Chronic administration of isotretinoin induces depressive- and anxiety-like behaviors by altering the neuroactive ligand-receptor interaction pathway in adolescent mice

Clinical case reports have linked isotretinoin to depressive symptoms. As acne incidence peaks in adolescence, we focused on adolescent exposure. However, prior studies on isotretinoin's effects in adolescents have yielded inconsistent results, and direct mechanistic evidence remains scarce. Here, we analyzed depressive-like behaviors in adolescent mice treated with isotretinoin. Pathological changes in the prefrontal cortex and hippocampus of isotretinoin-treated mice were observed. We characterized the metabolic and gene-expression signatures of the hippocampus and prefrontal cortex in isotretinoin-treated mice using RNA sequencing and untargeted metabolomics. The results show that isotretinoin induced depressive- and anxiety-like behaviors and caused significant pathological changes in the hippocampus and prefrontal cortex. In the prefrontal cortex, two differentially expressed genes (Nmb and Pmch) within the neuroactive ligand-receptor interaction pathway correlated positively with depressive-like behaviors; in the hippocampus, two genes (Pomc and Gh) within the same pathway correlated with anxiety-like behaviors. Six differential metabolites associated with the neuroactive ligand-receptor interaction pathway - Adenosine (hippocampus); Tyramine, Taurine, N-acetylaspartylglutamic Acid (NAAG), and ADP (prefrontal cortex); and Taurine (serum) - were associated with depressive-like behaviors. Taurine in the prefrontal cortex was also associated with anxiety-like behaviors. Finally, we reanalyzed metabolomics data from depressed patients to determine whether plasma Taurine levels are elevated. Our findings clarified the biological mechanisms underlying isotretinoin-induced depression and highlighted the neuroactive ligand-receptor interaction pathway, especially four genes (Nmb and Pmch in the prefrontal cortex; Pomc and Gh in the hippocampus) and one metabolite (Taurine in the prefrontal cortex) as potential targets for mitigating isotretinoin-induced depression and anxiety.