Stressful situations could activate hypothalamic-pituitary-adrenal (HPA) axis, which is relevant to differing tendency to alcohol seeking. In the present experiment, surgical and predator stimulation stresses were undergone, then the mice were tested for alcohol consumption using two-bottle free choice of 10% EtOH and water for 25 days. It was demonstrated that stresses dramatically initiated ethanol intake. During stresses and conditioned ethanol intake, expression of FKBP5 was down-regulated in blood. In the same time, FKBP5 and phosphorylation of glucocorticoid receptor (GR) were down- and up-regulated in prefrontal cortex (PFC) and Para ventricular nucleus (PVN), when over-expression of FKBP5 in both regions could control stresses and the conditioned ethanol intake. Importantly, only in PFC, stresses and ethanol synergistically invoked PKC epsilon translocated into nuclear and enhanced FKBP5 expression machinery including miR-17, 20a, 144, 294, 295, 302, 451. Collectively, we proposed that FKBP5 could pre-sensitize PKC epsilon-dependent gene network in PFC, and prime a hierarchy of signal flow from PFC to PVN. Then, FKBP5 may represent one of biomarkers for post-stress phenotypes including alcohol seeking behavior.
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