Regulation on the metabolic synaptic pathway in the dorsal raphe nucleus in a rat model chronic olanzapine-induced body weight gain

Objective To explore the proteomic difference and mechanism in the dorsal raphe nucleus (DRN) of rats with body weight gain induced by long-term olanzapine administration. Methods Thirty-six female Sprague-Dawley rats were randomly divided into two groups: an olanzapine treatment group (2.4 mg/(kg·d) and a vehicle control group (0.5% sodium carboxymethyl cellulose). Both treatments were administrated via drinking water for 24 continuous weeks. On the last day of 24th week, DRN samples were collected for proteomic analysis, quantitative real-time reverse transcription polymerase chain reaction (qPCR), Western blot (WB) analysis and bioassays. Differentially expressed proteins related to olanzapine treatment were subjected to bioinformatics analysis. Target genes were selected based on proteomic data for validation using qPCR and WB. Oxidative stress and inflammatory reaction were performed. Results Body weight gain in the olanzapine group was significantly higher than in the control group starting from the week 18, exceeding 10% by week 24. Proteomic analysis identified 156 upregulated and 37 downregulated proteins in the DRN of the olanzapine-treated rats compared to the controls. KEGG analysis enriched these differentially expressed proteins into serotonergic, glutamatergic, and GABAergic synapses, alongside calcium signaling pathways related to olanzapine treatment. Protein-protein interaction (PPI) network analysis indicated that several olanzapine-associated differentially expressed proteins, including Ddc, Gchfr, Chrnb2, Tph2, Gad1, Grm1, Slc17a7, Gabra2, Gabra4, Gng3, Gng13, and Gnb4, were closely correlated to metabolic disorders. qPCR and WB confirmed that Tph2, the rate-limiting enzyme for 5-HT biosynthesis were significantly downregulated in the DRN of the olanzapine-treated rats ( p < 0.01) compared to the controls; Furthermore, both the mRNA and protein expression levels of key genes within the glutamatergic synaptic ( Grm1, Slc17a7 ), the GABAergic ( Gabbr2, Gng3 ), and the calcium signaling ( Ryr3, ITPR1 ) pathways were significantly upregulated ( p < 0.05). Elevated levels of reactive oxygen species (ROS), malondialdehyde (MDA), and interleukin-1 beta (IL-1β) in the DRN indicate that chronic olanzapine treatment induces oxidative stress and an inflammatory reaction. Conclusion Long-term olanzapine treatment induces significant body weight gain in female rats. This metabolic dysregulation is associated with alterations in multiple central pathways within the DRN, including the 5-HT synaptic signaling pathway.