title: Alcohol withdrawal induces long-lasting spatial working memory impairments: relationship with changes in corticosterone response in the prefrontal cortex.
abstract: 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PFC activity, as assessed by increased phosphorylated C-AMP Response Element-binding protein (CREB) immunoreactivity in withdrawn mice.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of WM impairments after withdrawal and that blocking prefrontal mineralocorticoid receptors receptors restores WM in withdrawn animals.
authors: Université de Bordeaux, INCIA CNRS UMR 5287, France.|Université François Rabelais, Inserm U930, France.
authors: Gaelle
authors: G
authors: Dominguez
authors: Université François Rabelais, Inserm U930, France.
authors: Catherine
authors: C
authors: Belzung
authors: IRBA, France.
authors: Christophe
authors: C
authors: Pierard
authors: Université de Bordeaux, INCIA CNRS UMR 5287, France.
authors: Vincent
authors: V
authors: David
authors: Université de Bordeaux, INCIA CNRS UMR 5287, France.
authors: Nadia
authors: N
authors: Henkous
authors: Université de Bordeaux, INCIA CNRS UMR 5287, France.
authors: Laurence
authors: L
authors: Decorte
authors: Université de Bordeaux, INCIA CNRS UMR 5287, France.
authors: Nicole
authors: N
authors: Mons
authors: Université de Bordeaux, INCIA CNRS UMR 5287, France.
authors: Daniel
authors: D
authors: Beracochea
mesh_terms: D000437:Alcoholism / Q000097:blood / Q000150:complications*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003345:Corticosterone / Q000097:blood*; D004195:Disease Models, Animal; D006624:Hippocampus; D008297:Male; D008569:Memory Disorders / Q000097:blood / Q000139:chemically induced*; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D065852:Spatial Memory / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000150:complications*
chemical_list: D003345:Corticosterone
keywords: Alcohol withdrawal; corticosterone; hippocampus; prefrontal cortex; working memory