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Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The overall goal of this dissertation was to determine the role of the subthalamic nucleus (STN) in regulating the release of dopamine in the substantia nigra (SN). Experiments first established the existence of a direct connection between subthalamic neurons and SN dopaminergic cells. Further experiments showed that this connection triggers the dopamine release in the SN, and the mechanisms involved in this release were determined. Whole-cell current clamp recordings were performed in parasagittal brain slices obtained from 10 to 16 day-old rat pups. Electrical stimulations of the STN reliably triggered excitatory post-synaptic potentials (EPSPs) in dopaminergic neurons of the SN pars compacta (SNc). Pharmacological experiments with specific receptor antagonists indicated that this EPSP was mediated by NMDA, non-NMDA and metabotropic glutamate receptors. Stimulations of the subthalamic input triggered the release of dopamine. In a subset of neurons in the SN pars reticulata (SNr), repetitive stimulations of the STN produced a summating EPSP that was followed by an inhibitory postsynaptic potential (IPSP). A D2 receptor antagonist blocked this IPSP suggesting that it represents the D2 receptor-mediated response of the recorded cell to dopamine released upon stimulation of the STN. Pharmacological experiments using this assay indicated that NMDA, non-NMDA or metabotropic glutamate receptors were individually not required for dendritic release of dopamine; however, each contributed to this release. In dopaminergic neurons located in the SN pars compacta, the inhibitory effect of dopamine was revealed following block of L-type Ca channels, NMDA and non-NMDA glutamate receptors. These results indicated that dopaminergic neurons located both in the SNc and SNr respond to the dendritic release of dopamine triggered upon stimulations of the STN. Finally, a specific blocker of the dopamine transporter (GBR12935) blocked the IPSP reversibly in both SNr and SNc dopaminergic neurons. If release occurred by exocytosis, block of the transporter should increase extracellular levels of dopamine and produce an increase in the size of the recorded IPSP. Therefore, these results suggest that dopamine dendritic release triggered by activation of the subthalamic input was mediated by reversed transport of dopamine rather than by exocytosis. / 2999-01-01

Cocaine use has contributed to 5 million individuals falling into the cycle of addiction. Prior research in cocaine dependence mainly focused on rewards. Losses also play a critical role in cocaine dependence as dependent individuals fail to avoid social, health, and economic losses even when they acknowledge them. However, dependent individuals are extremely adept at escaping negative states like withdrawal. To further understand whether cocaine use may contribute to dysfunctions in aversive learning, this paper uses fMRI and an aversive learning task to examine cocaine dependent individuals abstinent from cocaine use (C-) and using as usual (C+). Specifically of interest is the neural signal representing actual loss compared to the expected loss, better known as prediction error (δ), which individuals use to update future expectations. When abstinent (C-), dependent individuals exhibited higher positive prediction error (δ+) signal in their striatum than when they were using as usual. Furthermore, their striatal δ+ signal enhancements from drug abstinence were predicted by higher positive learning rate (α+) enhancements. However, no relationships were found between drug abstinence enhancements to negative learning rates (α±-) and negative prediction error (δ-) striatal signals. Abstinent (C-) individuals' striatal δ+ signal was predicted by longer drug use history, signifying possible relief learning adaptations with time. Lastly, craving measures, especially the desire to use cocaine and positive effects of cocaine, also positively correlated with C- individuals' striatal δ+ signal. This suggests possible relief learning adaptations in response to higher craving and withdrawal symptoms. Taken together, enhanced striatal δ+ signal when abstinent and adaptations in relief learning provide evidence in supporting dependent individuals' lack of aversive learning ability while using as usual and enhanced relief learning ability for the purpose of avoiding negative situations such as withdrawal, suggesting a neurocomputational mechanism that pushes the dependent individual to maintains dependence. / Master of Science

Le facteur de transcription Nurrl est un récepteur nucléaire orphelin hautement impliqué dans le développement du système dopaminergique. Son expression persistante à l'âge adulte soulève toutefois de nombreuses questions quant à son rôle exact dans le cerveau mature. L'objectif de cette étude était d'évaluer les effets d'une diminution partielle du facteur de transcription Nurrl sur la transmission dopaminergique chez des souris adultes. Nous avons d'abord observé qu'une réduction partielle de Nurrl n'influence pas le comportement locomoteur des souris en conditions basales. Par contre, l'administration aiguë d'amphétamine chez les souris Nurrl (+/-) induit une brève augmentation de l'activité locomotrice précédant l'apparition marquée de mouvements verticaux et stéréotypés. La modulation de différents marqueurs tels que Nurrl, Nur77, Nor-1 et l'ENK fut également étudiée. De façon générale, nos résultats démontrent des modifications plus ou moins importantes de l'expression de ce neuropeptide et de ces récepteurs nucléaires en présence ou non du psychostimulant. Enfin, l'ensemble de ces résultats suggèrent qu'une réduction partielle de Nurrl induit des changements importants dans la transmission dopaminergique

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