19 General introduction 1 PATHOPHYSIOLOGY OF NEUROBEHAVIORAL SIDE EFFECTS The proposed pathophysiology behind neurobehavioral side effects of glucocorticoids commences in the brain, where both the GR and MR are present. Both receptors are expressed in different areas of the brain: the MR is mostly present in limbic areas whereas the GR is present in nearly every brain region.62,63 Because dexamethasone, through negative feedback on the HPA axis, suppresses the endogenous production of cortisol which has a high affinity for the MR, an imbalance between activation of the GR and MR occurs during high dose dexamethasone treatment.62,64 Dexamethasone-induced neurobehavioral problems may be due to overactivation of the GR, underactivation of the MR or an imbalance between activation of both receptors.65 Still, in animals as well as humans, it has been shown that the MR plays an important role in behavior and cognition. For instance, in MR knockout mice, an increased anxiety behavior has been observed due to the absence of functional MR.66 Conversely, overexpression of MR in the brain of mice resulted in decreased anxiety.67,68 In healthy humans, treatment with the MR antagonist spironolactone has been associated with impaired attention, memory and sleep.69,70 Furthermore, in patients with psychiatric disorders such as depression, schizophrenia or bipolar disorder, a decreased expression of MR in parts of the brain has been established.71,72 In contrast, treatment with MR agonist fludrocortisone showed a beneficial effect as add-on to standard depression treatment.73 The MR therefore may play an important role in the development of dexamethasone-induced neurobehavioral problems.
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