There is also evidence of involvement of the hypothalamus-pituitary-adrenal (HPA) axis, specifically the cortisol pathway (Table 1C), and particularly in astrocytes: 37% of the astrocyte-enriched genes that showed increased expression are downstream of the glucocorticoid signaling, and others are downstream of either IL1β or TGFβ1. Pathway and upstream analysis (Table 2, Supplemental Table S3) indicates that the glucocorticoid receptor is activated although its transcript level (NR3C1) is decreased. Cortisol-releasing-hormone (CRH) increases as a result of stress, ethanol abuse, chronic drinking, and the early stage of withdrawal (Armario, 2010; Gianoulakis et al., 2003; Roy et al., 2002), which should activate the glucocorticoid receptor. The HPA and CRH are also activated by alcohol consumption (Clarke & Schumann, 2009), increasing the amount of adrenocorticotropic hormone (ACTH) produced, which in turn stimulates the release of glucocorticoids (Mesotten et al., 2008). Glucocorticoids down-regulate the further release of CRH through a negative feedback loop to the hypothalamus, but increase the production of CRH outside the hypothalamus, e.g. in the central amygdala (Pastor et al., 2008). Dysregulation of the HPA axis is a known problem in alcoholism
