Alcohol withdrawal induces long-lasting spatial working memory impairments: relationship with changes in corticosterone response in the prefrontal cortex.
Addiction Biology. 2016-02-10; 22(4): 898-910
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This study intends to determine whether long-lasting glucocorticoids (GCs)
dysregulation in the prefrontal cortex (PFC) or the dorsal hippocampus (dHPC)
play a causal role in the maintenance of working memory (WM) deficits observed
after alcohol withdrawal. Here, we report that C57/BL6 male mice submitted to
6 months alcohol consumption (12 percent v/v) followed by 1 (1W) or 6 weeks (6W)
withdrawal periods exhibit WM deficits in a spatial alternation task and an
exaggerated corticosterone rise during and after memory testing in the PFC but
not the dHPC. In contrast, emotional reactivity evaluated in a plus-maze is
altered only in the 1W group. No behavioral alterations are observed in mice
still drinking alcohol. To determine the causal role of corticosterone in the
withdrawal-associated long-lasting WM deficits, we further show that a single
intraperitoneal injection injection of metyrapone (an inhibitor of corticosterone
synthesis) 30 minutes before testing, prevents withdrawal-associated WM deficits
and reestablishes PFC activity, as assessed by increased phosphorylated C-AMP
Response Element-binding protein (CREB) immunoreactivity in withdrawn mice.
Finally, we show that intra-PFC blockade of mineralocorticoid receptors by
infusion of spironolactone and, to a lesser extent, of GCs receptors by injection
of mifepristone reverses the WM deficits induced by withdrawal whereas the same
injections into the dHPC do not. Overall, our study evidences that long-lasting
GCs dysfunction selectively in the PFC is responsible for the emergence and
maintenance of WM impairments after withdrawal and that blocking prefrontal
mineralocorticoid receptors receptors restores WM in withdrawn animals.
© 2016 Society for the Study of Addiction.