MR blockade
Blocking the MR impairs certain forms of memory retrieval, including verbal, autobiographic, and visuo-spatial memory (Otte et al. , 2007; Rimmele et al. , 2013; Young et al. , 2016). This highlights the role of MR specifically in hippocampal-based memory. In contrast, MR blockade did not affect learning and immediate memory retrieval or working memory (Otte et al. , 2007; Cornelisse, Joels and Smeets, 2011; Young et al. , 2016). Non-hippocampal cognitive processes, such as selective attention and psychomotor speed, were also unaffected by spironolactone (Otte et al. , 2007; Cornelisse, Joels and Smeets, 2011). Thus, intact hippocampal MR activation appears important for optimal human memory regulation. However, MR blockade increases cortisol concentrations, potentially shifting MR/GR balance towards more GR activation, and so GR involvement must still be considered in these effects.
Another line of research investigated the role of MR after psychosocial stress. Interestingly, spironolactone treatment prevented stress-induced cortisol effects on response inhibition, stimulus-response learning and delay conditioning Vogel et al. , 2016, 2017), including cognitive function beyond hippocampus-dependent processes. On a neuronal level, stress is associated with a reduced activation of the hippocampus, enhanced amygdala activation and amygdala-striatal connectivity, which were found to depend on MR availability (Vogel et al. , 2016, 2017). These studies emphazise the importance of amygdalae MR, in line with the observation that MR blockade was most effective for emotional stimuli (Rimmele et al. , 2013).
In sum, MR blockade has mostly impairing effects on human cognition, which fits closely to the animal data. Of note, the observed effects reflect a one-time administration of a MR antagonist, while the effects of chronic or repeated MR blockade are less well investigated. Importantly, one study treated obese individuals with low-dose spironolactone over 6 weeks and found improved rather than impaired learning performance (Rotenstein et al. , 2015). This may be relevant to situations like obesity, which is associated with increased MR activity in peripheral tissues and possibly in central tissues as well (Infante et al. , 2017).