Aripiprazole alleviates the high prolactin levels induced by amisulpride via distinct molecular mechanisms: a network pharmacology and molecular docking study.

BACKGROUND

Amisulpride, a unique atypical antipsychotic, significantly increases prolactin secretion during schizophrenia treatment, resulting in adverse effects that reduce patient quality of life and treatment adherence. Aripiprazole, a partial dopamine D2 receptor agonist, reduces prolactin elevation induced by antipsychotic drugs used for schizophrenia treatment. The molecular targets and mechanisms underlying the contrasting effects of these two drugs on prolactin regulation are unclear. The objective of this study was to systematically explore the molecular mechanisms of prolactin regulation by aripiprazole and amisulpride using network pharmacology and molecular docking techniques.

METHODS

Relevant targets of amisulpride and aripiprazole and for schizophrenia and elevated prolactin treatment were obtained from online databases and screened for significance. A protein-protein interaction network was constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of the core targets were performed to identify key biological processes and signaling pathways, and a target-pathway-drug integrated network was established. The binding affinities of amisulpride and aripiprazole with core targets were predicted using molecular docking analyses.

RESULTS

Screening and matching drug and disease targets combined with GO and KEGG pathway enrichment analyses revealed several key signaling pathways involved in prolactin regulation, including MAPK, PI3K/AKT, and dopamine receptor pathways. The core targets of aripiprazole include MAPK3, PPARG, DRD2, and ESR1, and amisulpride primarily targets MMP9, CDC42, mTOR, and AKT1. Molecular docking analysis demonstrated that aripiprazole and amisulpride have high binding affinities for their respective targets, supporting the hypothesis that these drugs regulate prolactin levels through target-ligand interactions.

CONCLUSION

These findings highlight the distinct signaling pathways and molecular networks involved in prolactin regulation by aripiprazole and amisulpride and provide new insights into the mechanisms of these drugs in schizophrenia treatment. Further pharmacological and clinical research is needed to validate the complex regulatory networks and in vivo effects.