Alcohol and Drug Abuse Research Center-McLean Hospital

These studies are designed to examine the covariance between family history of alcoholism and in vivo detection of brain alcohol with proton magnetic resonance spectroscopic imaging (MRSI). There is an abundant literature which suggests that one effect of alcohol is to increase brain cell membrane rigidity and reduce partitioning of alcohol into the bilipid neuronal membrane layer. Recently we discovered that magnetic resonance spectroscopy (MRS) detection of brain alcohol is about two fold higher in heavy drinkers than in occasional drinkers after administration of an identical dose of alcohol. One implication of our finding is that MRS detection of alcohol in brain may be a biological correlate of chronic alcohol exposure. Although the precise mechanism(s) underlying greater MRS alcohol detectability in heavy drinkers are unknown, we postulate that this difference may result from reduced ethanol partitioning into the hydrophobic core of the neuronal membranes and reduced hydration of phospholipid headgroups with ethanol on the extensive axonal membrane surface. We have refined the analytic procedures for MRSI detection of brain alcohol by suitable manipulation of the times (echo times TE =20 ms and 270 ms) at which the alcohol signals are collected. In vivo proton MRSI enables amplified signals from nuclei in specific molecular entities (e.g., the methyl group in ethanol) to be detected from a chosen voxel of interest (VOI) in the human brain in vivo. Moreover, our preliminary data show that acutely-induced alcohol tolerance can be detected in men after two consecutive drinks.

Brain alcohol levels are determined with MRSI detection techniques in men and women who differ in current alcohol consumption and family history of alcoholism. Women and men will be selected with objective criteria for family history of alcoholism and current drinking patterns (occasional versus heavy drinkers). Inclusion criteria will be based in part on the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Retrospective reports of alcohol use will be validated by daily monitoring of alcohol intake, health and mental status with an Interactive Telephone Voice response program. MRSI measurements of alcohol detection in brain will be complemented by well validated psychomotor, cognitive and perceptual test assessments. Subjects will be studied under controlled research ward conditions. Alcohol or placebo will be administered in a counter-balanced order. Women will be studied during the mid-follicular phase of the menstrual cycle (days 6-8) and cycle phase will be verified with hormonal measures.

The goal of these studies is to determine if increased detection of brain alcohol is associated with a family history of alcoholism, current alcohol intake or an interaction of both in women and men. Data obtained will show if there are significant gender differences in MRSI-detected brain alcohol levels. In vivo MRSI detection of brain alcohol may prove to be a useful tool to ascertain risk for development of alcohol problems in women and men with a positive family history of alcoholism. To the best of our knowledge there have been no previous investigations of the concordance of neurobiological, genetic and alcohol consumption variables which may influence occurrence of alcohol dependence in men and women.

Key words: alcohol, magnetic resonance spectroscopic imaging (MRSI)

Grant Support: NIAAA R01 AA11618

Project Site. Alcohol and Drug Abuse Research Center, McLean Hospital, Belmont, MA

Project Director. J.H. Mendelson, M.D.

Contact Person. Rita Head, Administrative Assistant. Telephone (617) 855-2716. FAX: (617) 855-2519

Training Opportunities. Postdoctoral training opportunities are available through a NIDA supported training grant (DA07252) to Jack H. Mendelson, M.D. and the Alcohol and Drug Abuse Research Center.