Abstract
Background: Early adverse life stress is an important dangerous factor in the development of psychiatric disorders, particularly depression. Available clinical antidepressant agents, such as fluoxetine, [a selective serotonin reuptake inhibitor (SSRI)], are unsatisfactory because of their side effects. SiNiSan (SNS) is a classic Chinese medicine prescription regarded to disperse stagnated liver qi to relieve qi stagnation. Therefore, this study was designed to detect the effects and molecular mechanism of SNS treatment in rats subjected to maternal separation (MS).Method: Male neonatal Wistar rats were divided into six groups including control + ddH2O, MS + ddH2O, MS + fluoxetine (5 g/kg), MS + SNS -low dose (2.5 g/kg), MS + SNS -medium dose (5 g/kg), MS + SNS -high dose (10 g/kg). The volume of drugs and ddH2O in each group are according to the weight of rats every day (10 mL/kg). Each group comprised 16 pups with 8 young and 8 adult pups. Except for the control group, all MS groups were separated from their mothers for 4 h/day from 9:00 to 13:00 during postnatal days (PNDs) 1 to 21. After MS, the six groups were intragastrically administered with ddH2O, fluoxetine, and different doses of SNS until PND 28 (for young pups) and PND 56 (for adult pups). The pups were weighed every day, and depression-like behavior was assessed by sucrose preference test, open field test, and forced swimming test. Serotonin 1A (5-HT1A) receptor, phosphorylated protein kinase A (p-PKA) substrate, cAMP response element-binding protein (CREB), p-CREB and brain-derived neurotrophic factor (BDNF) in the hippocampus were examined by Western blot, and in situ 5-HT1A receptor expression was measured by IHC.Results: Young and adult MS rats exhibited depression-like behavior. However, the depression-like behavior was ameliorated by SNS in both age groups. The levels of 5-HT1A receptor, p-CREB, and BDNF in the hippocampus were reduced in young and adult MS rats. SNS treatment significantly up-regulated the expression of 5-HT1A receptor, p-CREB, and BDNF in the hippocampus of adult MS rats. However, few significant effects on the protein expression were observed in the young MS rats.Conclusion: MS in infancy could develop depression-like behavior in young and adult. SNS treatment may perform antidepressant effects on young and adult MS rats through the BDNF/PKA/CREB pathway.
Highlights
Adverse stress in early life is an important dangerous factor for suffering from many types of mental disease, such as depression, posttraumatic stress disorder, and schizophrenia
We explored the effect of SiNiSan treatment on young and adult Wistar rats maternally separated during early development by behavioral tests and expression detection of several relative proteins in the 5-HT1A receptor/CREB/BDNF signaling pathway
We found that 5-HT1A receptor, phosphor-CREB, and BDNF expression were significantly downregulated by postnatal Maternal separation (MS) in adult rats, and the expression of CREB and pPKA substrate was reduced only with downtrend compared with the nonMS group, as shown by Western blot (WB) analysis
Summary
Adverse stress in early life is an important dangerous factor for suffering from many types of mental disease, such as depression, posttraumatic stress disorder, and schizophrenia. Several reports have shown that adversity in early life is closely related to the occurrence and development of depression, which is likely to be accompanied with impulsive, suicidal, and selfinjurious behavior [1, 2]. MS may affect the development and neuroplasticity in the hippocampus of rats [7] These results indicate that the emotions and behavior of individuals could be significantly affected by postnatal MS in the long term. Adverse life stress is an important dangerous factor in the development of psychiatric disorders, depression. This study was designed to detect the effects and molecular mechanism of SNS treatment in rats subjected to maternal separation (MS)
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