Escitalopram Oxalate Improved Insomnia by Targeting SLC6A4 to Regulate the Hypothalamic-Pituitary-Adrenal Axis

INTRODUCTION: Escitalopram oxalate (ESC) was extensively reported to improve insomnia in patients with depression/anxiety. The serotonin transporter gene (SLC6A4) was involved in regulating insomnia. However, it is still unclear whether ESC improves insomnia by regulating SLC6A4 expression. Therefore, this study aimed to investigate whether ESC improves insomnia by regulating SLC6A4 based on clinical and animal experiments. METHODS: scale were used to evaluate patients' sleep quality, anxiety, and depression. For animal experiments, after all 18 ICR male mice were randomly divided into three groups (n = 6), the sodium pentobarbital-induced sleeping test, locomotor activity test, elevated plus maze, and open field test were used to evaluate mice's sleep quality and anxiety- and depression-like behaviors. The H&E staining was used to determine pathological injuries in mice's hippocampal tissues. The ELISA kits were adopted to detect the 5-HT, norepinephrine (NE), gamma-aminobutyric acid (GABA), and glutamate (Glu) levels in the hypothalamus tissue and the corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (CORT) levels in the serum. The PubChem, DrugBank, and Therapeutic Target Database were employed to predict the potential targets of ESC. The immunohistochemical staining and Western blot were applied to assay the SLC6A4, 5-HTR1A, and 5-HTR2A expression levels in the hippocampal tissues of mice. RESULTS: ESC shortened the sleep latency, extended the sleep time, enhanced the sleep efficiency, and improved anxiety and depression in patients and mice. ESC mitigated the pathological injuries in mice's hippocampal tissues. ESC effectively regulated mice's neurotransmitter levels and hypothalamic-pituitary-adrenal (HPA) axis homeostasis, including upregulating 5-HT and GABA and downregulating NE, Glu, CRH, ACTH, and CORT. Moreover, SLC6A4 was predicted as the potential target of ESC. ESC prominently inhibited SLC6A4 expression (p < 0.001) and regulated 5-HTR1A and 5-HTR2A expression (p < 0.001) in hippocampal tissues. CONCLUSION: Taken together, ESC was suitable for treating insomnia in the clinic and improved insomnia by targeting SLC6A4 to regulate the HPA axis in mice.