In the present study, behavioral, biochemical and molecular biological approaches were applied to investigate the preventive effects of taurine on CUMS-induced depression in late adolescent rats. We found that taurine pre-administration produced anti-depressant-like activity and prevented the dysregulation of hormones and neurotransmitters, while inhibited the up-regulation of neurotrophic factors. Depressive rats showed less sucrose intake in the SPT, reduced exploration ability and increased anxiety to the new environment in the OFT, as well as longer escape latency and moving distance in the MWM, which were similar to results from previous studies in both adults and adolescents receiving chronic stress16, 17. This finding suggests that a depressive rat model was successfully established in this study. Taurine pre-administered to CUMS rats could significantly inhibit the decrease of sucrose consumption, exploration ability, horizontal score and vertical score in the OFT, and number of platform crossings in the MWM, while hinder the increase of the moving distance and latency in the MWM, indicating an obvious preventive effect of taurine on the depression-like behavior. The results were similar to those from an experiment on young rats, in which taurine exerted important anti-anxiety effects18, and also in accordance with the results that taurine pretreatment prevented anesthetic isoflurane-induced cognitive impairment in rats19. We also found that taurine supplemented to control rats had no significant effects on behavior, which was in accordance with previous studies that added taurine to normal animals20. But Whirley et al. found neither antidepressant-like nor anxiolytic-like effects for taurine intraperitoneally injected for only 3 or 8 consecutive days in normal mice21, the differences of which may be attributed to two causes. First, the animals did not receive any stress and were all kept under normal conditions. In addition, the duration and dosages of taurine administration, which are essential to revealing the anti-depressant-like effect, were different from those in the present study. Our findings proved an antidepressant-like action of taurine in the classic depressive rat model induced by CUMS.

It has been demonstrated that stress-induced depression is closely associated with disorders of the neuroendocrine system, especially involves in the dysfunction of HPA axis. Clinical and animal experiments proved that chronic stress-induced depression is attributed to the attenuation and disruption of the CORT negative feedback system, which induce the accumulation of CORT in the hippocampus that further damage the structure and function of neurons in the hippocampus by injuring the nutrition unit, lowering the energy metabolism level of neurons, and increasing the vulnerability of neurons to damage, and finally lead to alterations in physiological responsiveness and behavior22, 23. During adolescence, which is an important time-point for brain development and active neuroplasticity, important neural pathways involved in stress regulation and HPA axis function are more vulnerable24. Studies have indicated an exaggerated and prolonged HPA axis response to stress in adolescents compared to that in adults25, and rats exposed to chronic stress during late adolescence are particularly sensitive to somatic and neuroendocrine disorder26, indicating that late adolescence may represent a time period of stress hypersensitivity. In the present study, the results that serum and hippocampal CORT in the rats of the CUMS group increased significantly were in accordance with previous studies. While both serum and hippocampal CORT were significantly lower in TI + M and TII + M groups, indicating that taurine pre-administration decreased the over secretion of CORT by regulating HPA under long-term stress, which was similar to the findings of our previous studies on hypertensive rats27. The present results on CORT illustrated that taurine could exert its preventive effects on the changes of memory and anxiety behaviors in un-treated rats exposed to CUMS partly through inhibiting neural damage caused by high concentrations of CORT both peripherally and in the hippocampus. However, pre-treatment of taurine at a dosage of 4–7 g/kg/d for only 3 days showed no effects on the blood level of CORT in cold stress rats28. The reason may be that in the present study we used different stresses, taurine doses and treatment strategies (i.p. 200 mg and 500 mg/kg/d for 35 days), which could better regulate HPA axis activity.

The “monoaminergic hypothesis” addresses the pathogenesis of depression by stating that depression is probably due to an absolute or relative deficiency in monoamine neurotransmitters including 5-HT, DA and NE29. The majority of data support a depletion and dysregultaion of 5-HT, DA and NE in the blood and brain of animals and patients in the back ground of depression. Mutation, reduction and knock out of the receptors of these neurotransmitters in the brain will result in changes in memory, anxiety and reward reaction30,31,32. Moreover, most clinical antidepressants are SSRIs and NE reuptake inhibitors (NRI), which were found to have effects on the treatment of depression in both adults and adolescents33, 34. 5-HT, DA and NE could be synthesized both in the periphery and in the brain, among which 5-HT is an intermediate product of tryptophan (Try) metabolism located primarily in peripheral and serotonergic neurons with profuse projections throughout the brain35. NE and DA could be synthesized by the adrenal medulla, sympathetic system in the periphery and neurons in the brain, with large numbers of noradrenergic and dopaminergic nerve fibers projecting to the hippocampus to release NE and DA for functions in memory, emotion and reward36. Thus, by detecting the levels of 5-HT, DA and NE, one could partly understand the function of the hippocampus. Other neurotransmitters related to depression are amino acid neurotransmitters, especially Glu, an excitatory amino acid. It has been reported that chronic stress and CORT release can increase the accumulation of Glu, which can open the Ca2+ channel by binding to N-methyl-D-aspartate receptor (NMDAR) and consequently causes an overload of calcium influx, inducing cytotoxic injury to neurons37. Meanwhile, the accumulation of Glu could in turn activate the HPA axis to secrete more GC, which would further strengthen the toxic effects of Glu in the hippocampus38. In the present study, neurotransmitters were detected by commercial ELISA kits, although the sensitivities of the kits for Glu, NE, 5-HT, DA were 1 mg/L, 1ng/ml, 1ng/ml and 1 pg/ml respectively, and the intra-assay coefficient of variation were all under 7%, this method was not a exact measurement, as the precursors and the analogues are difficult to be separated from the neurotransmitters, it is usually to get a higher value using ELISA. But because the main purpose of the present study was only to compare the concentrations among different groups, ELISA kits, as a convenient and easy operating method, is a good choice in this study. The results showed that rats in the CUMS group had lower levels of 5-HT, DA, NE, and a higher level of Glu in both the serum and hippocampus compared with rats in the normal control group, the changes of which were in accordance with the previous studies in depressive animal models and patients that decreased circulating or hippocampal levels of 5-HT, NE and DA were detected by ELISA, high-performance liquid chromatography (HPLC) and ultra-high-performance liquid chromatography-tandem mass-spectrometry (HPLC-MS), while Glu level was significantly increased, suggesting that CUMS has a significant effect of monoaminergic and glutamate neurotransmission in brain of rats39,40,41,42. Other in vitro research also found a significant increase in endogenous and K( + )-stimulated serotonin (5-HT) release in the hippocampal slices of depressive rats43. The changes in the neurotransmitters of rats exposed to CUMS were found to be significantly hindered by taurine pre-administration in the present study, the effects of which were similar to the clinical antidepressants that enhance the extracelluar 5-HT and the synaptic level of these neurotransmitters in the brain44, indicating that taurine may inhibit all the behavior disorders observed in un-treated rats exposed to CUMS by the directly regulation of these neurotransmitters. Further, since HPA hyperfunction could exacerbate the reduction in 5- HT, DA, NE, and the augmentation in Glu45, 46, taurine may also indirectly regulate 5- HT, DA, NE and Glu levels through its regulation of HPA activity. Additionally, because 5-HT, DA and NE takes effect in the hippocampus after combined to their receptors, their metabolites and receptors in the hippocampus should be investigated in future studies to illustrate the effects of taurine on the synthesis and secretion of these neurotransmitters.

Considerable evidence has demonstrated that peripheral increase in pro-inflammatory cytokines promoted by chronic stress can cause depression through transmitting immune-mediated signals from the periphery to the CNS47. Additionally, in the CNS, cytokines can also be generated by neural cells, microvessel endothelial cells, astrocytes, and microglia in the brain and can induce inflammatory responses affecting neurotransmitter systems to ultimately affect neurocircuits regulating motivation and increased anxiety behaviors relevant to depression48. In addition, cytokines can activate the HPA, promote the secretion of CORT and cause damage to neurons in the hippocampus. Our study found an elevation in the concentrations of IL-1β and TNF-α in both the periphery and hippocampus of depressive rats, while taurine pre-administration could slightly lower the levels of cytokines but without significant effects, suggesting that the alleviation effects of taurine on depression-like behavior in the present study were not through its anti-inflammation effects.

Evidence has shown that lacking neurotrophic factors is another pathogenesis of depression. It has been reported that BDNF, FGF-2 and VEGF, which are neurotrophic factor family members that regulate neural proliferation, neurogenesis, apoptosis, expression level of monoamine transmitters, and the function and plasticity of synapses, are closely associated with chronic stress-induced depression both in young adults and adults49, 50. It has been reported that under stress and depression conditions, the BDNF, FGF-2 and VEGF levels in the hippocampus decreased51, 52, while antidepressant treatment could increase the expression of these neurotrophic factors even to a normal range53,54,55. Meanwhile, depression and anxiety have also been reported to be reversed by BDNF and FGF-2 treatments56, 57. The present study observed that taurine pre-treatment significantly inhibited the decrease in the expressions of hippocampal BDNF, FGF-2 and VEGF of rats exposed to CUMS, suggesting that taurine may promote the survival, differentiation, growth and development of neurons in the hippocampus to further protect the neurons from injury and apoptosis through up-regulating BDNF, FGF-2 and VEGF. This result was similar to previous studies that taurine has been found to improve and regulate adult neurogenesis and neurotrophic protein phosphorylation and expression in the hippocampus58.

In conclusion, taurine pre-administered to CUMS rats could significantly inhibit the loss of anhedonia, learning ability and memory deficiency, prevent the increase of anxiety to the new environment, hinder the increase of CORT and disorders of neurotransmitters in both serum and hippocampus, prohibit the down-regulation of neurotrophic factors, indicating that taurine has anti-depressant effects and the mechanisms may involved in regulating the HPA function, promoting neurogenesis, cell proliferation, neuronal survival and growth in the hippocampus.