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Article Excerpt
EARLY STUDIES OF ALCOHOL USE and the hypothalamic-pituitary-adrenal (HPA) axis noted an increase in cortisol production among chronic heavy drinkers. This was manifested clinically by apparent adrenal insufficiency or a pseudo-Cushing's syndrome (Farmer and Fabre, 1975). In experimental conditions, chronic heavy drinkers demonstrated increased cortisol levels with ingestion of ethanol acutely and with greater increases in the early stages of withdrawal (Mendelson et al., 1971). This finding has been confirmed recently in clinical settings (Adinoff et al., 2003; Frias et al., 2000; Kutscher et al., 2002).
The clinical implications of an alcohol-related cortisol elevation are not clear where the hippocampus is concerned. Research on the rodent hippocampus has shown it to be rich in glucocorticoid receptors, and current thought places these bilateral structures as central in the stress response. In vivo studies have shown that sustained cortisol elevation damages hippocampal neurons selectively, perhaps because of the high concentration of glucocorticoid receptors (McEwen et al., 1992; Martignoni et al., 1992; Sapolsky et al., 1990). This appears to be especially true for the pyramidal neurons of the CA3 region, an observation that has recently been replicated in primates (McMillan et al., 2004). Early animal data suggest that injury to this specific region may play a role in the memory disorders related to the heavy, chronic drinking characteristic of alcohol dependence (AD; Garcia-Moreno et al., 2001; Lukoyanov et al., 1999; Nelson et al., 1999). Additionally, recent research suggests a link between apparent cortisol-mediated hippocampal volume reductions and problems in memory and other cognitive processes (Eriksson et al., 2001; MacLullich et al., 2005; O'Brien et al., 2004; Vythilingam et al., 2004).
In an early study of hippocampus volume (Beresford et al., 1999), we observed a significant decrease in total hippocampus volume (THV) measures among heavy-drinking subjects compared with light-drinking subjects. The current study sought to demonstrate that heavy chronic alcohol use--a potent stimulus to the HPA axis--(1) is associated with hypercortisolism that (2) may contribute to alcohol-related hippocampal injury. Two hypotheses guided this phase of investigation: (1) morning salivary cortisol concentrations would be higher in chronic, heavy-drinking AD subjects than in light-drinking non-AD control subjects; and (2) observed THV would be negatively associated with cortisol concentrations in the total subject group. We tested these hypotheses in the initial phase of a longitudinal study.
Method
Subjects
Both AD test subjects and non-AD control subjects were adult male veterans who were matched for age, gender, and ethnicity. AD heavy drinkers qualified for the study if they met all of the following criteria:
(1) chronic heavy drinking: consumed five or more standard drinks daily for at least 3 days weekly and 3 weeks monthly for at least 9 months of the previous year, as established through the Timeline Followback (TLFB; Sobell et al., 1979) interview;
(2) recent continuous heavy drinking: consumed five or more standard drinks daily for at least 3 days weekly for the past 30 days, as established through the TLFB;
(3) AD diagnosis: fulfilled Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association, 1994), criteria for AD as established through the Structured Clinical Interview for DSM-IV (SCID) Axis I disorders interview (Kessler et al., 2004; Peters et al., 1998; Sbrana et al., 2003; Ventura et al., 1998).
Similarly, non-AD light-drinking comparison subjects presented TLFB histories of the following:
(1) less than two standard drinks daily for no more than 3 days weekly, 4 weeks monthly for 9 months or less during the previous year;
(2) less than two standard drinks daily for no more than 3 days weekly for the previous 30 days; and
(3) none fulfilled DSM-IV criteria, either present or lifetime, for AD at the SCID interview.
Candidates were excluded from the study for SCID-verified psychiatric illnesses: schizophrenia, major depressive disorder, bipolar disorder, posttraumatic stress disorder, or polysubstance dependence. Systemic physical illness excluded those with any liver disease history, bilirubin above 1.2 mg/ml, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above 200 U/L, alcohol amnestic syndrome history, HIV seropositivity, history of head injury resulting in loss of consciousness, seizure-disorder history including those caused by ethanol withdrawal, blood evidence of folate or vitamin [B.sub.12] deficiency, dementia of any type, history of endocrine dysfunction (including Addison's disease, Cushing's disease, or exogenous steroid use within the past 5 years), or any history of genetically based reactions to alcohol use (Asian ancestry with history of the ethanol...
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