Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models

Cocaine use disorder (CUD) is an intractable syndrome, and rising overdose death rates represent a significant public health crisis that exacts tremendous personal and financial costs on patients and society. Sharp increases in cocaine use drive the urgent need for better mechanistic insight into this chronic relapsing brain disorder that currently lacks effective treatment options. To investigate the transcriptomic changes involved, we conducted RNA sequencing on two striatal brain regions that are heavily implicated in CUD, the nucleus accumbens and caudate nucleus, from postmortem brains of subjects with CUD and matched control subjects. Weighted gene co-expression analyses identified CUD-specific gene networks enriched in ionotropic receptors and associated with lowered neuroinflammation, contrasting the proinflammatory responses found in opioid use disorder. Integration of comprehensive transcriptomic datasets from mouse cocaine self-administration models revealed evolutionarily conserved gene networks in CUD that implicate especially D1 medium spiny neurons as drivers of cocaine-induced plasticity. Overall design: We performed RNA sequencing (RNAseq) on both the ventral (NAc) and dorsal (CN) striatum from postmortem tissue of persons with CUD and matched control subjects. We combined differential gene expression and network-based approaches to provide an integrative and unbiased characterization of transcriptional signatures triggered by chronic cocaine use across the striatum. Our analyses revealed a profound overlap between CUD-specific transcriptome changes in the NAc and CN, introducing the downregulation of neuroinflammatory processes, and upregulation of synaptic transmembrane transporters and ionotropic receptors.