Adolescent male Sprague-Dawley rats were either exposed to the synthetic cannabinoid WIN 55,212-2 (WIN) prior to cocaine administration or not. Skipped exon (SE) events were evaluated. Gene expression was evaluated via RNA-seq. Data available at GEO with accession number GSE134935. Data taken from Supplementary Dataset S3. Values presented are p-values.
rat WIN vs cont SE
Maria Scherma, Johanna S Qvist, Arun Asok, Shao-Shan C Huang, Paolo Masia, Matteo Deidda, Ya B Wei, Rajesh K Soni, Walter Fratta, Paola Fadda, Eric R Kandel, Denise B Kandel, Philippe A Melas
Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine.
Proceedings of the National Academy of Sciences of the United States of America
Vol 117, pp. 9991-10002
The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain's initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as
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