Abstract
RATIONALE: Alcohol withdrawal is associated with reduced activity, increased anxiety, and other signs of distress. OBJECTIVE: The goal of the current studies was to determine whether acute ethanol exposure would alter hypothalamic-pituitary-adrenal (HPA) axis reactivity and cytokine responses to stress challenges imposed during the withdrawal period. METHODS: Male Sprague-Dawley rats were intubated with 4 g/kg of ethanol to simulate acute binge-like ethanol intake. After characterizing the blood ethanol concentrations (BECs; Experiment 1), exploratory activity in a novel environment was explored at 10, 14 and 18 h after ethanol (Experiment 2) to characterize altered activity patterns indicative of withdrawal. In Experiment 3, rats were exposed to footshock during withdrawal to examine whether prior ethanol exposure would alter cytokine and HPA axis responses to stress. Experiments 4 and 5 investigated HPA axis sensitivity and gene expression changes during restraint imposed during withdrawal. RESULTS: Prior ethanol exposure produced a period of stress hyper-reactivity evidenced by an enhanced HPA axis response (increased corticosterone and adrenocorticotropic hormone) observed during withdrawal. While this hyper-reactivity in response to two different stress challenges (novel environment and restraint) was accompanied by profound behavioral changes indicative of withdrawal, no alterations in cytokine changes evoked by stress were observed. CONCLUSIONS: Taken together, these findings provide support for the hypothesis that alcohol withdrawal enhances HPA axis reactivity to stress challenges, though not likely as the result of heightened inflammatory signaling, and may have implications for understanding the mechanisms by which stress impacts relapse drinking in humans.