Chronic daily ethanol treatment induced changes in the HPA axis that persisted for at least 3 weeks after complete cessation of ethanol consumption. 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 some types of depression, that is, categories of individuals who all exhibit increased risk for high ethanol consumption. Thus, these chronic daily ethanol-induced persistent changes in the HPA axis may have significant roles in alcohol abstinence syndrome and may increase vulnerability to relapse.

Pineal melatonin secretion has been reported to commonly decrease with aging, whereas intra-abdominal adiposity, plasma insulin and plasma leptin levels tend to increase. We recently demonstrated that daily melatonin administration starting at middle age suppressed male rat intra-abdominal fat, plasma leptin and plasma insulin to youthful levels, suggesting that aging-related changes in pineal melatonin secretion and in energy regulation may be functionally related. Accordingly, we have now investigated the effects of daily melatonin treatment on energy regulation in young versus middle-aged male Sprague Dawley rats. Addition of melatonin to the drinking water (0.2 microg/mL) produced nocturnal and diurnal plasma melatonin concentrations in middle-aged rats (12 months) equivalent to those of young adult (5 months) rats. Administration of this melatonin dosage every day for 10 wk starting at 10 months of age suppressed (P < 0.01) relative intra-abdominal fat, non-fasted plasma insulin and plasma leptin by 27, 39, and 51%, respectively (vs. vehicle-treated controls). In contrast, administration of melatonin for 10 wk starting at 3 months of age did not significantly alter (P> 0.10) any of these parameters. The melatonin administration stimulated (102%, P < 0.001) behavioral responsiveness of the middle-aged rats in a test of response to novelty, restoring youthful levels, but did not significantly alter behavioral responsiveness of the young rats. These results suggest that suppression of intra-abdominal adiposity and plasma leptin and insulin levels and stimulation of behavioral responsiveness in response to daily exogenous melatonin begins at middle age, coincident with and likely dependent upon the aging-associated decline in endogenous pineal melatonin secretion. These results further suggest that appropriate melatonin supplementation may potentially provide therapy or prophylaxis not only for the insulin resistance, increased intra-abdominal fat and resulting pathologies that occur with aging, but also for some aging-associated behavioral changes.

These results suggest that repetitive daily alcohol consumption and withdrawal can induce not only persistent defects in HPA function, but also persistent increases in anxiety and behavioral responsiveness to novelty, all consistent with characteristics of abstinent alcoholics as well as with rats that self-administer increased amounts of alcohol and other drugs of abuse. This suggests that alcohol abuse can induce persistent common or interacting changes in neuroendocrine and behavioral responses that may increase risk for subsequent abuse.

Because each of these hormones has been demonstrated to modify forebrain POMC gene expression under some conditions, the overall changes in forebrain opiomelanocortinergic regulation in response to chronic daily ethanol/withdrawal and subsequent abstinence probably reflect, at least in part, regulation by multiple endocrine mechanisms, together with responses to stress, development of tolerance during chronic daily ethanol consumption, and rebound of function after termination of this consumption. Overall, the demonstrated changes in forebrain POMC gene expression are consistent with significant roles for forebrain opiomelanocortinergic regulation in mediating alcohol dependence, propensity to relapse, and the alcohol deprivation effect.