Ouabain induces the extinction of contextual fear memory in rats
subjected to chronic unpredictable stress.
Abstract
Ouabain (OUA) is an inhibitor of Na+, K+ -ATPase that has been
identified as an endogenous substance present in human plasma, and it
has been shown to be associated with the response to acute stress in
both animals and humans. Chronic stress is a major aggravating factor of
psychiatric disorders, including depression and anxiety. The present
work investigates the effects of OUA intermittent administration during
chronic unpredictable stress (CUS) protocol in the rat’s central nervous
system (CNS). Adult male Wistar rats were pretreated intraperitoneally
with ouabain (1.8 μg/kg), followed by CUS protocol for 14 days. The
levels of serum corticosterone, ACTH, and CRH serum were evaluated
through ELISA and the expression of CRH, CRHR1, and CRHR2 genes in the
hypothalamus and hippocampus of the animals through RT-PCR. Inflammatory
parameters were also investigated, as well as the behavioral CUS effects
on memory, that were assayed through the object recognition task,
contextual fear conditioning, and memory extinction paradigms. The
results suggest that intermittent OUA treatment reversed CUS-induced HPA
axis hyperactivity through the reduction of (i) glucocorticoids levels,
(ii) CRH-CRHR1 expression, and by decreasing neuroinflammation with the
reduction of iNOS activity, without interfering with the expression of
antioxidant enzymes. These changes in both the hypothalamus and
hippocampus may reflect in the rapid extinction of aversive memory. The
present data demonstrate, for the first time, the ability of OUA to
modulate the HPA axis as well as the disappearance of aversive memory in
rats.