| Popis: |
Cocaine use presents a worldwide public health problem with high socioeconomic cost. Current treatments for cocaine use disorder (CUD) are suboptimal and rely primarily on behavioral interventions. To explore pharmaceutical treatments for CUD, we analyzed genome-wide gene expression data from publically availble human brain tissues (midbrain, hippocampus and prefrontal cortex neurons) from 71 individuals (mean age = 39.9, 100% male, 36 with CUD and 35 matched controls). We leveraged the L1000 database to investigate molecular associations between neuronal mRNA profiles from 825 repurposable compounds (e.g., FDA approved) with human CUD gene expression in the brain. We identified 16 compounds that were negatively associated with CUD gene expression patterns across all brain regions (padj < 0.05), all of which outperformed current targets undergoing clinical trials for CUD (all padj > 0.05). We tested the effectiveness of these compounds using independent transcriptome-wide in vitro (neuronal cocaine exposure; n=18) and in vivo (mouse cocaine self-administration; prefrontal cortex, hippocampus and midbrain; n = 12-15) datasets. Among these medications, Ibrutinib demonstrated negative associations with both neuronal cocaine exposure and mouse cocaine self-administration. To obtain experimental confirmation of therapeutic effects of Ibrutinib on CUD, we used the Drosophila melanogaster model, which enables highthroughput quantification of behavioral responses in defined genetic backgrounds and controlled environmental conditions. Ibrutinib altered cocaine-induced changes in startle response and reduced the occurrence of cocaine-induced seizures (n = 61-142 per group; sex: 51%female). Our results identify Ibrutinib, an FDA approved medication, as a potential therapeutic for cocaine neurotoxicity. |
