Subsequently, we have studied whether local glucocorticoid blockade in the medial PFC would prevent the long-term deficits in working memory induced by protracted withdrawal from chronic alcohol consumption (31). Intraperitoneal administration of the corticosterone synthesis inhibitor metyrapone prior to testing prevented the withdrawal-associated working memory impairments, confirming the essential role of persistently increased glucocorticoid levels in behavioral impairments during withdrawal from chronic alcohol intake. Similarly, a single bilateral infusion of spironolactone into the medial PFC that diminished MR activation and to a lesser extent of mifepristone that diminished GRs activation fully restored working memory function in withdrawn mice. In contrast, neither spironolactone nor mifepristone had any effect when infused into the dorsal HPC, thus highlighting the importance of glucocorticoids specific to the PFC in neural substrates mediating the prolonged, detrimental effects of alcohol on behavioral performance. These findings are reminiscent of data showing that elevated glucocorticoid levels, via either systemic injection of corticosterone or local infusion of the GRs agonist RU 28362 into the medial PFC shortly before testing, similarly impair working memory (55), while the GRs antagonist RU 38486
