Center on Genetic Determinants of Alcohol Ingestion and Responses to Alcohol

Project Summary/Abstract: Overall Indiana Alcohol Research Center (IARC) The Indiana Alcohol Research Center (IARC) has devoted more than three decades to understanding alcohol use disorder (AUD) risk using neuroscientific and behavioral genetic tools. This prior work leads us to study the heritable, neurobiological, and behavioral factors that drive binge and high-intensity drinking (BHID). Most research on BHID focuses on harm from numbers of drinks or level of alcohol exposure but does not account for “front-loading”— the initial rapid drinking to ostensibly enhance alcohol’s rate of change in the brain and its resulting effects. Although such drinking is initially more intoxicating, compensatory (neuro-) adaptations can create an acute tolerance to rewarding effects, which in turn induces a need to increase consumption. Judgments about the next drink can then be affected so as to sustain intake, pushing alcohol exposure into high-intensity levels. The long-term goal of the IARC is to deploy its multidisciplinary efforts to understand the heritable origins of responses to alcohol and development of AUD. The objective of this next IARC cycle is to study brain circuits and behaviors that influence both the rapid front-loading and sustained drinking behaviors that elevate alcohol concentration to hazardous, high-intensity levels. In studies of both humans and our selected, alcohol-preferring animals, our specific aims will be to: (1) Study human neural, perceptual, and subject factors that relate to: a) preferences for a steeper rise in alcohol concentration and b) acute tolerance to a sustained binge-level exposure; (2) Study heritable differences in the structure and function of frontal brain circuitry hypothesized to underlie front-loading, high drinking, and behavioral inhibition in rat lines selected for high alcohol intake; (3) Study heritable differences in insula circuits hypothesized to mediate front-loading and subsequent sustained high drinking in rat lines selected for high alcohol intake, as well as potential related contributors to high intensity drinking; and (4) Study how adaptation in glutamatergic input to the dorsomedial striatum from basolateral amygdala and insula contributes to alcohol tolerance, driving a) sustained high-intensity drinking in the high-consuming cHAP mouse line, and b) binge-like drinking in the C56BL/6J inbred mouse strain. These projects are supported by service cores to (5) provide selected lines of alcohol-preferring and animals and (6) conduct higher-level network-analyses and computational modeling of results from the research components. (7) A Pilot Core assists new investigators to alcohol research and explores new ideas, while (8) an Information and Dissemination Core educates and advises the community, schools, healthcare providers, and state policy makers about both BHID and AUD. The IARC thus functions in a coordinated way to integrate human and animal research, and to determine how heritable risk and alcohol exposure contribute to BHID.