[Antidepressant mechanism of essential oil from Schizonepeta tenuifolia based on 5-HT1AR/cAMP/PKA signaling pathway].

This study aims to investigate the antidepressant effects of essential oil from Schizonepeta tenuifolia and its mechanism of action on intervening the 5-hydroxytryptamine 1A receptor(5-HT1AR)/cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA) signaling pathway in the depression mouse models induced by chronic unpredictable mild stress( CUMS). The 5-HT1AR agonist 8-OH-DPAT(1. 5 mg·kg~(-1)) and 5-HT2A receptor agonist DOI(1 mg·kg~(-1)) were administered to induce 5-hydroxytryptamine(5-HT) syndrome-like behaviors in mice, and the effects of essential oil from S. tenuifolia on the 5-HT system were observed. CUMS depression mouse models were employed, and after six weeks of continuous modeling, mice were divided into the model group, the vortioxetine group(10 mg·kg~(-1)), and the low-dose and high-dose(50, 100 mg·kg~(-1)) essential oil from S. tenuifolia groups based on the sucrose preference test( SPT) results, with a blank group as control. Mice in each group received continuous intragastric administration for four weeks, with the modeling procedure continuing during the treatment period. After four weeks of administration, the SPT, tail suspension test( TST), forced swimming test( FST), and open field test( OFT) were conducted to evaluate antidepressant-like effects of the drugs. Nissl staining was employed to assess hippocampal neuronal damage in mice. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of tryptophan(Trp) and 5-HT in the serum and hippocampal tissue. Immunohistochemistry(IHC) was used to detect 5-HT1AR expression levels in the hippocampus. The RNA-Seq technique was used to analyze differentially expressed genes in the mice's hippocampus, and the potential action targets were analyzed via GO and KEGG enrichment analyses. Subsequently, RT-qPCR and Western blot were employed to detect m RNA and protein expression levels of key target molecules in the 5-HT1AR/cAMP/PKA signaling pathway in the hippocampal tissue. RESULTS:: show that essential oil from S. tenuifolia significantly increases the times of mice's body squats, tremors, and hindlimb abduction induced by 8-OH-DPAT and reduces DOI-induced count of head twitching episodes of mice. The sucrose preference rate and central zone residence time in the OFT of CUMS model mice were significantly increased. In contrast, the immobility time in the FST and TST was markedly shortened. After using the essential oil from S. tenuifolia, the number of Nissl bodies in the hippocampal CA3 and DG regions of CUMS model mice, as well as the levels of Trp in the serum and hippocampus and 5-HT in the hippocampus, were increased. In contrast, 5-HT1AR expression level in hippocampal CA3 and DG regions was upregulated. RNA-Seq detection results suggest that the antidepressant effects of essential oil from S. tenuifolia may be highly associated with the cAMP/PKA signal transduction pathway. Validation experiments demonstrate that essential oil from S. tenuifolia significantly upregulates the m RNA and protein expression levels of tryptophan hydroxylase 2(TPH2), 5-HT1AR, PKA, cAMP response element-binding protein( CREB), brain-derived neurotrophic factor(BDNF), tropomyosin receptor kinase B( TrkB), synaptophysin( SYP), and postsynaptic density protein 95(PSD95) in the hippocampus, the cAMP protein level was also increased. In summary, essential oil from S. tenuifolia exerts antidepressant effects by activating the 5-HT1AR/cAMP/PKA signaling pathway in the hippocampus of CUMS-induced depressive-like model mice, thereby influencing 5-HT system function and elevating central 5-HT concentrations.