نبذة مختصرة : Addiction is a multifactorial neuropsychiatric disorder marked by compulsive drug-seeking behaviors despite adverse consequences. Neuroplasticity, the ability of the brain to adapt and reorganize, plays a crucial role in addiction, involving changes in gene expression, protein modifications, and synaptic organization. Alterations in redox homeostasis, particularly dysregulation of reactive oxygen species (ROS) signaling, are implicated in these neuroplastic changes. Drosophila melanogaster, with its well-characterized genome and genetic tools, serves as a valuable model for studying addiction-like behaviors such as drug self-administration (SA) and locomotor sensitization (LS). This research aims to identify genes and proteins involved in methamphetamine (METH) addiction using flies and approach integrating behavioral assays, genetic manipulations (selective breeding and genetic screening), and proteomic analyses. We developed the FlyCafe assay to measure METH consumption and demonstrated flies' preferential SA of METH. Through 30 generations of selective breeding, we established fly strains with high (HP) and low (LP) preferences for METH, revealing distinct phenotypic profile of LP flies, including increased activity and body weight, decreased sleep and negative geotaxis and increased dopamine, tyramine and glutamate relative to HP flies. Proteomic analysis of these strains identified differential proteins linked to metabolic processes, structural integrity, and protein turnover, including Bacchus, negative regulator of conversion of tyramine to octopamine, which was uniquely present in LP flies. Next, we showed that flies exhibiting LS displayed reduced preference for METH SA, and vice versa, suggesting shared molecular mechanisms through the period gene. We conducted a genetic screen to identify redox-related genes that regulate LS to volatilized METH (vMETH), uncovering several critical genes such as Cat, Sod1, Sod2, Gapdh1, and Men, which play functional roles in the regulation of LS. Remarkably, Sod1, ...
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