Do gene expression findings from mouse models of cocaine use recapitulate human cocaine use disorder in reward circuitry?

Abstract

Animal models of drug use have investigated possible mechanisms governing human substance use traits for over 100 years. Most cross‐species research on drug use/addiction examines behavioral overlap, but studies assessing neuromolecular (e.g. RNA) 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 differential expressed genes and systems of co‐expressed genes (gene networks) would show appreciable overlap across mouse cocaine self‐administration and human cocaine use disorder. We found modest, but significant relationships between differentially expressed genes associated with cocaine self‐administration (short access) and cocaine use disorder within reward circuitry. Differentially expressed genes underlying models of acute cocaine exposure (cocaine), context re‐exposure and cocaine + context re‐exposure were not consistently associated with human CUD across brain regions. Investigating systems of co‐expressed genes, we 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 (2029 common genes) and included both novel and previously implicated targets for cocaine use/addiction. Lastly, we conducted (expression‐based) phenome‐wide association studies of the nine common hub genes across conserved gene networks. Common hub genes were associated with dopamine/serotonin function, cocaine self‐administration and other relevant mouse traits. Overall, our study pinpointed and characterized conserved brain‐related RNA patterns across mouse cocaine self‐administration and human cocaine use disorder. We offer recommendations for future research and add to the dialogue surrounding pre‐clinical animal research for human disease.

Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine

“…However, equally interesting is the possibility that these two groups may achieve a similar behavioral phenotype through different mechanisms. For instance, the enrichment of dopaminergic synapse-related genes has been the major finding reported by previous studies, again largely performed in males (79,80). While our data confirm that dopaminergic pathway is shared across sex we still see important male-specific chromatin changes in genes encoding dopamine receptors, which are likely important for sex-specific cocaine-induced responses and could have not been anticipated by earlier, male-focused studies.…”

Genetics of substance use disorders: a review

“…Another issue is that there is no certain way to cross-map animal and human phenotypes, limiting the opportunities for translation. However, as a recent proof of principle, one study (Huggett, Bubier, Chesler, & Palmer, 2020 c ) found modest but significant overlap in differentially expressed genes and gene networks when comparing human CocUD case–control data with mice in a cocaine v. saline solution self-administration paradigm, suggesting commonalities in the reward circuitry of human CocUD and self-administration paradigms in rodents.…”

Molecular genetics of cocaine use disorders in humans

“…Convergent gene expression changes between animal and human studies have highlighted pathways and biological processes that may be relevant for CUD, including the ERK/MAPK signaling pathway, long-term potentiation, synaptic plasticity (synucleins), and mitochondrial function [103]. Other studies have used the data generated by the above-mentioned studies in humans to assess convergence of gene expression mechanisms with rodents, highlighting genes involved in dopamine and serotonin function such as SLC1A2, CALM3, ALDOA, ALDOC, and ENO2 [104] and in brain plasticity like APP, GRIN2A, GRIN2B, KCNA2, MAP4, PCDH10, PPP3CA, SNCB, and SV2C [105].…”