrando um espectro similar ao reportado na literatura. Finalmente, os MUAPs obtidos resultavam com formas de onda e espectros similares ao descrito na literatura. Além disto, em certos casos, obtiveram-se MUAPs com indentações, seja localizando as junções neuromusculares em bandas da ordem de 1 mm de espessura, seja quando o tempo de atraso axonal foi considerado junto com a velocidade de condução da FB em função da raiz quadrada do diâmetro da FB. Foram feitas simulações para os MG e bíceps braquial do homem. Neste último caso, foram obtidos MUAPs similares aos captados para pessoas saludáveis, e foi observada a freqüência de disparos dos potenciais de ação do motoneurônio no espectro do MUAP. Quanto às formas dos agrupamentos das FBs em uma MU, não se obtiveram diferenças significativas para as FBs posicionadas homogênea e aleatoriamente, exceto uma ligeira variação nas amplitudes. No entanto, ocurreu uma mudança na faixa espectral, quando as FBs estavam concentradas. / This work presents the mathematical model and simulation of motor unit action potentials of vertebrate muscles aiming at after simulation of the electromyogram. To obtain this, initially, it was made a compilation of several data about the distribution of muscle fibers (FBs) in motor units (MUs) of many muscles, and the mathematical models of the action potential of a single FB (SFAP) and MU (MUAP), reported in previous works. On the basis of this physiological data, first, the FB was located in a muscle, using an approximation in which the FBs are encircled with other six FBs in the muscle. To reach this, concentric hexagons were constructed to build the surface of the MU, and later the FBs were situated in the MU, covering a range between 75 and 2000 FBs, corresponding to mammals extremity muscles. Later, a new approximation were was madein order to distribute the 170000 FBs in the 272 MUs of the medial head of muscle medialis gastrocnemius (MG) of the cat, reaching, in a first simulation, the localization of almost 70% of the FBs at each MU. With the FBs lalready allocated in the muscle, and based in data of previous works, their axonal delay were approximated by a gaussian distribution, with mean of 2 ms (cat) or 10 ms (man) and standard deviation of less than 0,5 ms, discarding the axonal delay in the axonal branching, that were estimated to affectup to 29 times less. To SFAP generation, two models were used, the first analytical, resulting in delayed numerical simulations, and the other based on convolution of the second derivate of the current with a weight function, where the length of the FBs was imaginarily duplicated, in order to consider the end fiber effect. Using this, a simulation time 30 times lesser than the analytical one was obtained. Additionally, so as to simulate the external recording (i.e. in the skin), it was made an approximation to the function that models the circular shape surface electrodes located at distances greater than 1,79 mm of the FBs, showing a similar spectrum reported. Finally, the waves and spectrum of the simulated MUAPs resulted similar to the ones reported in the literature. Beyond this, in certain cases, MUAPs were simulated with some tuned, either locating the neuromuscular junctions with thickness bands of 1 mm, or, when the axonal delay and the FB muscle fiber conduction velocity were considered as a function of the square root fiber diameter. This was simulated for MUAPs of MG and biceps brachii muscles of human beings, in the last case it has reached the waveforms and tuned found in heath subjects, and it was visualized the mean frequency of firing rate at the spectrum. In order to know how much affects grouping for the FBs to waves a MU, they were not found significant differences with FBs located homogeneously and randomly, except a little variation in the amplitude of the MUAP. However, they presented a change in the spectral bandwidth when the FBs are more concentrated.

Les récepteurs mu aux opioïdes (MORs) jouent un rôle central dans l’addiction et ce majoritairement via le contrôle qu’ils exercent sur les phénomènes de récompense. Les effets des MORs sur le système de récompense sont généralement attribués à leur expression dans le circuit mésocorticolimbique. Les MORs sont toutefois exprimés dans d’autres régions du cerveau, notamment dans une petite structure cérébrale épithalamique qui exprime la plus forte densité de MORs : l’habénula médiane (MHb). Le rôle de cette population spécifique de récepteurs n’a jamais été exploré, malgré l’implication fortement suggérée dans la littérature de l’habénula dans l’addiction et les processus de récompense/aversion sous-jacents. Nous avons donc généré un modèle de souris knockout conditionnel chez lesquelles nous supprimons les MORs uniquement dans l’habénula et nous les avons soumis à des tests comportementaux dans le but d’évaluer les fonctions de ces récepteurs et leur impact sur le comportement avec un focus sur les processus aversifs, cognitifs et récompensant. Nos résultats révèlent que les récepteurs mu que nous supprimons dans l’habénula limitent l’aversion somatique et affective mais ne modulent ni les réponses locomotrices, analgésiques et de récompense à la morphine, ni les fonctions cognitives que nous avons testées. Nous identifions donc pour la première fois une population de MORs dans l’habénula qui freinent l’aversion et nous suggérons par là-même que les récepteurs mu de l’habénula pourraient être cruciaux dans le stage «sevrage aversif» des cycles d’addiction. / Mu opioid receptors (MORs) have been extensively studied for their addictive properties that are thought to operate through the control of reward processes. While the importance of MORs in reward is generally attributed to their presence in the mesocorticolimbic circuitry, their role in the medial habenula (MHb), the structure in which MORs are most densely expressed, remains unexplored to date. This is quite surprising given the increasing literature on the habenula’s role in addiction as well as reward/aversion processes. Here we generated a conditional knockout mouse model that lacks MORs solely in the MH band we investigated the contribution of habenular MORs in brain functions and behavioural out comes with emphasis on reward, aversion and cognition. While the performance of our mutant model did not differ in locomotor, analgesic and reward responses to morphine norincognitive tasks compared to control mice, we uncovered a novel role for MORs in aversive states.This is the first report demonstrating that MORs control both somatic and affective aversion specifically at the level of the MHb. Habenular MORs could thus be crucial to the aversive with drawal stage of addiction cycles that is thought to increase craving and prevent success in quitting.

Este trabalho apresenta a modelagem matemática e a simulação de potenciais de ação de unidades motoras de músculos de vertebrados visando a posterior simulação do eletromiograma. Para conseguir isso, inicialmente se fez uma compilação de dados existentes para a distribuição das fibras musculares (FBs) nas unidades motoras (MUs) de vários músculos, e as modelagens matemáticas descritos na literatura para o potencial de ação de uma FB (SFAP) e de uma MU (MUAP). Com base nos dados fisiológicos, primeiro se localizou as FBs em um músculo, por meio de uma aproximação de que as FBs estão rodeadas de outras seis no músculo. Para conseguir isto se construiram hexágonos concêntricos por MU, e posteriormente se localizou as FBs nas MUs, cobrindo uma faixa entre 75 e 2000 FBs, o que corresponde a músculos distais de mamíferos. Depois se fez uma aproximação para a distribuição de 170000 FBs nas 272 MUs da cabeça medial do músculo gastrocnêmio (MG) do gato, conseguindo numa primeira simulação localizar cerca de 70% das FBs para cada MU. Com esta localização das FBs no músculo baseados nos dados da literatura se aproximaram os retardos axonais por uma distribuição gaussiana, com média de 2 ms (gato) ou 10 ms (homem) e com desvio padrão de menos de 0,5 ms, desprezando o atraso axonal nas ramificações axonais, que foi estimado no máximo 29 vezes menor. Para a geração do SFAP trabalhou-se com dois modelos, um analítico, o qual resulta em simulações numéricas demoradas, e, outro numérico baseado na convolução da corrente com uma função peso. Para o modelo numérico dobrou-se imaginariamente o comprimento das FBs, para levar em conta o erro computacional de fim de fibra. O modelo numérico resultou em um tempo de simulação 30 vezes menor que o analítico. Adicionalmente, para simular a captação externa (i.e. na pele), fez-se uma aproximação para a função que modela os eletrodos de superfície de secção circular localizados a uma distância maior que 1,79 mm das FBs, mostrando um espectro similar ao reportado na literatura. Finalmente, os MUAPs obtidos resultavam com formas de onda e espectros similares ao descrito na literatura. Além disto, em certos casos, obtiveram-se MUAPs com indentações, seja localizando as junções neuromusculares em bandas da ordem de 1 mm de espessura, seja quando o tempo de atraso axonal foi considerado junto com a velocidade de condução da FB em função da raiz quadrada do diâmetro da FB. Foram feitas simulações para os MG e bíceps braquial do homem. Neste último caso, foram obtidos MUAPs similares aos captados para pessoas saludáveis, e foi observada a freqüência de disparos dos potenciais de ação do motoneurônio no espectro do MUAP. Quanto às formas dos agrupamentos das FBs em uma MU, não se obtiveram diferenças significativas para as FBs posicionadas homogênea e aleatoriamente, exceto uma ligeira variação nas amplitudes. No entanto, ocurreu uma mudança na faixa espectral, quando as FBs estavam concentradas. / This work presents the mathematical model and simulation of motor unit action potentials of vertebrate muscles aiming at after simulation of the electromyogram. To obtain this, initially, it was made a compilation of several data about the distribution of muscle fibers (FBs) in motor units (MUs) of many muscles, and the mathematical models of the action potential of a single FB (SFAP) and MU (MUAP), reported in previous works. On the basis of this physiological data, first, the FB was located in a muscle, using an approximation in which the FBs are encircled with other six FBs in the muscle. To reach this, concentric hexagons were constructed to build the surface of the MU, and later the FBs were situated in the MU, covering a range between 75 and 2000 FBs, corresponding to mammals extremity muscles. Later, a new approximation were was madein order to distribute the 170000 FBs in the 272 MUs of the medial head of muscle medialis gastrocnemius (MG) of the cat, reaching, in a first simulation, the localization of almost 70% of the FBs at each MU. With the FBs lalready allocated in the muscle, and based in data of previous works, their axonal delay were approximated by a gaussian distribution, with mean of 2 ms (cat) or 10 ms (man) and standard deviation of less than 0,5 ms, discarding the axonal delay in the axonal branching, that were estimated to affectup to 29 times less. To SFAP generation, two models were used, the first analytical, resulting in delayed numerical simulations, and the other based on convolution of the second derivate of the current with a weight function, where the length of the FBs was imaginarily duplicated, in order to consider the end fiber effect. Using this, a simulation time 30 times lesser than the analytical one was obtained. Additionally, so as to simulate the external recording (i.e. in the skin), it was made an approximation to the function that models the circular shape surface electrodes located at distances greater than 1,79 mm of the FBs, showing a similar spectrum reported. Finally, the waves and spectrum of the simulated MUAPs resulted similar to the ones reported in the literature. Beyond this, in certain cases, MUAPs were simulated with some tuned, either locating the neuromuscular junctions with thickness bands of 1 mm, or, when the axonal delay and the FB muscle fiber conduction velocity were considered as a function of the square root fiber diameter. This was simulated for MUAPs of MG and biceps brachii muscles of human beings, in the last case it has reached the waveforms and tuned found in heath subjects, and it was visualized the mean frequency of firing rate at the spectrum. In order to know how much affects grouping for the FBs to waves a MU, they were not found significant differences with FBs located homogeneously and randomly, except a little variation in the amplitude of the MUAP. However, they presented a change in the spectral bandwidth when the FBs are more concentrated.

Vacuum polarization integral involves the vector spectral functions which can be experimentally determined. As the dominant uncertainty source to the integral, the precision measurement of the %born cross section of $e^+e^-\rightarrow\pi^+\pi^-(\gamma)$ as a function of energy from $2\pi$ threshold to 3GeV is performed by taking the ratio of $e^+e^-\rightarrow\pi^+\pi^-(\gamma)$ cross section to $e^+e^-\rightarrow\mu^+\mu^-(\gamma)$ cross section which are both measured with {\babar\ }data using ISR method in one analysis. Besides that taking the ratio of the cross sections of the two processes can cancel several systematic uncertainties, the acceptance differences between data and MC are measured using the same data, and the corresponding corrections are applied on the efficiencies predicted by MC which can control the uncertainties. The achieved final uncertainty of the born cross section of $e^+e^-\rightarrow\pi^+\pi^-(\gamma)$ in $\rho$ mass region ($0.6\sim0.9$GeV) is 0.54\%. As a consequence of the new vacuum polarization calculation using the new precision result of the $e^+e^-\rightarrow\pi^+\pi^-(\gamma)$ cross section, the impact on the SM prediction of muon anomalous magnetic moment $g-2$ is presented, which is also compared with other data based predictions and direct measurement.

Cette thèse de théorie de la démonstration étudie les interactions entre le λ-calcul différentiel d'Ehrhard et Regnier d'un côté, et certaines émanations calculatoires de la logique classique (le λμ-calcul de Parigot et le λ-barre-μ-calcul de Herbelin) de l'autre. L'étude est initiée et guidée par la décomposition de ces calculs dans des extensions de la logique linéaire de Girard.<br /><br />Dans une première partie, on définit un cadre commun pour ces extensions, dans le formalisme des réseaux d'interaction de Lafont, et on y rappelle des résultats de la littérature ou du folklore. On donne en particulier la traduction du λμ-calcul et du λ-barre-μ-calcul dans les réseaux polarisés de Laurent et celle du fragment finitaire du λ-calcul différentiel dans les réseaux différentiels d'Ehrhard et Regnier.<br /><br />Dans la deuxième partie, on introduit les réseaux différentiels polarisés (RDP), comme l'extension par une polarisation à la Laurent des réseaux différentiels. La pertinence des règles de réduction nouvelles est soulignée par l'étude d'un modèle dénotationnel commun aux réseaux différentiels et aux réseaux polarisés.<br /><br />Enfin, on présente trois calculs de termes, chacun pouvant être considéré comme une lecture en arrière de tout ou partie des interactions définies par les RDP : un λμ-calcul différentiel, qui correspond à la réunion des réseaux différentiels et des réseaux polarisés ; un λ-barre-μ-calcul avec produit de convolution sur les piles, qui fait intervenir la structure de bigèbre des types polarisés introduite dans les RDP, mais pas la dérivée ; enfin, un λ-barre-μ-calcul différentiel qui développe toute l'expressivité des RDP.

Regulation of transcription initiation is the major determining event employed by the cell to control gene expression and subsequent cellular processes. The weak promoters, with low basal transcription activities, are activated by activators. Bacteriophage Mu mom gene, which encodes a unique DNA modification function, is detrimental to cell when expressed early or in large quantities. Mu has designed a complex, well-controlled and orchestrated regulatory network for mom expression to ensure its synthesis only in late lytic cycle. The phage encoded transcription activator protein C activates the gene by promoter unwinding of the DNA and thereby recruiting of RNAP to the promoter. C protein functions as a dimer for DNA binding and transcription activation. Mutagenesis and chemical crosslinking studies revealed that the leucine zipper motif, and not the coiled coil motif in the N terminal region, is responsible for C dimerization. The DNA binding domain of C is a HTH domain which is preceded by the leucine zipper motif. The C protein is one of the few examples in the bacterial proteins containing both leucine zipper and HTH domain. Most of the transcription activators either influence initial binding of RNAP or conversion of closed to open complex formation. Very few activators act at subsequent steps of promoter-polymerase interaction. Earlier studies showed high level of transcription from a mutant mom promoter, tin7. Addition of C further increased transcription from Ptin7 indicating that C may have a role beyond polymerase recruitment. Each steps of transcription initiation have been dissected using the Ptin7 and a positive control (pc) mutant of C, R105D. The results revealed multi-step transcription activation mechanism for C protein at Pmom. C recruits RNAP at Pmom and subsequently increases the productive RNAP-promoter complex and enhances promoter clearance. To further understand the C mediated transactivation mechanism, interaction between C and RNAP was assessed. C interacts with holo and core RNAP only in presence of DNA. Positive control mutants of C, F95A and R015D, were found to be compromised in RNAP interactions. These mutants were efficient in RNAP recruitment to Pmom but do not enhance promoter clearance. Trypsin cleavage protection experiment indicated that probably C protein interacts with b¢ subunit of RNAP. Interaction between C and RNAP appears to enhance the formation of productive RNAP-promoter complex leading to promoter clearance. The connection between activator-polymerase interaction and transcription activation is well documented where the recruitment of RNAP is influenced. In case of activators acting at post recruitment steps of initiation, the role of polymerase contact is poorly understood. Our study shows that activator-polymerase interaction can lead to increased promoter clearance at Pmom by overcoming abortive initiation.

Les architectures des systèmes sur puce (System-on-Chip, SoC) actuelles intègrent de nombreux composants différents tels que les processeurs, les accélérateurs, les mémoires et les blocs d'entrée/sortie, certains pouvant contenir des caches. Vu que l'effort de validation basée sur la simulation, actuellement utilisée dans l'industrie, croît de façon exponentielle avec la complexité des SoCs, nous nous intéressons à des techniques de vérification formelle. Nous utilisons la boîte à outils CADP pour développer et valider un modèle formel d'un SoC générique conforme à la spécification AMBA 4 ACE récemment proposée par ARM dans le but de mettre en œuvre la cohérence de cache au niveau système. Nous utilisons une spécification orientée contraintes pour modéliser les exigences générales de cette spécification. Les propriétés du système sont vérifié à la fois sur le modèle avec contraintes et le modèle sans contraintes pour détecter les cas intéressants pour la cohérence de cache. La paramétrisation du modèle proposé a permis de produire l'ensemble complet des contre-exemples qui ne satisfont pas une certaine propriété dans le modèle non contraint. Notre approche améliore les techniques industrielles de vérification basées sur la simulation en deux aspects. D'une part, nous suggérons l'utilisation du modèle formel pour évaluer la bonne construction d'une unité de vérification d'interface. D'autre part, dans l'objectif de générer des cas de test semi-dirigés intelligents à partir des propriétés de logique temporelle, nous proposons une approche en deux étapes. La première étape consiste à générer des cas de tests abstraits au niveau système en utilisant des outils de test basé sur modèle de la boîte à outils CADP. La seconde étape consiste à affiner ces tests en cas de tests concrets au niveau de l'interface qui peuvent être exécutés en RTL grâce aux services d'un outil commercial de génération de tests dirigés par les mesures de couverture. Nous avons constaté que notre approche participe dans la transition entre la vérification du niveau interface, classiquement pratiquée dans l'industrie du matériel, et la vérification au niveau système. Notre approche facilite aussi la validation des propriétés globales du système, et permet une détection précoce des bugs, tant dans le SoC que dans les bancs de test commerciales. / State-of-the-art System-on-Chip (SoC) architectures integrate many different components, such as processors, accelerators, memories, and I/O blocks. Some of those components, but not all, may have caches. Because the effort of validation with simulation-based techniques, currently used in industry, grows exponentially with the complexity of the SoC, this thesis investigates the use of formal verification techniques in this context. More precisely, we use the CADP toolbox to develop and validate a generic formal model of a heterogeneous cache-coherent SoC compliant with the recent AMBA 4 ACE specification proposed by ARM. We use a constraint-oriented specification style to model the general requirements of the specification. We verify system properties on both the constrained and unconstrained model to detect the cache coherency corner cases. We take advantage of the parametrization of the proposed model to produce a comprehensive set of counterexamples of non-satisfied properties in the unconstrained model. The results of formal verification are then used to improve the industrial simulation-based verification techniques in two aspects. On the one hand, we suggest using the formal model to assess the sanity of an interface verification unit. On the other hand, in order to generate clever semi-directed test cases from temporal logic properties, we propose a two-step approach. One step consists in generating system-level abstract test cases using model-based testing tools of the CADP toolbox. The other step consists in refining those tests into interface-level concrete test cases that can be executed at RTL level with a commercial Coverage-Directed Test Generation tool. We found that our approach helps in the transition between interface-level and system-level verification, facilitates the validation of system-level properties, and enables early detection of bugs in both the SoC and the commercial test-bench.

L’addiction ou dépendance aux substances psychoactives est une affection chronique, fréquente et grave, émaillée de rechutes et de périodes d’abstinence. Les études épidémiologiques montrent que l’abstinence aux opiacés est fortement associée à une prévalence accrue de la dépression. Nous résumons ici les principaux aspects cliniques de la dépendance aux opiacés et de la dépression, en détaillant leurs mécanismes physiopathologiques. Puis, nous présentons notre modèle d’abstinence aux opiacés chez la souris. Suite à un traitement morphinique chronique et au cours de l’abstinence apparaissent progressivement des comportements apparentés à la dépression. Ce traitement morphinique modifie profondément le fonctionnement du système sérotoninergique, notamment dans le noyau du raphé dorsal. De plus, les déficits comportementaux observés peuvent être prévenus par un traitement chronique par la fluoxétine, un antidépresseur ciblant ce système. Nous avons généralisé ce modèle à l’héroïne, un autre opiacé illicite. Nous avons révélé par des approches génétiques de délétion constitutive et conditionnelle les rôles distincts des 3 récepteurs opioïdes (mu, delta et kappa) lors de l’abstinence à l’héroïne. Enfin, nous avons initié une étude de caractérisation, à l’échelle de l’ensemble du génome, des adaptations transcriptomiques (ARN messagers et micro-ARN) dans le noyau du raphé dorsal au cours de l’abstinence à l’héroïne et du traitement antidépresseur. Ce travail devrait permettre d’améliorer notre compréhension des mécanismes neurobiologiques à l’œuvre dans la comorbidité entre dépendance aux opiacés et dépression et pourrait suggérer de nouvelles pistes thérapeutiques. / Addiction is a chronic, frequent and serious brain disease, with relapse alternating with abstinence periods. Epidemiological studies show that abstinence, notably from opiates, is strongly associated with depression.Here we present the main clinical aspects of opiate addiction and depression, and most recent advances in molecular pathophysiology of both disorders. Then, we present our mouse model of opiate abstinence. Following chronic morphine exposure, depressive-like behaviours progressively emerge. Morphine treatment profoundly disrupts serotonergic signalling, notably in the dorsal raphe nucleus. In addition, behavioural deficits can be prevented by chronic treatment with fluoxetine, an antidepressant targeting serotonergic neurons. We then generalized our mouse model to heroin, another major illicit opiate. Using constitutive and conditional knockout strategies, we documented distinct roles for all 3 opioid receptors (mu, delta and kappa) in heroin abstinence. Finally, we initiated a large-scale analysis of transcriptomic regulations (mRNA and micro-RNA) occurring in our model as a function of heroin abstinence and fluoxetine treatment.These studies should reveal an unforeseen contribution of the dorsal raphe nucleus to addiction. They should uncover new molecular mechanisms underlying depressive-like behaviors in mice during opiate abstinence and thus put forward new therapeutic targets in humans.

No description available.