Considerations
Pharmacological MR manipulation comes with some considerations. Fludrocortisone binds to some extent to the GR (Agarwal, Coupry and Philippe, 1977; Grossmann et al. , 2004). Furthermore, fludrocortisone administration reduces cortisol release (Nowacki, Wingenfeld, Kaczmarczyk, Chae, Abu-Tir, et al. , 2020), highlighting MR function in HPA axis feedback regulation, but complicating interpretation, given potential consequences for GR. Fludrocortisone also activates aldosterone-selective MR in the NTS, although, no effects were found on blood pressure (Otte, Wingenfeld, Kuehl, Richter, et al. , 2015; Wingenfeld et al. , 2015) or aldosterone release (Nowacki, Wingenfeld, Kaczmarczyk, Chae, Salchow,et al. , 2020). Spironolactone is known to have effects on PR and progesterone acts as an MR antagonist (Quinkler and Diederich, 2002; Struthers, Krum and Williams, 2008). Therefore, sex specific effects on MR function and cognition must be considered in future studies. Although some studies report none (Piber et al. , 2016; Deuter et al. , 2017), the consequence of genetic MR haplotypes did depend on sex (M D Klok et al. , 2011; Wirz et al. , 2017). Notably, age related differences were reported in fludrocortisone effects in major depressive disorder (MDD) patients (see below (Otte, Wingenfeld, Kuehl, Kaczmarczyk, et al. , 2015; Otte, Wingenfeld, Kuehl, Richter,et al. , 2015)) compared to controls (Hinkelmann et al. , 2015).
Overall, increasing evidence strongly suggest MR function as essential for cognitive and emotional function. These MR mediated effects seem to be moderated by age, sex, and potentially other variables. Thus, further research into MR effects is not only warranted in healthy humans but also in patients with stress-related mental disorders who often show alterations in cognitive and emotional function.