Alcohol withdrawal induces long‐lasting spatial working memory impairments: relationship with changes in corticosterone response in the prefrontal cortex

• Published in: Addiction biology Vol. 22; no. 4; pp. 898 - 910
• Main Authors: Dominguez, Gaelle, Belzung, Catherine, Pierard, Christophe, David, Vincent, Henkous, Nadia, Decorte, Laurence, Mons, Nicole, Beracochea, Daniel
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.07.2017; Wiley
• Subjects: Alcohol; Alcohol use; Alcohol withdrawal; Alcoholism - blood; Alcoholism - complications; Animals; Behavior, Animal - drug effects; Cognitive science; Corticosterone; Corticosterone - blood; Cyclic AMP response element-binding protein; Disease Models, Animal; Drinking behavior; Emotions; Glucocorticoids; Hippocampus; Immunoreactivity; Injection; Male; Memory Disorders - blood; Memory Disorders - chemically induced; Memory, Short-Term - drug effects; Mice; Mice, Inbred C57BL; Mifepristone; Mineralocorticoid receptors; Neuroscience; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Rodents; Short term memory; Spatial memory; Spatial Memory - drug effects; Substance Withdrawal Syndrome - blood; Substance Withdrawal Syndrome - complications; working memory; hippocampus; corticosterone; working memory; prefrontal cortex; Alcohol withdrawal
• ISSN: 1355-6215; 1369-1600; 1369-1600
• DOI: 10.1111/adb.12371

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. We showed here (1) that long‐lasting glucocorticoids dysregulation in the prefrontal cortex (PFC) is responsible for the maintenance of working memory (WM) deficits and phosphorylated CREB alterations in alcohol‐withdrawn (1 and 6 weeks) mice previously submitted to a 6‐months alcohol consumption (12% v/v); (2) that a systemic injection of metyrapone (which inhibits corticosterone synthesis) before testing restored both WM and PFC‐phosphorylated CREB activity in withdrawn mice; and (3) that the intra‐PFC blockade of mineralocorticoid receptors by spironolactone reverses the withdrawal‐associated WM deficits.