Alcohol withdrawal induces long-lasting spatial working memory impairments: relationship with changes in corticosterone response in the prefrontal cortex Gaelle Dominguez 1,2 , Catherine Belzung 2 , Christophe Pierard 3 , Vincent David 1 , Nadia Henkous 1 , Laurence Decorte 1 , Nicole Mons 1 & Daniel Beracochea 1 Université de Bordeaux, INCIA CNRS UMR 5287, France 1 , Université François Rabelais, Inserm U930, France 2 and IRBA, France 3 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 6weeks (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, emo- tional 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 corticoste- rone 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 with- drawn 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of WM impairments after withdrawal and that blocking pre- frontal mineralocorticoid receptors receptors restores WM in withdrawn animals. Keywords Alcohol withdrawal, corticosterone, hippocampus, prefrontal cortex, working memory. Correspondence to: Daniel Beracochea, Université de Bordeaux, INCIA CNRS UMR 5287, Bat B2, Allée Geoffroy St Hilaire, CS 50023, 33615 Pessac, France. E-mail: daniel.beracochea@u-bordeaux.fr INTRODUCTION Alcohol withdrawal is accompanied by several symptoms such as increased anxiety, difficulties of concentration and cognitive deficits (Voltaire-Carlsson et al. 1996; Watanabe et al. 2001). There is ample evidence that memory deficits are either aggravated or progressively developed after alco- hol withdrawal (Schandler et al. 1996; Lukoyanov, Madeira, & Paula-Barbosa 1999; Farr et al. 2005). One of the major disturbances associated with alcohol withdrawal is a dysreg- ulation of the hypothalamic-pituitary-adrenal axis, which is responsible for glucocorticoids (GCs) release. More specifi- cally, plasma GCs levels progressively increase with the onset of alcohol withdrawal (Adinoff et al. 1990). Studies have shown that excess plasma GCs concentrations at the time of retention testing can impair the retrieval of information and alter neuronal function (Newcomer et al. 1999; McEwen 2000; Sapolsky 2000). Moreover, studies on the modulatory role of GCs in human cognition have revealed that pharma- cological or pathological increases of cortisol are associated with impaired working memory (WM) (Starkman et al. 2001; Patil et al. 2007; Terfehr et al. 2011; Vaz et al. 2011). Thus, we assumed that the rise of GCs associated with alcohol-withdrawal could be responsible for the emergence of cognitive disorders. Indeed, it has been shown in abstinent patients that more severe cognitive deficits were found in ORIGINAL ARTICLE doi:10.1111/adb.12371 © 2016 Society for the Study of Addiction Addiction Biology