The infralimbic mineralocorticoid blockage prevents the stress-induced impairment of aversive memory extinction in rats

Individuals deal with adversity and return to a normal lifestyle when adversity ends. Nevertheless, in specific cases, traumas may be preceded by memory distortions in stress-related malaises, and memory extinction impairment is strictly associated with the symptoms of post-traumatic stress disorder. Glucocorticoids (GCs), the central stress mediator, target mineralocorticoid (MR) and glucocorticoid (GR) receptors and coordinate stress responses. Despite MRs being present in brain regions essential to cognition, emotions, and initial stress processing, such as the medial prefrontal cortex (mPFC), most studies attempt to elucidate the stress-induced deleterious actions of GCs via GR. Therefore, it is necessary to understand the relationship between stress, infralimbic mPFC (IL), and memory and how MR-mediated intracellular signaling influences this relationship and modulates memory extinction. We observed that acutely restraint-stressed male Wistar rats showed high corticosterone (CORT) levels, and previous intra-IL-spironolactone administration (a selective MR antagonist) decreased it 60 min after the stress started. Intra-IL-CORT118335, a novel mixed MR/GR selective modulator, increased CORT throughout stress exposure. Ten days after stress, all rats increased freezing in the memory retrieval test and acquired the aversive contextual memory. During the extinction test, intra-IL injection of spironolactone, but not CORT118335, prevented the stress-impaired memory extinction, suggesting that the IL-MR activity controls CORT concentration, and it is crucial to the establishment of late extinction impairment. Also, the concomitant GR full activation overrode MR blockage. It increased CORT levels leading to the stress-induced extinction memory impairment, reinforcing that the MR/GR balance is crucial to predicting stress-induced behavioral outcomes.