Possible disorders of the hypothalamic-pituitary-adrenal (HPA) endocrine axis have been implicated in both clinical and behavioral pathology resulting from the prolonged, heavy drinking of Alcohol Dependence. (AD) Studies report abnormally high levels of cortisol secretion during ethanol withdrawal as well as non-suppression of diurnal cortisol after dexamethasone in AD sufferers. Others found such neuro-endocrine abnormalities more frequently among Wernicke-Korsakoff Syndrome cases, suggesting a possible relation to brain injury. Studies from primates support this, observing chronically high levels of serum cortisol associated with degeneration of the hippocampal tissue. Noting previous research, we hypothesized that an increase in pituitary volume and a reduction in hippocampal volume would identify a sample of chronic, active, heavy drinkers. From volume measurements acquired by MRI scanning, we found that a decreased ratio of the hippocampus-to-pituitary volume (H:P ratio) characterized a group of recent, heavy drinkers as compared to a non-drinking control group. Although intriguing, this study was done in a convenience sample. We now propose to perform and extend this inquiry in a prospective fashion in order to establish whether a reduced H:P volume ratio serves as a state marker among AD subjects. If so, we ask a) does this indicate a reversible physiologic consequence of drinking or permanent structural change, and b) is reduced H:P ratio associated with hypercortisolemia, indicating loss of hippocampal feedback as a possible physiologic mechanism? To answer these questions, we will 1) measure baseline H:P volume ratios in 30, actively drinking, AD test subjects and in 30 matched, non-heavy drinking, non-AD control subjects, 2) measure H:P volume ratios serially in AD subjects after six months of ethanol abstinence, and 3) measure diurnal salivary cortisol secretion at baseline for both groups and serially for AD subjects. From this study we expect to develop valid, prospectively gathered, data that can begin to establish the clinical and patho-physiologic meaning of the decrease in the H:P volume ratio. We believe this line of investigation will ultimately shed new light on an important aspect of altered brain function due to sustained ethanol exposure as well as recovery of neuroendocrine functioning after cessation of heavy alcohol use.

R21AA014010

2003-04-05

2007-03-31