Meso-limbic Gene Expression Findings from Mouse Cocaine Self-Administration Recapitulate Human Cocaine Use Disorder

Abstract

Animal models of drug use have been employed for over 100 years to facilitate the identification of mechanisms governing human substance use and addiction. Most cross-species research on drug use/addiction examines behavioral overlap, but studies assessing neuro-molecular correspondence are lacking. Our study utilized transcriptome-wide data from the hippocampus and ventral tegmental area (VTA)/midbrain from a total of 35 human males with cocaine use disorder/controls and 49 male C57BL/6J cocaine/saline administering/exposed mice. We hypothesized that individual genes (differential expression) and systems of co-expressed genes (gene networks) would demonstrate appreciable overlap across mouse cocaine self-administration and human cocaine use disorder. We found modest, but significant associations between differentially expressed genes associated with cocaine self-administration (short access) and cocaine use disorder within meso-limbic circuitry, but non-robust associations with mouse models of acute cocaine exposure, (cocaine) context re-exposure and cocaine + context re-exposure. Investigating systems of co-expressed genes, we also found several validated gene networks with weak to moderate conservation between cocaine/saline self-administering mice and disordered cocaine users/controls. The most conserved hippocampal and VTA gene networks demonstrated substantial overlap (2,029 common genes) and included novel and previously implicated targets of cocaine use/addiction. Lastly, we conducted expression-based phenome-wide association studies of the nine common hub genes across conserved gene networks and found that they were associated with dopamine/serotonin function, cocaine self-administration and other relevant mouse traits. Overall, our study identified and characterized homologous transcriptional effects between mouse models of cocaine self-administration and human cocaine use disorder that may serve as a benchmark for future research.