THE LOW LEVEL OF RESPONSE TO ALCOHOL: RELATIONSHIPS TO OTHER RISK MARKERS, POSSIBLE BRAIN MECHANISMS, SPECIFIC GENES, AND ENVIRONMENTAL MEDIATORS

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M A Schuckit University of California, San Diego Medical School, 3150 Villa La Lolla Drive, La Jolla, California, 92037
Purpose: To review recent developments regarding the low level of response to alcohol (low LR) as a genetically-influenced risk factor for heavy drinking and alcohol use disorders (AUDs). Results: The low LR is the most intensively studied among the several response-related characteristics that are likely to contribute to the AUD. As shown in work dating back to 1975, this is an endophenotype that contributes to the risk for AUDs but not to other substance use disorders, and is unrelated to impulsivity. This presentation reviews how focusing on this phenotype, studies have been able to diminish the large heterogeneity associated with the broad AUD definitions, and facilitate development of animal models for LR itself. Longitudinal studies of LR have identified environmental mediators of the impact of this phenotype on heavy drinking and alcohol problems, while human and animal studies have identified gene variations that contribute to LR, and thus to the AUD risk. Recent cross-sectional and longitudinal investigations using fMRI have highlighted a potential underlying mechanism through which LR may operate. This involves the need for greater cognitive effort to recognize subtle differences between stimuli as measured in the insula and frontal gyri, with imaging findings adding to LR itself in predicting heavier drinking and alcohol problems five years later. The development of an inexpensive way to measure LR along with information about several environmental mediators of the effect of this phenotype on adverse alcohol outcomes led to successful interventions that diminished heavy drinking over 55 weeks in college freshmen. Conclusions: While much work still needs to be done with this endophenotype, the low LR to alcohol is an example of how an emphasis on a more narrowly defined characteristic can facilitate progress that advances our understanding of how genes and environment contribute to the AUD risk.

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