This study investigates the association of
ischemia-induced spatial memory impairment to alterations of the HPA axis and noradrenergic activation post insult. Experiment 1 characterized the effects of 10 min forebrain
ischemia on
corticosterone (CORT) secretion following
ischemia and in response to spatial memory assessment in the Barnes maze, as well as the impact of pre-
ischemia treatment with the
glucocorticoid inhibitor
metyrapone (175 mg/kg; s.c.). The results showed that
cerebral ischemia represents a significant physiological stressor that upregulated CORT secretion 1, 24 and 72 h post-
ischemia but not at 7 days. In response to testing in the Barnes maze ischemic animals showed elevated CORT secretion simultaneously with spatial memory deficits. The single dose of
metyrapone attenuated the
ischemia-induced adrenocortical hyper-responsiveness and subsequent
memory deficits despite not providing neuroprotection in the hippocampal CA1 pyramidal cells. To
complement these findings, we examined whether
norepinephrine which provides positive feedback to the HPA axis and is upregulated following
brain ischemia could influence memory performance at delayed intervals after
ischemia. Experiment 2 demonstrated that pre-testing administration of the alpha2-adrenoceptor agonist
clonidine (.04 mg/kg, s.c.) attenuated
ischemia-induced working memory impairments in a radial maze while opposite effects were obtained with the antagonist
yohimbine (.3 mg/kg, s.c.). Post-testing administration of
clonidine produced spatial reference memory impairments in ischemic rats. The findings from the current study demonstrate increased sensitization and responsiveness of systems regulating stress
hormones at long intervals post
ischemia. Importantly, we demonstrate that these effects contribute to post ischemic
cognitive impairments which can be attenuated pharmacologically even in the presence of hippocampal degeneration at time of testing.