Post-traumatic stress disorder (PTSD) is a debilitating stress-related psychiatric disorder that can develop following trauma exposure in some individuals. Among others, it is characterized by a dysregulated hypothalamic – pituitary – adrenal axis, which is predominantly regulated by the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The neurobiological processes leading to disease remain largely unknown. In vitro models are promising tools to investigate specific neurobiological underpinnings of the stress response in the brain. Here, we investigated the suitability of SH-SY5Y-derived neurons as a cost-efficient model to study the role of the GR and MR in neurons. Through different experiments, in which cells were characterized and exposed to different types of corticosteroids, we show that (i) these cells express sufficient and seemingly functional GR and MR to be relevant for stress modelling, (ii) different doses of cortisol induce distinct transcriptomic effects, (iii) the three corticosteroids cortisol, dexamethasone, and aldosterone induced similar transcriptomic effects. Surprisingly, adding the antagonists mifepristone and spironolactone did not affect the effects of dexamethasone and aldosterone, and (iv) the transcriptomic effects of dexamethasone were attenuated after repeated exposures. In sum, the SH-SY5Y-derived neurons may serve as a simplistic tool to study basic stress networks around the MR and GR. This cell culture model might be a promising tool to improve our understanding of stress related disorders such as PTSD at a molecular level.