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Modification de l'expression de gènes impliqués dans le métabolisme cérébral du cholestérol par l'exposition à l'alcool et à la cocaïne

Abstract : Drug addiction is a chronic brain disease characterized by drug-seeking and compulsive drug taking, a loss of control over drug taking despite the negative consequences and the emergence of a negative emotional state in the absence of the drug. Addiction involves persistent neuroadaptations at the cerebral level. Recent evidences show that cholesterol plays a crucial role in brain function by participating in various cellular processes in particular in the control of neurotransmission. The aim of this thesis was to investigate the potential role of cholesterol in addiction and in particular a potential dysregulation of cholesterol metabolism in response to drugs of abuse. In this work, we investigated the expression of genes encoding proteins involved in the metabolism of cerebral cholesterol after a chronic voluntary consumption of alcohol from the rats and after acute or chronic exposure to cocaine. We analyzed gene expression in brain structures involved in addiction such as the prefrontal cortex, the nucleus accumbens, the amygdala and the hippocampus. We found that exposure to alcohol and cocaine modifies the expression of proteins involved in the synthesis, the transport and the degradation of cholesterol in drug-specific, treatment- specific (acute / chronic) and region-specific manners. In the second part of the thesis, we used a viral approach to overexpress CYP46A1, the cerebral cholesterol degradation enzyme in the prefrontal cortex, in order to evaluate the impact of this overexpression on cocaine-seeking in a model of relapse. The overexpression of CYP in this structure has no effect on drug-seeking for cocaine. Future studies are needed to determine whether altering cholesterol metabolism in other structures, for example the nucleus accumbens, may have beneficial effects on relapse. Altogether these studies show that exposure to drugs of abuse might modulate cerebral metabolism of cholesterol. This thesis project opens new perspectives on the role of cholesterol cerebral metabolism in addiction which may ultimately result in new therapeutic avenues for the treatment of this costly psychiatric disorder.
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Josette Alsebaaly. Modification de l'expression de gènes impliqués dans le métabolisme cérébral du cholestérol par l'exposition à l'alcool et à la cocaïne. Médecine humaine et pathologie. Université de Poitiers; Université Saint-Joseph (Beyrouth), 2019. Français. ⟨NNT : 2019POIT2263⟩. ⟨tel-02460782⟩

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