Abstract
SSRI antidepressant fluoxetine is widely used to treat psychological stress related disorders, however the underlying working mechanisms is not fully understood, as SSRIs can rapidly increase the extracellular serotonin levels but it normally takes weeks to reveal their therapeutic effect in the stress-related psychological disorders. Our previous study demonstrated that purely psychological stress without any physic stimuli induces a biphasic change in the expression of brain-derived neurotrophic factor (BDNF), which immediately decrease and then gradually increase after the stress; and that the latter BDNF increase in response to the psychological stress involves the activation of serotonin system. To investigate the role of BDNF in the fluoxetine treatment for stress-related psychological disorders, we examined the mRNA and protein levels of BDNF in the brain of Sprague-Dawley (SD) rats, which were pretreated with fluoxetine at 10 mg/kg or vehicle solution for 14 days, over 24 hour after an acute psychological stress exposure. In situ hybridization and immunohistochemistry were performed to detect the expression of BDNF at different time points in various brain regions after the psychological stress. We found that fluoxetine treatment completely blocked the BDNF decrease induced by the psychological stress, and also enhanced the gradual increase in the expression of BDNF in most of the brain regions except VTA after the psychological stress. The results suggest that the enhancement in BDNF levels induced by chronic fluoxetine treatment mediates the therapeutic effect against psychological stress.
Highlights
Acute and chronic psychological stress can provoke life-threatening diseases, such as depression and post-traumatic stress disorder [1]
To investigate the regulation of brain-derived neurotrophic factor (BDNF) mRNA in three animal groups respectively receiving: 1) non psychological stress but pre-treated with vehicle control (CON) for 14 days; 2) psychological stress (PS); and 3) psychological stress and pre-treated with fluoxetine at 10 mg/kg for 14 days (FPS), we analyzed the mRNA expression of BDNF by using in situ hybridization (ISH) with bdnf oligo-probe in various brain regions, which included hippocampus brain regions of CA1 and CA3, dentate gyrus (DG), prefrontal cortex (PFC), shell of nucleus accumbens (NAc), central amygdaloid nuclei (AG), midbrain periaqueductal gray (PAG), dorsomedial hypothalamic nucleus (DM) and ventral tegmental area (VTA) over 24 hours after the stress exposure (Figure 1)
This result means that psychological stress in communication box (CB) paradigm induced a biphasic change of BDNF mRNA: an immediate decrease followed by a gradual increase last for at least 24 hours, which is in accordance with our previous observation [20]
Summary
Acute and chronic psychological stress can provoke life-threatening diseases, such as depression and post-traumatic stress disorder [1]. Neurotrophic factors were shown to be important mediators of stress responses, Brain Derived Neurotrophic Factor (BDNF) in particular [7,8,9]. They can protect the organism from stress-induced aversive processes leading to diseases by preventing neuronal damage and facilitating neuronal growth as well as the neuroplasticity for memory formation. The stress models used in most of these studies with adult animals involved physical meddling of the animals, such as body restrain or electric foot shock These models can hardly represent purely psychological stress, which are more relevant in human societies. Serotonin and BDNF interact at multiple levels in the brain with strict temporal, 5-HT receptor subtype and spatial specificities [26]
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