Chronic daily ethanol and withdrawal: 1. Long-term changes in the hypothalamo-pituitary-adrenal axis

Background: Hypothalamo-pituitary-adrenal (HPA) function has been demonstra ted to be compromised for weeks and even months after alcoholics cease etha nol consumption. Because nonalcoholic subjects with family history-associat ed increased risk for alcoholism also exhibit compromised HPA function, if, is not clear whether defects in the HPA axis of abstinent alcoholics refle ct a preexisting condition that may be responsible for increased risk for a lcohol abuse versus a persisting adaptational change in response to prolong ed alcohol abuse. Consequently, we investigated whether chronic daily ethan ol consumption and withdrawal by male Sprague Dawley(R) rats would induce p ersistent HPA changes consistent with those demonstrated in abstinent alcoh olics. Methods and Results: In an initial experiment in which ethanol (5%, w/v) wa s incrementally introduced to liquid diet over a 1 week period followed by 4 weeks of chronic ethanol consumption, not only ethanol-treated rats but a lso pair-fed control rats exhibited decreased (p < 0.05 vs, ad-libitum-fed controls) anterior pituitary pro-opiomelanocortin (POMC) mRNA concentration s and associated decreases in plasma corticosterone and adrenocorticotropin (ACTH) levels for at least 3 weeks after gradual withdrawal of ethanol fro m the diet. Pair-feeding-induced decreases (p < 0.05) in thymus and spleen weights suggested that the pair-fed controls were likely stressed in this m odel, probably in response to the marked and irregular suppression of liqui d diet consumption immediately after introduction of ethanol. Consequently, a second model was developed in which ethanol was introduced to the liquid diet much more gradually (i.e., over3 weeks). In contrast with the rapid e thanol-introduction model, this more prolonged ethanol introduction followe d by 4 weeks of chronic daily ethanol consumption increased plasma corticos terone levels (p < 0.05), increased adrenal gland weight (p < 0.05), and de creased thymus and spleen weights (both p < 0.01) without altering any of t hese parameters in the pair-fed controls. Three weeks after gradual withdra wal of ethanol from the diet, anterior pituitary POMC mRNA concentrations w ere suppressed (p < 0.05) and thymus and spleen weights were increased (p < 0.05) versus both pair-fed and ad-libitum-fed controls, accompanied by tre nds for decreased basal plasma corticosterone and adrenal weights. Conclusions: Chronic daily ethanol treatment induced changes in the HPA axi s that persisted for at least 3 weeks after complete cessation of ethanol c onsumption. These persistent alterations in the HPA axis are similar to the aberrant HPA regulation of abstinent alcoholics, sons of alcoholics, Lewis rats, and individuals who suffer from posttraumatic stress disorder and so me types of depression, that is, categories of individuals who all exhibit increased risk for high ethanol consumption. Thus, these chronic daily etha nol-induced persistent changes in the HPA axis may have significant roles i n alcohol abstinence syndrome and may increase vulnerability to relapse.